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R.C. Doebele
Moderator of
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MS04 - Mesothelioma Genetics and Novel Targets (ID 21)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Mesothelioma
- Presentations: 4
- Moderators:R.C. Doebele, A.K. Nowak
- Coordinates: 10/28/2013, 14:00 - 15:30, Bayside 104, Level 1
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MS04.1 - BAP1 Gene Mutation and Mesothelioma Pathogenesis (ID 471)
14:00 - 15:30 | Author(s): A. Napolitano, M. Carbone
- Abstract
- Presentation
Abstract
Malignant mesothelioma (MM) is a lethal cancer whose pathogenesis results from complex interactions between host genetics and environmental carcinogens, such as asbestos and erionite fibers. Recently, BAP1 (BRCA associated protein 1) has been identified as a novel MM tumor suppressor gene. BAP1 is located at the 3p21, a region frequently deleted in MM, and encodes for a deubiquitinase enzyme known to target histones and other proteins. Originally discovered as a BRCA1 interacting protein, BAP1 appears to exert its anti-tumor activities mainly in a BRCA-independent manner, through its association in multi-protein complexes with diverse functions. For example, when associated to the Polycomb protein ASXL1, BAP1 is important for the regulation of the cell epigenome, via modulation of histone H2A ubiquitination and thus chromatin accessibility. In complex with other proteins (e.g. HCF-1, OGT, and YY1), BAP1 is also important in the transcriptional regulation of several genes and in the stability of target proteins such as PGC-1α. Recent reports also suggest a possible involvement of BAP1 in DNA repair pathways. However, the relevance of BAP1 to the biology of normal and cancer cells remains largely unexplained, in fact manipulation of BAP1 in cancer cells has often yielded unexpected or even contradictory results. For example, silencing of BAP1 in MM and uveal melanoma cell lines resulted in reduced cell growth (Bott et al; Matatall et al). We discovered that germline BAP1 mutations cause a novel cancer syndrome characterized by a significant excess of both pleural and peritoneal MM, uveal and cutaneous melanoma and possibly other tumors. In the same study, we reported that 22% sporadic MM tumors harbored somatic BAP1 mutations (Testa et al). In a separate study using 53 primary pleural MM collected in the USA, 42% of tumors harbored either BAP1 loss, BAP1 somatic mutations (detected in 23% of the samples), or both. Moreover, another 25% of tumors showed no BAP1 staining by immunohistochemistry (IHC) despite apparently normal BAP1 status, raising the possibility of post-translational deregulation of BAP1 in a subset of cases. In this MM cohort, there was a significant association between BAP1 status and patients’ age (66.7 years in mutant BAP1 compared to 58.6 years in wild-type BAP1), but there was no significant correlation with other variables such as sex, overall survival, histological subtype or asbestos exposure (Bott et al). In a recent meeting, using a bigger sample size, the same group confirmed that somatic BAP1 mutations occur in about 20% of pleural MM. They reported that the only clinical variable significantly different among those with and without BAP1 mutations was smoking (former or current), with BAP1 mutations more prevalent among smokers (75% vs. 42%). A Japanese study reported BAP1 gene alterations (either deletions or sequence-level mutations) in 61% of their 23 MM samples (Yoshikawa et al). Their data, but not those reported by Bott et al, also suggested an association between BAP1 mutations and the epithelioid histological MM subtype. Whether this discrepancy results from the different methodologies in sample preparation and detection of BAP1 mutations or it is an intrinsic difference between the two populations (e.g. due to ethnicity) has still to be determined. A third recent study, with a separate cohort of 52 pleural MM, reported absence of BAP1 IHC staining in 60% of pleural MM, confirming previous results (Arzt et al). The Authors also confirmed the absence of a correlation between BAP1 expression and asbestos exposure, and suggested that expression of BAP1 in tumor samples is inversely correlated to survival. The discovery of BAP1 germline and somatic mutations has renewed after decades the interest in MM genetics. Because germline BAP1 mutations predispose to multiple cancers and because BAP1 loss of heterozygosity is frequent in different tumor types, BAP1 would appear to act as a classical tumor suppressor. However, this definition is unsatisfactory because manipulation in vitro of BAP1 expression has often given unexpected and paradoxical results, complicating our understanding of its mechanisms of action. BAP1 absence (due to genetic, genomic, epigenomic or post-translational causes) was reported