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R. Camidge
Moderator of
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ED 11 - Extending Personalized Treatment Beyond EGFR (ID 11)
- Event: WCLC 2015
- Type: Education Session
- Track: Community Practice
- Presentations: 4
- Moderators:R. Perez-Soler, R. Camidge
- Coordinates: 9/09/2015, 14:15 - 15:45, 401-404
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ED11.01 - What Testing Is Needed for Clinical Treatment? (ID 1814)
14:15 - 15:45 | Author(s): P.A. Bunn, Jr
- Abstract
- Presentation
Abstract:
The current IASLC/CAP/AMP guidelines indicate that testing for EGFR mutations and ALK fusions is recommended before instituting therapy in patients with advanced lung cancers with adenocarcinoma features. The guidelines indicate that the guidelines would be updated as other therapies become available for specific drivers. Since these guidelines were published, considerable information has become available on molecular changes that cause resistance to the first generation EGFR and ALK tyrosine kinase inhibitors (TKIs) and new 2nd and 3rd generation drugs to treat molecular resistance are in the clinic are likely to be approved in 2015. New drugs are also in development for other molecular drivers that have been reported in lung cancer including fusions that activate ROS1, RET, NTRK, and FGFR; mutations that activate KRAS, BRAF,HER2, and FGFR; and amplifications that activate MET, FGFR and HER2. It is also likely that some of these agents will approved in the near future. These developments bring into focus the most appropriate methods to test for molecular drivers in lung cancer. The techniques include direct sequencing, PCR testing for mutation hot spots, Next generation whole exome sequencing for mutations, translocations and amplifications, immunohistochemical testing for activated proteins or specific mutations, FISH testing for specific translocations, fusions, and amplifications. The sequential testing of one gene at a time is very inefficient especially with respect to the time it takes to complete testing, with the total cost and with respect to the amount of tissue necessary to complete the testing. Thus, multiplex testing is becoming far more common. However, in the US, the FDA’s companion diagnostic tests are one a time for specific tests for specific drugs. This one off policy is threatening the ability to perform one test for multiple analytes simultaneously. Hopefully, these issues can be resolved in the near future. What are the molecular changes that appear to be drivers for which there exist therapeutic TKIs? We can first discuss the development of resistance to 1st generation EGFR and ALK TKIs. About half of all patients who progress on a 1st generation EGFR TKI will have a secondary gatekeeper mutation, T790M that limits binding of 1st generation EGFR TKIs to the EGF receptor. 3rd generation EGFR TKIs such as AZD9291 and CO1686 (rocelitinib) have been shown to produce objective clinical responses in about 60% of patients with T790M who progress on a first generation EGFR TKI. These responses are associated with a median PFS of about 10 months. These drugs bind irreversibly to the T790M receptor and to activating mutations such as del19 and L858R but do not bind to the wildtype receptor. Therefore they have far less skin rash and diarrhea compared to the 1st generation inhibitors. Rocelitinb may cause hyperglycemia in up to a third of patients that is believed to be caused by a metabolite that inhibits IGFR. The use of oral anti-hyperglycemic agents such as metformin may be required for glucose control in these patients. Rocelitinib may also cause prolongation of the QTc on EKGs and thus monitoring is required. This side effect is rare but requires monitoring. AZD9291 may be associated with slightly more skin rash and diarrhea and uncommon reports of pneumonitis have been reported. The mechanism of resistance to these agents is under investigation but most often appears to be activation of alternative signaling pathways or phenotypic switching to a mesenchymal state. There are multiple tests available to detect the T790M mutation and many studies are evaluating its presence in circulating free DNA. Such analyses seem to be quite specific but less sensitive to analyses of tumor tissue. Testing for mutations in circulating free DNA is quite appealing because it does not require another tumor biopsy. Crizotinib which was the first agent approved for ALK positive cases, is also a potent ROS1 and MET inhibitor. ROS1 may be activated by fusion to other genes on the same chromosome and detected by FISH or Next generation sequencing. Crizotinib has been reported to produce objective response is about 60% of cases with ROS1 fusions with median progression free survival of about 16 months. Crizotinib has also been reported to produce objective responses in about 2/3 of patients with high MET amplification although the number of patients studied is very low. Additional studies are ongoing. Because MET amplification is frequent in patients who progress on 1st generation EGFR TKIs that do not have T790M, MET inhibitors are also being studied on this setting. Both ceritinb and alectinib have been approved for patients with ALK fusions who have progressed on crizotinib. It is clear that the two drugs have different activity among various resistance mutations for ALK. Thus, rebiopsy of tumor or testing of circulation free DNA may become standard in patients progressing on ALK TKIs as it is in patients progressing on EGFR TKIs. BRAF mutations occur in about 2% of advanced NSCLC patients and the V600E mutation is the most common. BRAF TKIs such as vemurafinib have been reported to produce frequent responses in NSCLC patients with V600E BRAF mutations. In melanoma the combination of BRAF inhibitors with MEK inhibitors has been more effective than BRAF inhibitors alone and this combination is being studied in NSCLC patient with BRAF mutations. HER 2 may be activated by either mutation or amplifications and the response to various HER inhibitors may vary by the method of activation. About 2% of patients have activation by amplification and about 2% by mutation (usually exon 20 insertions). The irreversible pan HER TKIs such as neratinib, afatinib and dacomitinib have not produced high response rates in these patients. However a phase 1 trial of the combination of niratinib with temsirolimus produced higher responses in both breast and lung cancers and a phase 2 study of the combination in lung cancers with HER2 mutations/amplifications is in progress. Other HER2 inhibitors have been reported to produce occasional responses but we await formal study of such agents. RET and NTRK fusions have been reported I about 1% of patients and there are sporadic reports of responses to specific TKIS. Formal studies are in progress but may not be reported for some time due to the rarity of the abnormalities and the fact that multiple TKIs are available. FGFR may be activated by amplification, fusion and mutations and there are both quite specific FGFR TKIs and multi-TKIs that have been studied in small numbers of patients. It is fair to say that response rates to specific FGFR TKIs are low in patients with squamous cell carcinoma patients with FGFR amplification. Additional studies with other biomarkers and other agents are ongoing. The most frequent oncogenic driver in lung cancer is KRAS. No specific TKI has been developed. Downstream inhibitors such as MEK inhibitors and FAK inhibitors have the most study to date. Response rates as single agents are relatively low and combination studies are in progress. In summary, the increased numbers of TKIs specific for various molecular drivers in lung cancer is becoming far more important not only a diagnosis but also at the time of progression. Future studies will focus on multiplex testing and testing of circulating free DNA.
