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Robert C. Doebele
Moderator of
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 15
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.01 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 9008)
15:45 - 17:30 | Presenting Author(s): Tony SK Mok | Author(s): Solange Peters, D. Ross Camidge, Shirish M Gadgeel, S. Ignatius Ou, D. Kim, Rafal Dziadziuszko, F. De Marinis, R. Sangha, A. Zeaiter, J. Noe, E. Nueesch, T. Liu, Isabell Loftin, C. Williams, Alice Shaw
- Abstract
- Presentation
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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MA 07.02 - Response to Ensartinib in TKI Naïve ALK+ NSCLC Patients (ID 10247)
15:45 - 17:30 | Presenting Author(s): Heather A Wakelee | Author(s): R.E. Sanborn, Jorge Nieva, S.N. Waqar, C. Brzezniak, J. Bauman, Joel W. Neal, G. Dukart, F. Tan, K. Harrow, C. Liang, L. Horn
- Abstract
- Presentation
Background:
Ensartinib is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK. Ensartinib has demonstrated significant anti-tumor activity in both ALK TKI-naïve and crizotinib-resistant NSCLC patients. We report on data from ALK TKI treatment naïve patients.
Method:
Pts with advanced solid tumors and ECOG PS 0-1 were treated with ensartinib 225 mg qd on a continuous 28-day schedule. In expansion phase, pts were required to have measurable ALK+ NSCLC with tissue confirmed centrally via FISH or IHC. Asymptomatic brain metastases were allowed. Targeted NGS of cfDNA was performed retrospectively at baseline and on study and compared with tissue results.
Result:
As of 01Apr2017, 102 pts enrolled. In the ALK TKI naïve cohort, 15 (8 female, 7 male) ALK+ NSCLC pts treated at doses ≥ 200 mg evaluable for response. 4 pts had received prior chemotherapy. Median age 59 (34-80) yrs, 60% had ECOG PS 1. Partial response (PR) achieved in 13 pts (87%). Six pts had ALK detected via plasma NGS. In two patients who did not respond to ensartinib, tissue was positive via FISH and plasma was negative. Seven patients had insufficient plasma for NGS evaluation. Median PFS in the initial 13 evaluable ALK+ pts was 25.6 mos with the longest being 44+ mos. The PFS for all patients is still maturing. In 3 pts with central nervous system (CNS) target lesions and no prior radiation, 1 had a complete response (CR) and 2 had PR for an ORR of 100%. Most common drug-related AEs (>20% of pts) included rash (54%), nausea (34%), pruritus (26%), vomiting (25%), and fatigue (21%). Most AEs were Grade (G) 1-2. Most common G3 tx-related AE was rash (12 pts).
Conclusion:
Ensartinib was well-tolerated and induced responses in ALK TKI naïve ALK+ NSCLC pts, including pts with CNS lesions. Enrollment is ongoing in the phase 3 study of ensartinib vs. crizotinib in ALK TKI naïve NSCLC patients.
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MA 07.03 - Incidence, Predictors and Prognostic Significance of Thromboembolic Events in Patients with Advanced Alk-Rearranged NSCLCs (ID 9532)
15:45 - 17:30 | Presenting Author(s): Jon Zugazagoitia | Author(s): M. Biosca, J.F. Grau, J. Olivera, L. Bei, M.E. Olmedo, A. Gómez Rueda, N. Muñoz, S. Ponce, M. Domine, V. Zenzola, Ernest Nadal, J.C. Ruffinelli, A.M. Luna, B. Hernández, M. Martínez, C. Font, M. García-Morillo, I. Gallego, D. Sánchez Cabrero, J. Miranda, E. Martínez De Castro, J.D. Cacho, V. Calvo, J. Martínez, E. Noguerón, R. Mondéjar, I. García Escobar, C. Salvador-Coloma, Ó. Juan, M. Sánchez Cánovas, J. Valdivia, M..P. Ochoa, R. López Castro, B. Obispo, C. Pangua, M. Sereno, L. Fernández Franco, X. Mielgo, J. Calzas, A. Blasco, F. Aparisi, L. Chara, D. Lora, A.J. Muñoz, Luis Paz-Ares, A. Manzano
- Abstract
- Presentation
Background:
The incidence of venous thromboembolic events all along the course of the disease in advanced-stage lung adenocarcinomas is approximately 15 %. It is plausible that the different molecular subtypes might influence on the risk of thrombosis. Based on our clinical observation, and supported by limited data from isolated small series, patients bearing ALK rearranged tumors could be at a particularly high-risk of thromboembolic disease.