in about 60% of pleural MM. No studies so far have thoroughly investigated BAP1 expression in MMs arising from other sites. BAP1 expression is not associated to asbestos exposure, suggesting that its role in MM pathogenesis may be independent from the known asbestos-related pathways. Other clinicopathological associations are at this moment too weak to be conclusive, possibly due to limited tumor sample sizes, methodological differences in the studies or finally ethical differences of the analyzed populations. It appears, but remains unproven, that patients with germline BAP1 mutations have less aggressive MMs compared to sporadic MMs in which BAP1 mutations do not appear to influence prognosis. More experiments are urgently required to see whether BAP1 expression could be use in diagnostic, prognostic, or therapeutic settings. In fact, defining a therapeutically accessible synthetic lethal target in the setting of BAP1 loss could eventually benefit the approximately 40-60% of patients with BAP1 negative MMs. Even more speculatively, the same synthetic lethal target could be studied as chemoprevention drug targets in individuals with germline BAP1 mutations. The impact of this work obviously extends to other cancers with BAP1 mutations.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS04.2 - Sequencing the Mesothelioma Genome - Where Are We Now and Where Are We Going? (ID 472)
14:00 - 15:30 | Author(s): R. Bueno
- Abstract
- Presentation
Abstract not provided
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MS04.3 - New Molecular Targets in Mesothelioma (ID 473)
14:00 - 15:30 | Author(s): R. Stahel
- Abstract
- Presentation
Abstract not provided
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MS04.4 - Current Clinical Trials of Targeted Therapies (ID 474)
14:00 - 15:30 | Author(s): P. Baas
- Abstract
- Presentation
Abstract not provided
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Author of
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MO06 - NSCLC - Chemotherapy I (ID 108)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:R. Perez-Soler, P.M. Ellis
- Coordinates: 10/28/2013, 16:15 - 17:45, Parkside Ballroom A, Level 1
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MO06.08 - A phase 2 randomized open-label study of ramucirumab (IMC 1121B; RAM) in combination with first-line platinum-based chemotherapy in patients (pts) with recurrent or advanced non-small cell lung cancer (NSCLC): final results from non-squamous (NSQ) pts (NCT01160744) (ID 1471)
16:15 - 17:45 | Author(s): R.C. Doebele
- Abstract
- Presentation
Background
Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in NSCLC pathogenesis. RAM is a human IgG1 monoclonal receptor targeted antibody that inhibits VEGF receptor-2 (VEGFR-2) binding and signaling. This study investigates RAM in combination with first-line platinum-pemetrexed chemotherapy in advanced NSCLC.Methods
Eligible patients had Stage IIIb/IV NSCLC, ECOG PS ≤ 2, and no prior chemotherapy or VEGF/VEGFR therapy for metastatic disease. Non-squamous (NSQ) pts with advanced NSCLC were randomized 1:1 to either Arm A: pemetrexed + carboplatin/cisplatin (PEM + Cb/Cis) followed by PEM maintenance or Arm B: Ramucirumab 10 mg/kg + pemetrexed + carboplatin or cisplatin (RAM + PEM + Cb/Cis), followed by RAM + PEM maintenance once every 3 weeks. Patients received the first-line therapy from 4 to 6 cycles (21-day cycle); patients without evidence of disease progression entered a maintenance phase. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), change in tumor size, duration of response, and safety.Results
From Oct 2010 to 2012, 140 pts were randomized (PEM + Cb/Cis: 71; RAM + PEM + Cb/Cis: 69). Overall, baseline patient characteristics were balanced between arms. The median PFS was 5.6 m PEM + Cb/Cis and 7.2 m for RAM + PEM + Cb/Cis; HR 0.75 (90% CI, 0.55, 1.03; p =0.132). ORR (CR + PR) was 38% for PEM + Cb/Cis and 49.3% including one complete response in the RAM + PEM + Cb/Cis arm (p=0.18). Disease control rate (CR + PR + SD) was 70% PEM + Cb/Cis and 86% for RAM + PEM + Cb/Cis ( p = 0.031). Median OS at the time of final PFS analysis was 10.4 m for PEM + Cb/Cis and 13.9 m for RAM + PEM + Cb/Cis; HR 0.83 (90% CI, 0.56, 1.22; p=0.43). Grade ≥ 3 adverse events (AEs) occurring in >10% of patients on RAM containing arm were: anemia, neutropenia, thrombocytopenia, nausea, fatigue, back pain, and hypertension.Conclusion
While the primary endpoint of significant prolongation of PFS was not met, RAM has evidence of clinical activity in combination with PEM + Cb/Cis in patients with NSQ NSCLC. Addition of RAM to PEM + Cb/Cis did not result in excessive or unexpected toxicity.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO10 - Molecular Pathology II (ID 127)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Pathology
- Presentations: 2