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ED11.02 - Communicating with Pathologists About Molecular Testing (ID 1815)
14:15 - 15:45 | Author(s): C.O. Lara-Torres
- Abstract
- Presentation
Abstract:
Technologic and scientific development in medicine and the biomedical sciences has led to almost immediate transfer of knowledge and methodology applied initially in the research lab to the clinic, producing a profound impact in screening, diagnosis and treatment. These enormous amount of information and specialized skills in the medical practice have made it necessary to integrate multidisciplinary teams to improve quality of cancer care.Lung cancer is the most common neoplasia worldwide as well as the leading cause of cancer-related death, with more than 50% of patients presenting with stage IV disease at diagnosis (1). Therefore, lung cancer management usually requires the collaboration of surgeons, medical oncologists, radiation oncologists, pathologists, nurses, and other health care professionals (2). Given the fact that many patients will present with locally advanced or metastatic disease, only small amounts of tissue or cell preparations will be available for morphologic analysis, immunohistochemistry and molecular testing. Recommendations from academic centers and agencies are in favor of limiting the amount of immunohistochemical stains in order to save tissue for molecular assays, stressing the need to integrate pathologist to multidisciplinary teams, where clinical information is exchanged, and specific differential diagnosis and objectives established in a case-to-case basis (3). The traditional role of pathologist in lung cancer has been to establish histological diagnosis of malignancy, as well as proper taxonomic allocation according to widely accepted classification schemes. (4) This approach sets pathologist within single moment interventions early in the course of patient management, aside from opportunities to collaborate during the rest of care. However, the advent of personalized medicine, characterized by the identification of biological features in cells that predict benefit from specific targeted drugs, opened up the way for pathologist to actively participate with the team in the selection of treatment and patient follow-up. Overall, from 60-70% of NSCLC have specific mutations of well characterized oncogenic drivers, some of them with 1st line treatment drugs and many with targeted therapies under development. Current guidelines of advance stage disease recommend initial characterization of EGFR mutation status and ALK rearrangement, although there is building evidence to support testing of a number of actionable genes such as HER2, BRAF, MET, RET, ROS1, or other biomarkers with predictive capacity such as microsatellite instability (5). Multiple methods and technological platforms have been developed to identify gene mutations, and although most of them have very high specificity values, the sensitivity to detect a mutant clone from a background of wild type DNA is wide. Conventional Sanger sequencing will identify a mutation if it is present in 10-20% of the sampled cells, pyrosequencing increases the level to 1%, mutant-enriched polymerase chain reaction (PNA-LNA PCR, ARMS, etc.) can detect a mutant gene among as many as 10[3] wild-type alleles (0.1-1%) with comparative performance to next generation sequencing(6). These differences in analytical sensitivity do not only affect the number of EGFR mutated cases identified, but may also impact the clinical results obtained when using TKI therapy. For example, studies suggest that high EGFR mutation allele burden at diagnosis may be associated with increased progression-free survival and overall survival in patients treated with tyrosine kinase inhibitors, based in sensitivity differences between conventional sequencing and allele-specific PCR(7,8). In the light of these challenges, pathologist face the need to secure tissue availability and adequacy for testing in order to increase the diagnostic yield of molecular characterization. This demands the establishment of changes in sample management and processing, depending on the biological material to be tested. For example, rapid on-site evaluation may be performed in cytological specimens from fine needle aspirates. In the case of CT-guided transthoracic biopsies, one initial core may be submitted for frozen section or studied with cytological imprints to assess tumor viability. If proper cellular material is identified, this core may be entirely used for molecular testing and subsequent cores destined for histological processing. Once the tissue is paraffin-blocked, the tissue cuttings product of facing the block may be saved in a sterile, DNAase/RNAase-free tube for later use if necessary. It is established that patients will ultimately develop resistance to targeted therapies through different mechanisms, either the emergence of mutations in the target gene or the acquisition of mutations or over-expression of oncogenes that overcome this inhibition. Studies have proved that at tumor progression, a number of cases may have a morphological switch from adenocarcinoma to sarcomatoid carcinoma or small-cell carcinoma (9), requiring therapy adjustments. Re-biopsy allows molecular evaluation as well as morphologic analysis, however; it is an invasive procedure that not all patients may undergo. Alternative highly sensitive molecular methods may be used for patient follow-up without the need of invasive interventions. Blood sample-based PCR or NGS can detect circulating free DNA from the tumour (liquid biopsy), the concordance rate between tissue and plasma for EGFR mutation going from 58.3% to 93.1%, stressing the need of analytical improvement. Of especial interest is the fact that when examining the appearance of the T790M mutation in serial blood samples, this mutation could be detected in the plasma DNA before clinically evident disease progression. (10) NSCLC diagnostics is rapidly changing to combine a dual morphologic-molecular approach, where initial HE-slide examination is used to confirm malignancy and to allocate the tissue sample to a group of molecular test relevant to the cellular composition of the tumour. Continuous increase in the number of genes responsible of oncogenesis in lung carcinoma ensures the development of new targeted drugs as well as active communication from all the members of the multidisciplinary team. References 1) Aisner DL, Marshall CB. Molecular pathology of non-small cell lung cancer: a practical guide.Am J Clin Pathol. 2012 Sep;138(3):332-46. 2) Pan CC, Kung PT, et al. Effects of Multidisciplinary team care on the survival of patients with different stages of Non-Small Cell Lung Cancer: A National Cohort study. PLoS One. 2015 May 12;10(5):e0126547. 3) Lindeman NI, Cagle PT, Beasley MB, et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med 137:828-860, 2013 4) Cagle PT, Myers J.Precision medicine for lung cancer: role of the surgical pathologist. Arch Pathol Lab Med. 2012 Oct;136(10):1186-9. 5) Dacic S, Nikiforova MN.Present and future molecular testing of lung carcinoma. Adv Anat Pathol. 2014 Mar;21(2):94-9. 6) Young EC, Owens MM, Adebiyi I, et al. A comparison of methods for EGFR mutation testing in non-small cell lung cancer. Diagn Mol Pathol. 2013 Dec;22(4):190-5. 7) Kim HS, Sung JS, Yang SJ. Predictive efficacy of low burden EGFR mutation detected by next-generation sequencing on response to EGFR tyrosine kinase inhibitors in non-small-cell lung carcinoma. PLoS One. 2013 Dec 20;8(12):e81975. 8) Zhou Q, Zhang XC, Chen ZH. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Aug 20;29(24):3316-21. 9) Sequist LV, Waltman BA, Dias-Santagata D. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011 Mar 23;3(75):75ra26. 10) Sorensen BS, Wu L, Wei W, et al. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer. 2014 Dec 15;120(24):3896-901.
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ED11.03 - 1st Line and Beyond for ALK, ROS-1, BRAF, RET, FGFR Positive Lung Cancer (ID 1816)
14:15 - 15:45 | Author(s): D.R. Spigel
- Abstract
Abstract:
Remarkable progress has been made in the treatment of ALK-rearranged NSCLC with the initial approval of crizotinib. Multiple next-generation agents are impacting care as approved therapies in some regions of the world or in first- and second+-line clinical trials where early data are promising. Additional development of crizotinib and newer agents in ROS-1-positive NSCLC is quickly changing how patients are evaluated at diagnosis. Moreover, maturing data in BRAF-mutated NSCLC with BRAF and MEK inhibitors, along with early data in RET- and FGFR-positive NSCLC support broader and earlier testing in the care of patients with advanced NSCLC. The data for, and challenges of, selecting the best first-line (and beyond) options for patients with ALK, ROS-1, BRAF, RET, FGFR, or other altered NSCLC will be reviewed.
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ED11.04 - Prioritizing New Agents When More than One Is Available and Combining Targeted Agents (ID 1817)
14:15 - 15:45 | Author(s): R. Camidge
- Abstract
- Presentation
Abstract:
When more than one drug exists for the same target (e.g. erlotinib, icotinib, gefitinib and afatinib for EGFR mutant NSCLC), decisions in terms of which drug to commence targeted therapy with may be based on personal experience, side effects and cost. Until head-to-head trials in the same sensitive target population read out, any potential efficacy differences remain speculative. Other than to switch out drugs based on tolerability issues, the anti-cancer benefit from sequential use of different drugs in the same class/generation as a strategy separate from any benefit of ongoing target suppression post-progression with the same drug also remains largely unproven. However, as new generation drugs are developed, drugs directed against the same dominant driver now exist which have activity against both the initial form of the target and common acquired resistance forms (e.g. ceritinib and alectinib for ALK+ NSCLC, or rociletinib and AZD9291 for EGFR mutant NSCLC). While initial licensing strategies have focused on sequential use of such drugs after first generation drugs, studies are also underway looking to see if first line use of these next generation drugs could be more beneficial in the relevant molecularly selected population. As mechanisms of acquired resistance become better understood, specific actionable second drivers, co-existing with the initial sensitive form of the oncogenic driver, are now being identified (e.g. MET amplification with EGFR mutations). Preclinically, inhibition of both drivers is required to achieve cancer control in this setting. Clinically, trials of combination therapy are showing promise with determination of the exact predictive cutpoint in continuous variables such as MET emerging as a key issue. With more extensive molecular testing being deployed upfront, rather than in tiered testing strategies and separate from in the acquired resistance setting, multiple potential molecular drivers on each patient are now being reported to treating physicians. When some of these are known acquired mechanisms of resistance (e.g. MET or T790M in EGFR mutant), concern may arise re whether initial therapy will be effective. However, most diagnostic assays do not give information on the proportion of each molecular aberration. Consequently, a highly sensitive test can detect a small clonal fraction of a resistance mechanism that will later be selected out by use of the initial targeted therapy, but does not preclude an initial response. In contrast, germline abnormalities present in all cells, such as can occur with T790M, would preclude an initial response to the relevant targeted therapy. As such germline events are very rare, initial use of a targeted agent still makes most sense. While defined oncogenic drivers are often perceived to be mutually exclusive (e.g. EGFR and ALK), exceptions do occur. While there appears to be no specific growth advantage to having two oncogenic drivers in the same cell in the absence of a specific selection pressure, such examples of double drivers could reflect false positives, true positives where one of them is somehow non-functional (e.g. an ALK rearrangement detected by FISH, which is not transcribed), or true positives where each is present in a different cell population. Again, as proportional positivity is not a feature of most diagnostic assays, starting with monotherapy for the abnormality that is either easiest to target or has the lowest chance of being non-functional (e.g. a point mutation over a chromosomal abnormality), makes the most clinical sense. At acquired resistance, rebiopsy and reanalysis for changes in biology including the dominance of the other initial driver should be strongly considered. Perhaps the biggest challenge has been the proliferation of multiplex reports detailing a range of abnormalities in the same cancer, where the exact driver status and biological significance of the abnormalities remains unclear. Caution should be exercised in assuming that all changes are true drivers and extreme caution should be exercised if attempting to combine available targeted drugs that have not been combined before in the absence of a formal phase I study.
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Author of
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ED 11 - Extending Personalized Treatment Beyond EGFR (ID 11)
- Event: WCLC 2015
- Type: Education Session
- Track: Community Practice
- Presentations: 1
- Moderators:R. Perez-Soler, R. Camidge
- Coordinates: 9/09/2015, 14:15 - 15:45, 401-404
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ED11.04 - Prioritizing New Agents When More than One Is Available and Combining Targeted Agents (ID 1817)
14:15 - 15:45 | Author(s): R. Camidge
- Abstract
- Presentation
Abstract:
When more than one drug exists for the same target (e.g. erlotinib, icotinib, gefitinib and afatinib for EGFR mutant NSCLC), decisions in terms of which drug to commence targeted therapy with may be based on personal experience, side effects and cost. Until head-to-head trials in the same sensitive target population read out, any potential efficacy differences remain speculative. Other than to switch out drugs based on tolerability issues, the anti-cancer benefit from sequential use of different drugs in the same class/generation as a strategy separate from any benefit of ongoing target suppression post-progression with the same drug also remains largely unproven. However, as new generation drugs are developed, drugs directed against the same dominant driver now exist which have activity against both the initial form of the target and common acquired resistance forms (e.g. ceritinib and alectinib for ALK+ NSCLC, or rociletinib and AZD9291 for EGFR mutant NSCLC). While initial licensing strategies have focused on sequential use of such drugs after first generation drugs, studies are also underway looking to see if first line use of these next generation drugs could be more beneficial in the relevant molecularly selected population. As mechanisms of acquired resistance become better understood, specific actionable second drivers, co-existing with the initial sensitive form of the oncogenic driver, are now being identified (e.g. MET amplification with EGFR mutations). Preclinically, inhibition of both drivers is required to achieve cancer control in this setting. Clinically, trials of combination therapy are showing promise with determination of the exact predictive cutpoint in continuous variables such as MET emerging as a key issue. With more extensive molecular testing being deployed upfront, rather than in tiered testing strategies and separate from in the acquired resistance setting, multiple potential molecular drivers on each patient are now being reported to treating physicians. When some of these are known acquired mechanisms of resistance (e.g. MET or T790M in EGFR mutant), concern may arise re whether initial therapy will be effective. However, most diagnostic assays do not give information on the proportion of each molecular aberration. Consequently, a highly sensitive test can detect a small clonal fraction of a resistance mechanism that will later be selected out by use of the initial targeted therapy, but does not preclude an initial response. In contrast, germline abnormalities present in all cells, such as can occur with T790M, would preclude an initial response to the relevant targeted therapy. As such germline events are very rare, initial use of a targeted agent still makes most sense. While defined oncogenic drivers are often perceived to be mutually exclusive (e.g. EGFR and ALK), exceptions do occur. While there appears to be no specific growth advantage to having two oncogenic drivers in the same cell in the absence of a specific selection pressure, such examples of double drivers could reflect false positives, true positives where one of them is somehow non-functional (e.g. an ALK rearrangement detected by FISH, which is not transcribed), or true positives where each is present in a different cell population. Again, as proportional positivity is not a feature of most diagnostic assays, starting with monotherapy for the abnormality that is either easiest to target or has the lowest chance of being non-functional (e.g. a point mutation over a chromosomal abnormality), makes the most clinical sense. At acquired resistance, rebiopsy and reanalysis for changes in biology including the dominance of the other initial driver should be strongly considered. Perhaps the biggest challenge has been the proliferation of multiplex reports detailing a range of abnormalities in the same cancer, where the exact driver status and biological significance of the abnormalities remains unclear. Caution should be exercised in assuming that all changes are true drivers and extreme caution should be exercised if attempting to combine available targeted drugs that have not been combined before in the absence of a formal phase I study.
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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.10 - Rociletinib in NSCLC Patients with Negative Central Testing for T790M in TIGER-X (ID 951)
16:45 - 18:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. New insights into mutEGFR NSCLC suggest clonal heterogeneity – activating EGFR mutations are truncal (present in all tumor clones) and T790M is a dominant branch mutation with variable clonal frequency between patients and over time. The extent of this clonal heterogeneity may relate to rociletinib efficacy. Here we present preliminary findings to evaluate this hypothesis from an ongoing Phase 1/2 clinical trial.
Methods:
TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with metastatic or unresectable locally advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). Screening included mandatory tumor biopsy and T790M testing. For Phase 1, patients could be T790M negative, positive or unknown. For Phase 2, T790M negative patients (by validated central testing) could have a contemporaneous local T790M+ result.
Results:
As of March 2015, 36 patients were enrolled in TIGER-X who were T790M central negative by cobas® or Qiagen therascreen® and evaluable for efficacy. Sensitivity analysis indicated that the 2 assay platforms were comparable for T790M detection. 69% (25/36) were T790M negative centrally but positive locally; 4/36 (11%) were negative by both central and local testing; and 7/36 (19%) were centrally negative with no local result. Median number of previous TKIs was 1 and median number of previous therapies was 2; 81% (29/36) were treated with a TKI as their most recent prior therapy. In central negative/local+ patients the ORR was 40% (10/25). In central negative/local negative patients the ORR was 25% (1/4). The most common treatment emergent adverse events in this subset (all grades) were fatigue, diarrhea, nausea and hyperglycemia.
Conclusion:
These preliminary findings suggest that patients who test negative for T790M using a sensitive tissue test may still benefit from treatment with rociletinib. In part, this clinical activity may be driven by T790M tumor heterogeneity, demonstrated by the discordant T790M results described. In addition, inhibition of IGF-1R/IR by the previously reported (Soria 2014) rociletinib metabolite M502 may also be driving some of the activity observed. This possible explanation is important, since the response rates reported herein are higher than described for other T790M inhibitors in T790M-negative patients. Furthermore, TKI re-treatment effect is unlikely to be a major driver of these results, since the majority of patients came on study directly after progression on another EGFR TKI. To further explore these findings, the open-label TIGER-2 (NCT02147990) and the randomized Phase 3 TIGER-3 (NCT02322281) studies include T790M negative patients.
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MINI 04 - Clinical Care of Lung Cancer (ID 102)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gaspar, V. Westeel
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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MINI04.08 - Malignant Pleural Effusions Are Predictive of Peritoneal Carcinomatosis in Patients with Advanced EGFR Positive Non-Small Cell Lung Cancer (ID 3191)
16:45 - 18:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
Lung cancer is the most frequent cause of cancer death and metastatic disease at the time of initial diagnosis is common. Peritoneal carcinomatosis (PC) from lung cancer is a rare clinical event with a reported incidence of 1.2% (Satoh et al. 2001). However, there are limited data on what factors predict peritoneal progression in lung cancer. Over the last decade, molecular analysis of NSCLC has provided more detailed classification of patterns of metastatic spread. It has also been shown that oncogene-addicted subsets of NSCLC have different patterns of metastatic spread (Doebele et al. 2012). We investigated whether certain baseline patterns of metastatic spread in patients with advanced EGFR mutation positive (EGFR+) NSCLC can predict subsequent PC.
Methods:
We identified 156 patients with EGFR+ (Exon 19 or L858R) mutations from 2009 - 2014, of which 139 had metastatic NSCLC. 11 patients developed PC. This was defined as the presence of biopsy-proven adenocarcinoma from peritoneal fluid or radiographic patterns consistent with omental metastases. We identified areas of metastatic disease in predefined sites (brain, liver, lung, adrenal, soft tissue and pleura) at the time of diagnosis or metastatic recurrence. We noted if patients developed T790M, a resistance mutation to targeted therapy, in EGFR+ patients. A Fisher-Exact test was used to determine statistical significance between metastatic site and subsequent PC.