- Moderators:W.A. Franklin, A. Mahar
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 104, Level 1
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MO10.10 - Detection of RET fusions by FISH in unselected NSCLC (ID 2434)
16:15 - 17:45 | Author(s): R.C. Doebele
- Abstract
- Presentation
Background
Activation of the RET gene by fusion has been described in 1-2% of unselected population of non-small-cell lung cancer (NSCLC) and there is early evidence suggesting that patients with RET activated tumors obtain clinical benefit from RET inhibitors. The major fusion partner is KIF5B, but CCDC6, NCOA4 and TRIM33 have also been reported. The prevalence of RET fusions in different lung cancer subtypes and clinicopathologic characteristics of remain unclear. In this study, we sought to identify RET rearrangements in NSCLC using FISH and to investigate the association with histology and clinical features.Methods
A 3-target, 3-color FISH probe set [3’RET in red, 5’RET in green, 5’KIF5B in yellow] was developed to simultaneously detect (a) disruption between 3’ and 5’ RET and (b) specific fusion between 5’KIF5B-3’RET. This probe set was used to interrogate a cohort of Caucasian NSCLC patients using tumor microarray. Inclusion of specimens on the tissue microarray was independent of gender, age, smoking history, histology and any known molecular profile and was only based on patient informed consent and tissue availability.Results
Among 348 evaluable NSCLC patients, 6 (1.7%) were found to be positive for RET rearrangement (RET+): 2 showed typical KIF5B:RET pattern, 2 showed patterns consistent with CCDC6: RET fusion; and 2 had split 3’-5’ without suggestion of the fusion partner identity. The histology was adenocarcinoma in 4, large cell carcinoma in 1 and squamous cell carcinoma in 1. All RET+ tumors were wild type for EGFR and negative for ALK and ROS1 rearrangements. The mean age of RET+ patients at the time of diagnosis was 62 years (49-74) and they were predominantly male (5) and former (4) or current smokers (1). The 10p11-q11 region displayed high level of genomic instability, with RET doublets, KIF5B and RET doublets, unbalanced KIF5B copy number gain, fusion KIF5B with 5’ and 3’RET, and abnormal separation between KIF5B and RET in 8.5%, 5.1%, 9.6%, 2.3%, and 2% of specimens, respectively. These atypical patterns will be further investigated by RT-PCR.Conclusion
The customized 3-target, 3-color probe set successfully detected KIF5B:RET rearrangements and identified patterns suggestive of RET rearrangements with non-KIF5B partners in small subset of unselected NSCLC. Interestingly, only a minority of RET + patients were never smokers and 1/3 of them had non-adenocarcinoma histology. Despite the benefits of using enrichment strategies based on clinicopathologic variables for molecular testing of NSCLC in search for personalized therapy, these findings argue against using variables such as smoking status and histology for screening selection when the aim is to detect all potential RET+ patients.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO10.12 - ROS1 Fusions Diagnosed by Break-Apart FISH in NSCLC (ID 968)
16:15 - 17:45 | Author(s): R.C. Doebele
- Abstract
- Presentation
Background
Chromosomal rearrangements which generate constitutively activated ROS1 receptor tyrosine kinase (6q22.1) have been found in several tumor types, including non-small cell lung cancers (NSCLC). In clinical trials, the oral kinase inhibitor crizotinib has shown promise in treating tumors with ROS1 rearrangements. Currently, fluorescence in situ hybridization (FISH) using dual-color, break-apart (BA) probes is used to detect ROS1 rearrangements in clinical samples; however, further optimization of this method is necessary to ensure patients are accurately diagnosed. This study explores BA FISH assay characteristics in NSCLC samples.Methods
Tumor sections from 464 NSCLC patients were screened for ROS1 rearrangement using ROS1 BA FISH. Of these samples, 206 were co-screened for ALK rearrangement. The copy number of fused and isolated 3’/5’ signals, as well as the incidence of atypical patterns (doublet and clustered multiple fusions) was investigated. Cells were considered ROS1 positive (ROS1+) when ≥ 15% of nuclei displayed split 5’/3’ signals or single 3’ signals. Specific fusion transcripts in ROS1+ cases were identified by RT-PCR or inverse PCR.Results