Results:Table 1 - Sites of metastasis and presence of T790M mutation in patients with PC and without PC
The presence of a pleural effusion was universal in all 11 EGFR+ patients who subsequently developed PC and this finding was statistically significant (P = 0.0001). 9 out of 11 patients with PC were identified to have a T790M mutation, a finding that was statistically significant (P = 0.0001). Except one patient, all EGFR+ patients developed PC following targeted tyrosine kinase therapy.Metastatic site / mutation PC No PC P value Lung 9.1% 38.6% P = 0.06 Liver 18.2% 15.8% P = 0.689 Bone 36.4% 46.8% P = 0.549 Brain 0% 23.7% P = 0.3570 Adrenal 0% 6.4% P = 0.123 Soft tissue 9.1% 2.2% P = 0.265 Pleural effusion 100% 26.6% P = 0.0001 T790M mutation 81.1% 34.5% P = 0.0001
Conclusion:
The presence of a malignant effusion is highly predictive of developing PC in patients with EGFR+ NSCLC. Although the underlying mechanism of PC is not entirely clear, it may be related to serosal communication with subsequent micrometastatic seeding of the peritoneal cavity. The T790M mutation, the most common acquired resistance mechanism to EGFR kinase inhibitors, was significantly more prevalent in the group that developed PC, although it remains unclear whether this mutation has any causative effect on spread to the peritoneum.
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MINI 13 - Genetic Alterations and Testing (ID 120)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:Y. Koh, R.K. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 205+207
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MINI13.01 - Clinicopathological Profiles of ROS1 Positive Patients Screened by FISH (ID 1450)
10:45 - 12:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
ROS1 fusion variants represent an important subset of oncogenic driver mutations in approximately 0.7 – 3.4% of non-small cell lung cancers. Since the frequency of ROS1 positive lung cancer patients is relatively low, it is unclear whether there are significant clinicopathologic associations for positive cases. Thus far, ROS1 positive patients tend to be younger and never-smokers with tumors displaying adenocarcinoma histology. This study describes a further cohort of ROS1 positive lung cancer patients in an effort to identify clinicopathologic associations.
Methods:
The data represent a retrospective analysis of the clinicopathological profiles of primary and metastatic lung cancer patients tested for ROS1 gene rearrangements by break-apart (BA) FISH at the University of Colorado School of Medicine.
Results:
The cohort consisted of 452 patients enriched for triple-negative (EGFR-, KRAS- and ALK-) non-squamous cell carcinomas screened for ROS1 rearrangements using the BA FISH assay. Nineteen cases (4.2%) were identified as positive for rearrangement, the majority (68%) of which were female, with a mean cohort age of 54.9 years (range 30-79); as compared to negative cases which included 56% female patients (P= 0.1083), and had a mean cohort age of 62.9 (range 21-90) (P= 0.0058). Seventeen out of the 19 ROS1 positive tumors were classified as adenocarcinomas, one was diagnosed as adenosquamous carcinoma, and the histology on one specimen was not otherwise specified (NOS). Among 12 individuals with information on pathologic stage at diagnosis, the majority (75%) were stage IV. The prevalent FISH pattern for rearrangement was a split 5’ and 3’ signal (68%) with the remaining specimens showing primarily single 3’ signals (21%) or a mix of split and single 3’ signals (11%).
Conclusion:
The ROS1 positive tumors in this cohort were primarily classified as adenocarcinomas, diagnosed at an advanced stage, in patients significantly younger and more likely to be women, although the sample set was biased for non-squamous lesions thereby limiting the application of this information to squamous cell lung carcinoma. The higher prevalence of ROS1 positive cases in this cohort compared to unselected cohorts is best explained by the inclusion of specimens with known negative status for EGFR and KRAS mutations and ALK fusions. As such, these data are in agreement with previous descriptions of ROS1 positive cohorts. Screening for ROS1 rearrangements in lung cancer patients displaying adenocarcinoma histology and negative for EGFR, KRAS and ALK activating events should identify a higher frequency of ROS1 rearranged tumors compared to unselected approaches and facilitate this subset of patients to be treated with targeted ROS1 inhibitors.
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.03 - Dose Optimization of Rociletinib for EGFR Mutated NSCLC (ID 967)
16:45 - 18:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible mutant selective tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. A maximum tolerated dose was not identified in Phase 1 with 1000 mg BID the highest dose studied. Here we assess the efficacy and safety of the three doses of rociletinib (500 mg BID, 625 mg BID and 750 mg BID) selected for Phase 2 study.
Methods:
TIGER-X (NCT01526928) is a Phase 1/2 open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutant NSCLC progressing after ≥1 EGFR tyrosine kinase inhibitor (TKI). Efficacy is assessed using RECIST. Safety is evaluated using standard adverse event (AE) reporting.
Results:
As of April 2015, a total of 231 central T790M positive patients were evaluable for efficacy and 343 for safety (any T790M). All patients were enrolled in the USA (85%), Europe (9%) and Australia (6%). Baseline characteristics were similar in each dose group. The median number of prior therapies was 2. 85% had EGFR TKI as their most recent prior therapy and 10% had a history of diabetes/hyperglycemia. Immature ORRs are 53% (500 mg BID), 52% (625 mg BID) and 43% (750 mg BID), with disease control rates of 89% (500 mg BID), 87% (625 mg BID) and 82% (750 mg BID). The most common ≥grade 3 treatment-related AE was hyperglycemia [16% (500 mg BID), 25% (625 mg BID) and 35% (750 mg BID)] which was managed with oral hypoglycemic agents. Only one patient discontinued the study for hyperglycemia. Grade 3 QTc prolongation was uncommon, occurring in 2% (500 mg BID), 7% (625 mg BID) and 10% (750 mg BID) of patients, and demonstrated a relationship to dose. There were no clinically relevant cutaneous toxicities with 7 cases of grade 1 rash and 4 cases of grade 1 stomatitis (no dose relationship) and no paronychia.
Conclusion:
All 3 Phase 2 doses of rociletinib are active and well tolerated in a Western patient population with advanced NSCLC. The lack of cutaneous toxicities confirms the selectivity of rociletinib for mutant forms of EGFR and is an important contributor to QOL and maintaining dose intensity (Lacouture et al. 2011). Overall, the adverse event frequency appears to be related to dose, but antitumor activity does not, thus the risk/benefit profile may be optimal at the lowest dose studied.
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MINI16.04 - Activity of Rociletinib in EGFR Mutant NSCLC Patients with a History of CNS Involvement (ID 965)
16:45 - 18:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) with activity against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). An overall response rate of 67% has previously been reported in this trial for T790M positive patients treated with the 500 and 625 mg BID doses (Soria 2014). Here we provide preliminary data on the activity of rociletinib in the subgroup of patients with a history of CNS disease.
Methods:
Patients with a history of CNS disease were permitted if asymptomatic and stable, as defined by steroid requirements. The primary activity endpoint was RECIST overall response rate. However, patients who developed progressive disease (PD) while on study treatment were allowed to continue therapy with rociletinib if deemed clinically beneficial by the investigator.
Results:
As of 16 March 2015, a total of 401 patients received therapeutic dose levels of rociletinib (500, 625 and 750 mg BID) including 170 (42%) patients with a history of CNS metastases. Based on this interim analysis, the RECIST overall response rate among these patients with a history of CNS disease is 41%. To date, 42 patients with a history of CNS disease have continued therapy with rociletinib post-progression. Of those who continued for at least 14 days the average treatment duration beyond PD was 89 days (range: 14 - 336 days). Twenty-two of the 42 patients with a history of CNS disease with PD also received brain radiation and continued rociletinib treatment for an average of 120 days (range: 22 – 336 days) after PD. Rociletinib is held on radiation days only. Progression-free survival data for these subgroups is not yet mature. The three most common adverse events in the patient population with a history of CNS disease are similar to those found in the general TIGER-X patient population: hyperglycemia, diarrhea and nausea.
Conclusion:
In patients with a history of CNS disease, a factor associated with poor prognosis, rociletinib is active with a RECIST response rate of 41%. Local CNS radiation has been administered safely with rociletinib held on radiation days and continued afterwards. Prolonged use of rociletinib post CNS radiation suggests ongoing systemic benefit is still experienced by these patients. The role of rociletinib in NSCLC patients with CNS involvement is being further explored in the ongoing TIGER clinical development program.
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MINI 21 - Novel Targets (ID 133)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:B.P. Levy, D.S. Tan
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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MINI21.11 - A Novel Cell Line Model of EGFR Exon 20 Insertion Mutations (ID 2828)
16:45 - 18:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
In-frame insertions in exon 20 of EGFR are infrequent activating mutations in the tyrosine kinase domain that have decreased sensitivity to EGFR inhibitors and currently have no available targeted therapies. In vitro studies ectopically expressing some of the common insertions (3 to 21 bp between codons 762 and 770) show reduced sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Non-small cell lung cancer (NSCLC) patients whose tumors harbor these mutations do not respond to EGFR kinase inhibitors. To date, there are no known patient-derived cell lines that harbor the EGFR exon 20 insertions that recapitulate patient insensitivity to EGFR TKIs. Here we report the isolation and characterization of a patient derived cell line with an EGFR exon20 insertion.