ROS1 rearrangements (ROS1+) were found in 21 patients (5%). The copy number of native ROS1 differed significantly between positive and negative tumors (mean of 1.5 versus 2.5, p<0.0001). The percent of cells with FISH patterns compatible with ROS1 rearrangement ranged from 30% to 100%, with a mean of 81%, in ROS1+ patients. The distribution of positive cells between scored regions within ROS1+ tumors was investigated for 13 cases and found to follow a normal distribution, ruling out intra-tumoral heterogeneity. Among ROS1+ specimens, 71% had a split signal pattern, 19% displayed a single 3’ pattern, and 10% had both a split and single 3’ pattern of positivity. For positive tumors, ROS1 fusion partners were identified as SDC4 (S2;R32 and S2;R34), EZR (E10;R34) and CD74 (C6;R32 and C6;R34). Atypical negative patterns such as fused doublets, clusters, 3’ doublets, 5’ doublets, and single 5’ signals were observed in 4%, 1%, 1%, <1%, and <1% of negative patients. ALK and ROS1 were scored simultaneously in the same cells in 206 patients, including 5 ROS1+ and 10 ALK+; no double positive cases were found. In ROS1 negative specimens, mean native ALK copy numbers were significantly higher than native ROS1 in ALK negative samples (3.2 versus 2.3, p<0.0001).Conclusion
ROS1+ tumors were detected in 5% of patients in this large NSCLC cohort. Since these patients were subject to various selection strategies, this frequency cannot be transferred to an unselected NSCLC population. The low native ROS1 copy number in the rearranged cells and lack of evidence of intra-tumoral heterogeneity suggests ROS1 rearrangements occur early in tumorigenesis, consistent with their known oncogenic driver role. Data from this sample also show that, in FISH negative cases, ROS1 copy number was lower than native ALK. This suggests ROS1 may exist in a relatively more stable portion of the genome, potentially explaining why ROS1 rearrangements exist at a lower frequency than ALK rearrangements in NSCLC.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MS27 - Mechanisms of Acquired Resistance to Targeted Therapy (ID 44)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Medical Oncology
- Presentations: 1
- Moderators:S. Yano, B. Solomon
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Auditorium B, Level 1
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MS27.2 - Resistance to ALK Inhibitors (ID 590)
10:30 - 12:00 | Author(s): R.C. Doebele
- Abstract
- Presentation
Abstract
ALK gene rearrangements occur in approximately 5% of lung adenocarcinomas and less frequently in other histologic subtypes. Crizotinib is currently the standard of care for ALK+ NSCLC (1). Treatment with crizotinib leads to remarkable objective response rates, durable progression free-survival and superiority over standard second line chemotherapy. Unfortunately, patients eventually experience disease progression on crizotinib. Disease progression may occur primarily in the central nervous system (CNS) alone, likely because of poor penetration of crizotinib into this space, or simultaneously with systemic progression outside of the CNS (2). Systemic disease progression likely occurs via cellular resistance that occurs by multiple mechanisms, which have been observed in vitro or in patient tumor samples derived following progression on crizotinib. Mutations in the kinase domain of ALK currently account for approximately 25% of observed drug resistance (3-5). Resistance mutations occur at the ‘gatekeeper’ position, L1196M, but multiple other ALK kinase domain mutations have been observed in patient samples or in cell lines with induced drug resistance. Indeed, in the first case of published crizotinib resistance, the tumor harbored two separate ALK mutations (6). This pattern stands in contrast to EGFR mutant lung cancer, where the observed rate of resistance mutations is 50-60% and the majority of resistance mutations occur at the gatekeeper position, T790M (7). Also in contrast to EGFR mutant lung cancer, resistance mutations in ALK do not appear to confer a fitness disadvantage to the tumor cell (3). Mutations induce resistance by allowing persistent ALK signaling despite the presence of crizotinib. Copy number gain of the ALK fusion has also been observed in both cell line models and in patient tumor samples following crizotinib resistance (3, 4). It is hypothesized that that a fraction of ALK fusion proteins are not inhibited by clinically achievable doses of crizotinib and that increased expression may allow sufficient downstream signaling for tumor cell survival. Collectively, we have termed resistance mutations and copy number gain as ‘ALK-dominant’ mechanisms of resistance, because the tumor cells are still predicted to be ‘addicted’ to ALK signaling. Multiple mechanisms of ‘bypass’ signaling have been observed in both cell line models and post-progression tumor biopsies. These include activating mutations in EGFR and KRAS, and ligand dependent activation of EGFR or KIT (3, 4). In some cases the ALK gene rearrangement is no longer observed in post-crizotinib biopsy, also suggestive of an alternate or bypass signaling pathway. We have termed these bypass signaling mechanisms as ‘ALK non-dominant’ resistance as the tumor cells may no longer be dependent on ALK signaling. Approximately 50% of patients have