Methods:
The CUTO-14 cell line was derived from a malignant pleural effusion of a lung adenocarcinoma patient harboring the EGFR exon 20 insertion p.A767_V767dupASV after obtaining IRB-approved informed consent. PCR amplification of EGFR exon 20 and subsequent Sanger sequencing was performed on genomic DNA isolated from CUTO-14. H3255 (L858R) and HCC827 (exon 19 del) cell lines were used as controls because they harbor sensitizing EGFR mutations. Cell viability was evaluated by MTS proliferation assay. Phosphorylation status and signaling was analyzed by western blot and an EGFR phosphorylation array. For tumor xenograft studies, nude mice were injected with 1.5 x 10[6] cells in matrigel and evaluated weekly for tumor growth.
Results:
Genomic sequencing of CUTO-14 demonstrated that the cell line maintains the pA767_V767dupASV EGFR exon 20 insertion. CUTO-14 showed relative resistance to gefitinib inhibition compared to HCC827 and H3255 in ERK1/2 phosphorylation assays. CUTO-14 also demonstrated reduced sensitivity to gefitinib compared to HCC827 and H3255 in cell proliferation assays. Tumor formation was observed in mice after injection in nude mice.
Conclusion:
CUTO-14 cells represent a novel model for the investigation of therapeutic strategies for EGRF exon 20 insertions mutations. The cell line has the ability to develop tumors in vivo and importantly shows reduced sensitivity to EGFR TKIs mimicking the lack of response in patients with these mutations.
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MINI 29 - Meta Analyses and Trial Conduct (ID 156)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:D. Morgensztern, M. Redman
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 2a-3b
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MINI29.07 - CNS Disease Enrollment Criteria for NSCLC Drug Trials (ID 908)
18:30 - 20:00 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
CNS metastases are common in NSCLC, yet clinical trials of new drugs in NSCLC have widely varying inclusion and exclusion criteria in relation to CNS disease. CNS disease that has received local therapy may be dormant, confounding any subsequent drug benefit, whereas untreated CNS disease may reduce PFS if CNS and systemic drug exposure differs. Recently, RANO guidelines propose explicitly explored activity in CNS disease within solid tumor drug trials. The true extent of variation in CNS related enrollment criteria in NSCLC clinical trials has not been documented before.
Methods:
ClinicalTrials.gov was interrogated on September 11, 2014 looking for interventional drug trials including advanced NSCLC. The following characteristics were extracted: 1) trial phase; 2) experimental arm therapy (chemotherapy, targeted therapy, immunotherapy, anti-angiogenic); 3) location (US, International only, US + International); 4) sponsor (Industry, University/IIT, Cooperative Group, NCI); 5) CNS disease allowance (strict exclusion, allowed after local treatment (surgery/radiation), unrestricted/untreated disease allowed). Industry sponsorship was divided into ‘large pharmaceutical’, (top decile by number of sponsored trials) and ‘small pharmaceutical’ (lower 9 deciles). Exclusion of CNS metastasis was treated as a binary variable and grouped as ‘strict exclusion’ vs. ‘allowed CNS metastasis’ (‘allowed with treatment’ and ‘allowed untreated’). Univariable and multivariable logistic regression models were fit to test the association between exclusion of CNS metastasis and trial characteristics. Statistical significance was set at 0.05 with no adjustment for multiple testing.
Results:
Of 735 trials involving NSCLC, 325 (44%) were excluded from analysis mostly because of allowance of early stage NSCLC (50%, n=164), or no active therapy inclusion (45%, n=146). In the remaining 406 trials, patients with CNS metastases were excluded in 58 (14%), allowed after local treatment in 165 (41%), and allowed with no prior treatment in 104 (26%). CNS criteria were not referenced in the available information in 79 (19%) trials which were excluded from further analysis. On univariable analysis, the odds of CNS metastasis exclusion on trial were significantly lower in trials with vs. without targeted therapy (OR 0.44, 95% CI: 0.25-0.78, p=0.005) and significantly higher in trials with vs. without immunotherapy (OR 2.13, 95% CI: 1.06-4.28, p=0.04). No other univariable associations were significant. In multivariable analysis, after adjustment for all other factors, only trials located at international only vs. US only sites had greater odds of exclusion of CNS metastasis (OR 1.64, 95% CI 0.84-3.22; p=0.03).
Conclusion:
Although univariable analysis suggests class of agent may influence trial design, in multivariable analysis trial location was the only variable associated with strict exclusion of CNS metastases. This raises the possibility of exclusion based on historical/cultural rather than scientific factors. With 18% of trials (58/327) excluding all CNS disease and 50% (165/327) only allowing CNS disease if previously treated, less than a third of NSCLC trials permit unequivocal assessment of CNS activity (104/327). Given the high frequency of CNS disease in NSCLC, sponsors should consider consciously tailoring trial designs to more explicitly explore efficacy in this patient population.
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.02 - Phase II Study of Defactinib, VS-6063, a Focal Adhesion Kinase (FAK) Inhibitor, in Patients with KRAS Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 2875)
18:30 - 20:00 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
KRAS mutations, which occur in approximately 30% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either p53 or INK4a/Arf (CDKN2A) are sensitive to FAK inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK. This trial examined the effect of FAK inhibition in patients with KRAS mutant NSCLC and various permutations of p53 and CDKN2A alterations.
Methods:
This multi-center, non-randomized, open-label, multi-cohort trial enrolled patients with advanced KRAS mutant NSCLC who had received at least one prior (platinum-based chemotherapy doublet) line of therapy. The primary endpoint was progression-free survival (PFS) at 12 weeks. Patients were enrolled into one of four cohorts defined by INK4a/Arf and p53 status. In all cohorts, patients received defactinib 400 mg orally BID until disease progression.
Results:
Fifty-three patients with KRAS mutant NSCLC were enrolled across 9 US sites as of the data cut-off date (13-Mar-2015). Forty-seven patients were enrolled to one of the four molecularly defined cohorts. The median age was 62 years (range 33-80); 48% were female. The median number of prior lines of therapy was 3 (range 1-8) 15 (28%) pts met the 12 week PFS endpoint, with one patient achieving a PR. Median PFS was 46 days (range 12-205 days). Eight patients remained on study as of the data cut-off date. Clinical efficacy did not correlate with secondary mutation status across this KRAS mutant population. Adverse events considered at least possibly related to defactinib were experienced by 35 pts (76%). The majority of these were grade 1 or 2. 11 patients (24%) experienced at least possibly related grade 3-5 events, including 2 grade 5 respiratory failure events. Underlying disease was a confounding factor in many pts. The most commonly reported treatment emergent adverse events of any grade were fatigue (24%) and increased bilirubin (24%).
Conclusion:
In pretreated pts with KRAS mutant NSCLC defactinib demonstrates promising clinical activity with disease control rates comparable to other molecularly targeted agents for this pt population. Defactinib was generally well tolerated. Further development is warranted. Clinical trial: NCT01778803.
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ORAL 01 - Chemotherapy Developments for Lung Cancer (ID 88)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G. Blumenschein, S. Lee
- Coordinates: 9/07/2015, 10:45 - 12:15, 401-404
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ORAL01.02 - Therapy of Advanced Metastatic Lung Cancers with an Anti-Trop-2-SN-38 Antibody-Drug Conjugate, IMMU-132: Interim Phase II Clinical Results (ID 930)
10:45 - 12:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
Sacituzumab govitecan (IMMU-132) is a new Antibody Drug Conjugate (ADC) comprising SN-38, the active metabolite of the topoisomerase I inhibitor, camptothecin (irinotecan), conjugated to an anti-Trop-2 humanized antibody at a high drug-antibody ratio (7.6). In vitro and in vivo preclinical data suggest that IMMU-132 delivers up to 136-fold more SN-38 than its parental drug, irinotecan, in a human cancer xenograft. Trop-2 is widely expressed in most epithelial cancers, including non-small and small-cell lung cancers (NSCLC and SCLC).The safety and efficacy of this new ADC is being examined in advanced metastatic lung cancers.
Methods:
A Phase II clinical trial (ClinicalTrials.gov, NCT01631552) is ongoing in subsets of previously-treated patients with metastatic lung cancer, administering IMMU-132 on days 1 and 8 of 21-day treatment cycles. A phase 1 run-in phase selected 8 and 10 mg/kg weekly dosage as safe for tumor cohort phase 2 expansion. Treatment is continued based on tolerance or until progression, with safety and response assessments made every week and 8-12 weeks, respectively.
Results:
Forty-four lung cancer patients were given IMMU-132 doses at 8 mg/kg (N = 23) or 10 mg/kg (N = 21); 38 patients (18 NSCLC and 20 SCLC) are assessable for efficacy. Patients were heavily pretreated (median of 3 prior lines). Objective tumor responses (all partial responses by RECIST1.1) and median progression-free survival (PFS) are reported below per tumor. These studies are being expanded.
IMMU-132 was well tolerated with limited grade 3/4 toxicities above the 3% threshold per patient. Neutropenia was the only Grade 3/4 toxicity (G3, 14%; G4, 7%) together with hyponatremia (G3, 2%; G4, 2%). Other drug-related G3 toxicities included diarrhea (7%), anemia (5%), leukopenia (5%), hyperglycemia (5%) and atrial fibrillation (5%); no patient developed antibodies to the conjugate.Tumor type Prior lines of therapy: median (range) Objective Response Rate (PR) Median PFS (maturity) in months NSCLC (N=18) 3 (1-8) 33% 5.4 (56%) SCLC (N=20) 2.5 (1-7) 25% 2.4 (70%)
Conclusion:
Repeated cycles of IMMU-132 monotherapy are well tolerated. Objective response rate and progression-free survival data in previously-treated metastatic lung cancer (5.4 months in NSCLC) are encouraging and warrant further evaluation of IMMU-132 in these lung cancers.
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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.07 - Atezolizumab (MPDL3280A) Combined with Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer (NSCLC): A Phase Ib Safety and Efficacy Update (ID 2208)
10:45 - 12:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
Despite advances in treatment for NSCLC, the standard first-line treatment for metastatic disease remains platinum-based doublet chemotherapy with historical overall response rates (ORRs) of ≈30%. Preclinical data suggest that chemotherapy treatment can result in antigen release in the tumor microenvironment, potentially enhancing effects of cancer immunotherapy. Atezolizumab (MPDL3280A) is a human monoclonal antibody that targets the PD-L1/PD-1 immune checkpoint, while leaving the PD-L2/B7.1 interaction intact (which may reduce the risk of autoimmune lung toxicity). As atezolizumab has shown promising activity in advanced NSCLC, we investigated atezolizumab in combination with chemotherapy.
Methods:
A Phase Ib study was conducted to evaluate atezolizumab with chemotherapy in locally advanced or metastatic NSCLC patients who had not received chemotherapy for advanced disease. Pts received atezolizumab 15 mg/kg IV q3w with standard chemotherapy (carboplatin plus either paclitaxel [Arm C], pemetrexed [Arm D; nonsquamous] or weekly nab-paclitaxel [Arm E]) for 4-6 cycles followed by atezolizumab maintenance until progression. RECIST v1.1 was used to assess ORRs (unconfirmed) in pts dosed by Jun 29, 2014 (data cutoff: Sep 29, 2014). PD-L1 expression was centrally evaluated using the SP142 IHC antibody assay.
Results:
37 NSCLC pts were safety evaluable (8 in Arm C; 14 in Arm D; 15 in Arm E). Across these arms, 54% of pts were male, with a median age of 65 y (range, 40-82 y). 81% had non-squamous NSCLC, and 19% had squamous NSCLC. Median safety follow-up was 22.0 wks (range, 0.1-49.4 wks). Across arms, all-Grade AEs regardless of attribution included those commonly associated with chemotherapy, such as nausea (Arms C & D, 50%; Arm E, 73%), fatigue (Arm C, 38%; Arm D, 36%; Arm E, 73%) and constipation (Arm C, 25%; Arm D, 71%; Arm E, 27%). The most common Grade 3-4 atezolizumab-related AEs included anemia (Arms D & E, 7%), neutropenia (Arm C, 13%; Arm D, 7%) and thrombocytopenia (Arms D & E, 7%), with no pneumonitis or autoimmune renal toxicity observed. One potentially atezolizumab-related Grade 5 AE was observed in Arm D (candidemia after prolonged neutropenia). 30 pts were efficacy evaluable, and responses were observed in all arms regardless of PD-L1 expression (Table). Updated clinical data will be presented.Table. RECIST v1.1 Responses in Patients with NSCLC
Arm C: carboplatin + paclitaxel (n = 5) Arm D: carboplatin + pemetrexed (n = 12) Arm E: carboplatin + nab-paclitaxel (n = 13) All Indicated Arms (n = 30) ORR, % 60% 75% 62% 67% 95% CI, % 19%-92% 45%-93% 33%-83% 48%-82% CR, n 0 0 2 2 PR, n 3 9 6 18
Conclusion:
Atezolizumab plus standard first-line chemotherapy was well tolerated in advanced NSCLC pts, with no unexpected toxicities. Clinical activity was promising and supportive of a potential synergy of atezolizumab with chemotherapy. Based on these results, several Phase III studies have been initiated.
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 3
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.03 - Updated Efficacy/Safety Data From the Phase 2 NP28761 Study of Alectinib in ALK+ NSCLC (ID 1261)
16:45 - 18:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
ALK gene rearrangements occur in approximately 3–6% of patients with non-small-cell lung cancer (NSCLC). Crizotinib has demonstrated efficacy in ALK+ NSCLC, however many patients experience systemic and/or central nervous system (CNS) disease progression within one year of treatment. Alectinib, a CNS-penetrant and highly selective ALK inhibitor, has shown preclinical activity in the CNS (Ou, et al. JTO 2013) and clinical efficacy in crizotinib-naïve (Ohe, et al. ASCO 2015) and pre-treated (Ou, et al. ASCO 2015; Gandhi, et al. ASCO 2015) ALK+ NSCLC patients. We will present updated efficacy and safety outcomes from the phase II NP28761 study (NCT01871805).
Methods:
North American patients ≥18 years of age with ALK+ NSCLC (by FDA-approved FISH test), disease progression following first-line crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included investigator-assessed ORR; progression-free survival (PFS); quality of life (QoL); CNS response rate; disease control rate (DCR); and safety.
Results:
At data cut-off (24 October 2014), 87 patients were enrolled in the intent-to-treat population. Median age was 54 years; 74% had received prior chemotherapy; 60% of patients had baseline CNS metastases, of whom 65% (34/52) had prior brain radiation therapy. Median follow-up was 20.7 weeks. ORR by IRC was 48% (95% CI 36–60); median PFS was 6.3 months (Table 1). In patients with measurable CNS lesions at baseline (n=16), IRC CNS ORR was 69% (95% CI 41–89) and CNS DCR was 100% (complete response, 13%; partial response, 56%; stable disease, 31%). In patients with measurable or non-measurable CNS disease (n=52), IRC CNS ORR was 39% (95% CI 25–53) and 11 patients (21%) had complete CNS responses. The most common grade ≥3 AEs were elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%) and aspartate aminotransferase (5%); no GI toxicities leading to treatment withdrawal were reported. Clinically meaningful improvements were seen in EORTC QLQ-C30 items, including Global Health Status. Figure 1
Conclusion:
Alectinib (600mg twice daily) was well tolerated and demonstrated clinical efficacy in patients with ALK+ NSCLC disease who had progressed on prior crizotinib. A clinical benefit with alectinib was also observed in patients with CNS lesions at baseline. These data are preliminary; updated efficacy and safety data from a cut-off date of 27 April 2015 will be presented.
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ORAL33.05 - Pooled Analysis of CNS Response to Alectinib in Two Studies of Pre-Treated ALK+ NSCLC (ID 1219)
16:45 - 18:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
The central nervous system (CNS) is a frequent site of progression in ALK+ NSCLC patients treated with crizotinib, thus good CNS efficacy is of crucial importance for new ALK inhibitors. Two recent phase II studies examined the efficacy and safety of alectinib in patients with ALK+ NSCLC who progressed after crizotinib; data from both studies were pooled to further examine the efficacy of alectinib in the CNS.
Methods:
Both phase II, single-arm, multicenter studies enrolled ALK+ NSCLC patients previously treated with crizotinib. One study was conducted in North America only (NP28761; NCT01871805), the other was global (NP28673; NCT01801111). All patients received 600mg oral alectinib twice daily. A primary endpoint of both studies was objective response rate (ORR) by independent review committee (IRC) and key secondary endpoints included CNS ORR by IRC and CNS duration of response (DOR). Response was determined according to RECIST v1.1. All patients underwent imaging at baseline to assess CNS metastases.