been shown to harbor each class (dominant vs. non-dominant) resistance and this may have implications for post-progression therapy in these patients (1). Next generation ALK inhibitors such as LDK378, AP26113, and CH/RO5424802 which potently inhibit the ALK kinase and have activity against many of the resistance mutations in vitro, may be the favored post-progression therapy for patients with ALK dominant resistance. All of these drugs have also demonstrated anecdotal evidence of activity in the CNS. Although not ALK-specific, HSP90 inhibitors, such as ganetespib, IPI-504, and AUY-922, can inhibit ALK signaling by decreasing proper folding of the chimeric ALK fusion proteins and may also overcome ALK dominant resistance (8). ALK non-dominant resistance may require dual inhibition of ALK and a bypass signaling pathway to overcome resistance and the selection of drugs would be dependent on the alternate signaling pathway. Currently, no post-crizotinib therapies are approved in ALK+ lung cancer, but systemic chemotherapy remains as useful treatment strategy and some evidence suggests that pemetrexed-based regimens may be an optimal initial choice in the absence of a clinical trial (9). References 1. Camidge DR, Doebele RC. Treating ALK-positive lung cancer--early successes and future challenges. Nat Rev Clin Oncol. 2012;9:268-77. 2. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443-5. 3. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18:1472-82. 4. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012;4:120ra17. 5. Huang D, Kim DW, Kotsakis A, Deng S, Lira P, Ho SN, et al. Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. Genomics. 2013. 6. Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:1734-9. 7. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-7. 8. Normant E, Paez G, West KA, Lim AR, Slocum KL, Tunkey C, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene. 2011;30:2581-6. 9. Camidge DR, Kono SA, Lu X, Okuyama S, Baron AE, Oton AB, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011;6:774-80.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O03 - NSCLC - Targeted Therapies I (ID 113)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:J. Ross, J.C. Yang
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside Auditorium B, Level 1
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O03.06 - First-In-Human Evaluation of CO-1686, an Irreversible, Highly, Selective Tyrosine Kinase Inhibitor of Mutations of EGFR (Activating and T790M) (ID 1354)
10:30 - 12:00 | Author(s): R.C. Doebele
- Abstract
- Presentation
Background
Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition. CO-1686 is an oral, covalent TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest greatest efficacy when plasma concentrations exceed 200ng/ml for >16hrs/day.Methods
This is an ongoing first-in-human dose finding study (3+3) of oral CO-1686 administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. All patients must undergo tumor tissue biopsy within 28 days before study drug dosing for central EGFR genotyping. Endpoints include safety, pharmacokinetics (PK), and efficacy.Results
As of 12 June 2013, 45 patients have been treated with CO-1686. 31/42 (74%) were T790M+; data for three patients is pending. The median age is 58 years, 82% are female, 75% are white, and 73% ECOG 1. The median number of previous therapies was 4 (range: 1- 6), with a median of 1 (range: 1- 4) previous EGFR TKI therapies. Dosing started at 150mg QD and escalated to 900mg QD, 900mg BID and 400mg TID, with a maximum tolerated dose not yet reached. Treatment-related AEs (all grades) occurring in > 5% patients were: fatigue (19%), diarrhea (15%), nausea (14%), anemia (10%), arthralgia (7%), muscle spasms (10%), myalgia (7%), headache (7%). The majority of events were mild or moderate. Unlike other EGFR inhibitors, rash and diarrhea were not commonly seen. This AE profile is consistent with the expected lack of wild type EGFR inhibition with CO-1686. The PFS for T790M+ patients with CO-1686 plasma concentrations > 200ng/mL for > 16 hours was 194 days compared with 72.5 days for those that achieved these concentrations for < 16 hours (Figure 1). At the highest evaluated dose, 900mg BID, four T790M+ patients were evaluable for response; 3 of the 4 achieved PRs, one achieved SD. One patient at a lower dose cohort also achieved a PR. Further safety and efficacy data will be presented at the meeting. Figure 1Conclusion
CO-1686 has demonstrated good tolerability and efficacy against proven T790M+ EGFR mutant NSCLC with a strong suggestion of a dose-response relationship. Additional evaluation of the optimal dose and formulation of CO-1686 are underway to further explore its potential for improved activity and better tolerability over other existing EGFR TKIs.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