Results:
The pooled analysis population comprised 225 patients (n=87 from NP28761 and n=138 from NP28673); baseline characteristics were similar to each study population, with most patients being non-smokers, <65 years old with ECOG performance status 0/1. Median follow-up was 27.7 weeks. Fifty patients had measurable CNS disease at baseline (MD) while a further 85 had non-measurable disease (NMD) at baseline; both groups together (M+NMD) comprised 135 patients, 60% of the overall study population. In the MD group, 34 patients (68%) had received prior radiotherapy, but 24 of them had completed that radiotherapy >6 months prior to starting alectinib. For the M+NMD group, 94 patients (70%) had received prior radiotherapy, with 55 completing this >6 months prior to starting alectinib. In the MD group, 30/50 patients had a CNS response (60.0%; 95% CI 45.2–73.6%), with 7 complete responses (CR; 14.0%) and a CNS DCR of 90.0% (78.2–96.7%). In the M+NMD group, 22 additional patients had a CR (29/135; 21.5%), giving a CNS ORR of 38.5% (30.3–47.3%), with a CNS DCR of 85.2% (78.1–90.7%). Complete responses were seen in patients with and without prior radiotherapy. Median CNS DOR after only 17% of events in both groups was 7.6 months (5.8–7.6) in the MD group (n=30) and 7.6 months (5.8–10.3) in the M+NMD group (n=52), which is similar to the systemic DOR reported in both studies (Ou et al, ASCO 2015; Gandhi et al, ASCO 2015). Tolerability was also similar to the overall study population.
Conclusion:
Alectinib showed promising efficacy in the CNS in ALK+ NSCLC patients previously treated with crizotinib, achieving a complete response rate of 22% and a DCR of 85%, irrespective of prior radiotherapy. The CNS response was sustained for an equivalent duration to the systemic response, suggesting that alectinib could provide an effective treatment for patients with ALK+ NSCLC while actively targeting CNS metastases. The ongoing phase III clinical studies will assess the systemic and CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.
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ORAL33.06 - Brigatinib (AP26113) Efficacy and Safety in ALK+ NSCLC: Phase 1/2 Trial Results (ID 2125)
16:45 - 18:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
Brigatinib (AP26113), an investigational oral tyrosine kinase inhibitor with FDA breakthrough therapy designation for the treatment of patients with crizotinib-resistant advanced ALK+ NSCLC, has preclinical activity against both rearranged ALK and clinically identified crizotinib-resistant mutant ALK.
Methods:
This is an ongoing phase 1/2, single-arm, open-label, multicenter study in patients with advanced malignancies (N=137; NCT01449461). Patients received escalating total daily doses of brigatinib from 30–300 mg during phase 1. Daily regimens of 90 mg, 180 mg, or 90 mg for 7 days followed by 180 mg were evaluated in phase 2. Safety is reported for all treated patients; antitumor efficacy (ORR and PFS per RECIST v1.1) is reported for ALK+ NSCLC patients.
Results:
Seventy-nine (58%) patients had ALK+ NSCLC. Median age was 54 (29–83) years, 49% were female, 90% had prior crizotinib, and 47% had ≥2 prior chemotherapy regimens. As of February 17, 2015, 45/79 (57%) ALK+ NSCLC patients remained on study, with median time on treatment of 12.6 months (1 day to 35.5 months; n=79); ORR/PFS for evaluable ALK+ NSCLC patients was 74%/13.4 months (additional data shown in Table). In a post hoc independent radiological review of patients with brain metastases at baseline (as of January 19, 2015), 8/15 (53%) patients with measurable brain lesions ≥10 mm had an intracranial response (≥30% decrease in sum of longest diameters of target lesions) and 9/30 (30%) patients with only nonmeasurable lesions had disappearance of all lesions. Treatment-emergent AEs in ≥30% of total patients, generally grade 1/2, included nausea (52%), fatigue (42%), diarrhea (40%), headache (33%), and cough (32%). Early-onset pulmonary events, which occurred ≤7 days after treatment initiation and included dyspnea, hypoxia, and new pulmonary opacities on chest CT consistent with pneumonia or pneumonitis, were reported in 13/137 (9%) patients overall (6/44 [14%] at 180 mg qd; 2/50 [4%] at 90 mg qd [maintained or escalated to 180 mg qd after 7 days]).Response and PFS With Brigatinib All Evaluable ALK+ NSCLC Patients n=78 Prior Crizotinib n=70 No Prior Crizotinib n=8 Response, n(%) OR (CR+PR) 58(74) 50(71) 8(100) [95% CI] [63–84] [59–82] [63–100] CR 7(9) 4(6) 3(38) PR 51(65) 46(66) 5(63) SD 11(14)[a] 11(16)[a] 0 PD 6(8) 6(9) 0 Termination before scan 3(4) 3(4) 0 Median duration of response,[b] mo 11.2[c] 9.9[d] Not reached[e] Median PFS,[b] mo 13.4 13.4 Not reached [a]Includes non-CR/non-PD for 4 patients with no measurable disease at baseline [b]Kaplan-Meier estimate [c]n=55 evaluable [d]n=48 evaluable [e]n=7 evaluable
Conclusion:
Brigatinib has promising antitumor activity in ALK+ NSCLC patients with (71% ORR; PFS 13.4 months) or without (100% ORR) prior crizotinib, including patients with brain metastases (53% ORR in patients with measurable brain lesions). Early-onset pulmonary events were less frequent when starting at 90 vs 180 mg qd. A pivotal global phase 2 trial (ALTA) of brigatinib 90 mg qd vs 90 mg qd for 7 days followed by 180 mg qd in crizotinib-resistant ALK+ NSCLC is ongoing.
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ORAL 37 - Novel Targets (ID 146)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.S. Ramalingam, E. Thunnissen
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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ORAL37.06 - Defining MET Copy Number Driven Lung Adenocarcinoma Molecularly and Clinically (ID 2379)
16:45 - 18:15 | Author(s): R. Camidge
- Abstract
- Presentation
Background:
Increases in MET copy number define an oncogenic driver state sensitive to MET inhibition (Camidge et al, ASCO 2014). However, the level at which the genomic gain is relevant remains uncertain. When testing is performed by fluorescence in situ hybridization (FISH), variable cut-points in both mean MET/cell and MET/CEP7 ratio have been used. Partially overlapping datasets from the Lung Cancer Mutation Consortium (LCMC1) and Colorado Molecular Correlates (CMOCO) Laboratory were explored for a distinct MET-copy number driven lung adenocarcinoma subtype.
Methods:
MET was assessed by FISH. Data from non-adenocarcinomas and EGFR mutant patients with acquired resistance to an EGFR inhibitor were excluded. Positivity criteria were mean MET/cell ≥5 (low ≥5-<6, intermediate ≥6-<7, high ≥7) or MET/CEP7 ≥1.8 (low ≥1.8-≤2.2, intermediate >2.2-< 5, high ≥5). MET metrics were compared by race, sex, smoking status, stage at diagnosis, number of metastatic disease sites, site of metastases, presence of other known drivers (EGFR, KRAS, ALK, ERBB2, BRAF, NRAS, ROS1 and RET), response to first line chemotherapy and overall survival using Fisher’s exact tests, chi-square tests, Spearman correlations and log-rank tests, as appropriate. Statistical significance was set at the 0.05 level without adjustment for multiple comparisons.
Results:
1164 unique adenocarcinomas were identified (60% female, 85% Caucasian, 66% ex/current smokers). MET/CEP 7 data was available on 1164 and mean MET/cell on 700. 52/1164 (4.5%) had MET/CEP7 ≥1.8 (48% female, 83% Caucasian, 69% smokers). 50/52 (98%) had ≥1 other oncogenic driver tested (25/50 (50%) positive). 113/700 (16%) had mean MET/cell ≥ 5 (57% female, 82% Caucasian, 58% smokers). 109/113 (96%) had ≥ 1 other oncogenic driver tested (73/109 (67%) positive). Among patients with ≥1 additional driver oncogene tested, alternate drivers in low, indeterminate and high categories of mean MET/cell were 44/60 (67%), 17/24 (70%) and 12/28 (43%) respectively and for MET/CEP7: 16/29 (55%), 9/18 (50%) and 0/4 (0%) respectively. MET positive with additional drivers were excluded from further analyses. Men exceeded women in MET/CEP7 (men 4% vs women 1.6%, p = 0.019) and mean MET/cell positive cases (men 9.6% vs women 5.4%, p = 0.058). 6.4% of adrenal metastasis cases were MET/CEP7 positive vs 2% all other sites, p=0.031. Mean MET/cell: 12% adrenal vs 5% other sites, p=0.082. MET/CEP7 or mean MET/cell positive and negative groups did not differ by other variables (p > 0.05).
Conclusion:
The proportion of ‘MET positive’ adenocarcinomas varies by definition and positivity cut-point. Mean MET/cell ≥5 defines nearly 4x more positives than MET/CEP7 ≥1.8 and no mean MET/cell positive category was free from overlap with other drivers. As only high MET/CEP7 had no overlap with other drivers, MET/CEP7 ≥ 5 is the clearest candidate for a pure MET-copy number driven state, however cases free from other drivers do exist at lower MET positivity levels. MET/CEP7 positive cases free from other known drivers are more likely to be male, but unlike other known oncogenic states, race and smoking status are not significant in determining positivity. MET positivity may have a specific biological phenotype, being more likely to present with adrenal metastases.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-076 - TIGER-1: A Phase 2/3 Study of First Line Rociletinib or Erlotinib in EGFR-Mutant NSCLC (ID 944)
09:30 - 17:00 | Author(s): R. Camidge
- Abstract
Background:
Activating EGFR mutations including the L858R mutation and exon 19 deletions (del19) are key drivers of non-small cell lung cancer (NSCLC) in 10%–15% of patients of European and 30%–35% of Asian descent.[1] Acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib can be driven by additional EGFR mutations, with exon 20 T790M accounting for 50%–60% of cases.[2] Rociletinib (CO-1686) was designed to inhibit T790M as well as L858R and del19 while sparing wild-type EGFR and has demonstrated response rates up to 67% in patients with T790M mutations who had progressed on first or later line EGFR inhibitor therapy. Rociletinib continues to be well tolerated by patients in ongoing studies.[3] Given that T790M mutated subclones commonly emerge during treatment with existing EGFR inhibitors, early targeting of T790M along with initial activating mutations is a rational approach to delay progression.
Methods:
TIGER-1 (NCT02186301) is a randomized, open label study of rociletinib vs erlotinib in patients with mutant EGFR NSCLC. Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced treatment-naive NSCLC (no prior therapy in the metastatic setting and no CNS disease), with documentation of ≥1 activating EGFR mutation (excluding exon 20 insertions) and biopsy within 60 days will be enrolled in this 2-part study. All patients will be randomized 1:1 to rociletinib (500 mg twice daily) or erlotinib (150 mg once daily) and treated until death, qualifying adverse events or disease progression. Patients will be stratified by sensitizing EGFR mutation (T790M, del19, L858R, or other) and territory (Asian vs non-Asian geography). The same patient eligibility criteria will be used for the Phase 2 and Phase 3 portions of TIGER-1. The phase 2 portion is currently enrolling and will transition to the Phase 3 portion upon enrollment of the 201[st] patient. The maturing Phase 2 dataset will contribute to decision-making rules for the Phase 3 interim analyses. The Phase 3 portion will incorporate larger cohorts; the final sample sizes will be determined by interim analyses where the chances of success will be estimated at pre-planned enrollment milestones. The primary endpoint is PFS; secondary efficacy endpoints include objective response rate, duration of response, disease control rate and overall survival. Safety will be assessed via standard adverse event reporting. PFS and OS will be summarized with Kaplan-Meier plots. The stratified log-rank and hazard ratio will compare PFS distributions for rociletinib- vs erlotinib-treated patients. Enrollment is ongoing. 1. Herbst R et al. N Engl J Med. 2008 2. Yu H et al. Clin Cancer Res. 2013 3. Sequist LV J Clin Oncol. 2014
Results:
Not applicable
Conclusion:
Not applicable
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P1.01-084 - A Phase 2 Study of TH-4000 in Patients with EGFR Mutant, T790M-Negative, Advanced NSCLC Progressing on an EGFR TKI (ID 2209)
09:30 - 17:00 | Author(s): R. Camidge
- Abstract
Background:
While EGFR-TKI therapy is initially effective for patients with EGFR-mutant NSCLC, eventual resistance to EFGR-TKI therapy is expected. For patients with non‑T790M resistance to EGFR-TKIs, the optimal treatment is unclear. Sensitizing mutations in EGFR are often heterozygous with co-expression of both wild type (WT) and mutant EGFR. Tumor hypoxia upregulates WT EGFR signaling through several HIF-dependent mechanisms. Clinical studies indicate that EGFR-mutant NSCLC with WT EGFR present is associated with a poorer response to EGFR-TKIs. NSCLC is known to be a hypoxic tumor; thus, hypoxia-induced activation of WT EGFR signaling may be a mechanism of EGFR-TKI resistance. TH-4000 is a clinical-stage hypoxia-activated prodrug that releases an irreversible pan-ErbB TKI targeting WT EGFR, mutant EGFR and HER2. Hypoxic tumor targeting using TH-4000 may allow a greater therapeutic index with greater intratumoral TKI levels and less dose-limiting systemic toxicity seen with current EGFR-TKIs. In xenograft models of EGFR-mutant NSCLC that co‑express WT EGFR, TH-4000 reverses resistance to current EGFR-TKIs, and is effective as a single‑agent. A Phase 1 study was conducted in patients with advanced solid tumors; the maximum tolerated dose (MTD) of TH-4000 administered as a 1-hour weekly intravenous (IV) infusion was established at 150 mg/m[2]. The most common treatment-related adverse events were dose-dependent and included rash, QT prolongation, nausea, infusion reaction, vomiting, diarrhea and fatigue.
Methods:
A multicenter Phase 2 trial was initiated to evaluate the safety and activity of TH-4000 as a single‑agent in patients with EGFR‑mutant, T790M-negative Stage IV NSCLC progressing on an EGFR TKI. Hypoxia PET imaging with [18F]-HX4 and molecular analyses of tumor tissue and plasma are incorporated in the study design to identify potential predictors of response to treatment. The primary endpoint is response rate. Secondary endpoints include progression-free survival, duration of response, overall survival, pharmacokinetics and safety, as well as evaluation of imaging, serum, and tissue biomarkers that may be associated with tumor response. Up to 37 patients will be enrolled with recurrent EGFR-mutant Stage IV NSCLC which has progressed while on treatment with EGFR-TKI, absence of EGFR T790M mutation, measureable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients must also have adequate pre-therapy tumor tissue available to enable tumor biomarker assessment. TH-4000 (150 mg/m[2]) is administered weekly by IV infusion over 60 minutes. The study design incorporates a Simon two-stage design (alpha = 0.10; beta = 0.10). Recruitment is ongoing.
Results:
Not applicable
Conclusion:
Not applicable
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-090 - A Phase 2, Single Arm Study of Lucitanib in Patients with Advanced/Metastatic Lung Cancer and FGF, VEGF, or PDGF-Related Genetic Changes (ID 2878)
09:30 - 17:00 | Author(s): R. Camidge
- Abstract
Background:
Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B). Clinical activity was observed in a phase 1/2 study of lucitanib monotherapy in cancer patients with tumor amplification of FGF-related genes or in tumors with predicted sensitivity to VEGF inhibitors. Genomic evidence of FGF, VEGF or PDGF axis aberrancy is seen in up to 15% of patients with lung cancer, which provides a strong rationale to assess lucitanib in this setting.
Methods:
The current study evaluates daily oral lucitanib monotherapy in 40 patients with amplification or activating mutations in FGF, VEGF or PDGF-related genes. This is an international, multicenter, open-label, single-arm study. The primary endpoint is objective response rate (ORR; RECIST 1.1) with secondary endpoints of response duration, clinical benefit rate, progression-free survival, and safety. Exploratory objectives include volumetric assessment of tumor growth kinetics, serial circulating tumor DNA measurement, and identification of additional biomarkers of lucitanib activity. Key inclusion criteria include: patients with advanced/metastatic non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) or large cell lung cancer and tumor tissue evidence of relevant genomic aberrancies. Patients must have measurable disease and at least one previous treatment for advanced disease. Key exclusion criteria include: carcinoid histology, symptomatic CNS metastases, anti-cancer treatment for lung cancer within 28 days or 5 half-lives before first dose of lucitanib. This study is enrolling patients in the United States and Europe at centers skilled in the identification of patients with relatively uncommon genetic tumor alterations.
Results:
not applicable
Conclusion:
not applicable