Method:
We included consecutive patients diagnosed with advanced-stage ALK fusion positive non-small cell lung cancers (NSCLC) between January 2012 and December 2016. Clinical data were contributed by 29 Medical Centers from Spain and one large Academic Cancer Center from Portugal. Investigators at each institution retrospectively reviewed patients’ medical records. A thromboembolic event was defined as any venous or arterial thromboembolism, or both, at any site, documented by appropriate imaging studies, that occurred at the time or after advanced-stage cancer diagnosis.
Result:
A total of 241 ALK-rearranged NSCLCs were included in our study. Half of the patients were never smokers (52 %), and most had stage IV pulmonary adenocarcinomas (n=204, 85%). Baseline brain and liver metastasis were detected in 22 % and 25 % of the patients respectively. Seventy-three patients (30 %) developed thromboembolic disease. In 54 patients (74 %) thromboembolic complications occurred within the first 6 months from diagnosis. In the multivariate competing-risk regression analysis, the presence of baseline liver metastases (HR of 1.85, CI 95 % 1.09-3.15; p = 0.021) and baseline leukocyte counts > 11.0000 cells/mm3 (HR of 2.34, CI 95 % 1.43-3.82; p = 0.001) were independent predictors of thromboembolic disease. Remarkably, 50 % of the patients with either liver metastases or leukocytosis at diagnosis developed thromboembolic disease. Patients experiencing thromboembolic events had shorter median overall survival (OS) (20 months) than patients without thrombosis (36 months) (p = 0.035). In the multivariate Cox Model, thromboembolic disease remained associated with worse OS (HR of 1.70, CI 95 % 1.10-2.62; p = 0.016) when considered as a time-varying covariate. The presence of baseline thromboembolic disease (n = 24) was associated with a numerical non-significant increased risk of death (HR 1.67, CI 95 % 0.96-2.91; p = 0.068).
Conclusion:
Venous and/or arterial thromboembolic complications occur in a high proportion of patients with advanced-stage ALK fusion positive NSCLCs, particularly in the presence of baseline liver metastasis or leukocytosis. The development of thromboembolic disease is associated with a lower OS in these patients.
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- Abstract
- Presentation
Background:
Brain metastases are common in patients with advanced non–small cell lung cancer (NSCLC). Approximately 1% of NSCLC patients have ROS1-rearranged, and these patients achieved prolonged survival when treated with crizotinib, which is approved for the treatment of ROS1-rearranged NSCLC. However, this efficacy might not translate to intracranial control of disease. Herein, we evaluated the clinical impact of crizotinib on brain metastases in patients with advanced ROS1-rearranged NSCLC.
Method:
Between April 2014 and October 2016, 53 ROS1-rearranged NSCLC patients treated with crizotinib were retrospectively evaluated for baseline characteristics, brain metastases status, progression patterns and the overall prognosis.
Result:
Of the 53 ROS1-rearranged NSCLC patients who received crizotinib as treatment, 13 (24.5%) patients had baseline brain metastases before crizotinib treatment. Among patients without baseline brain metastases who developed progressive disease after initiation of crizotinib (n=27), 22.2% were diagnosed with brain metastases. Among patients without baseline brain metastases, systemic progression-free survival (PFS) and overall survival (OS) after initiation of crizotinib was significantly longer than that of patients with brain metastases (median PFS: 20.4 months vs. 11.0 months, p = 0.003; median OS: not reached vs. 16.5 months, p = 0.027). There was no significant difference in systemic PFS and OS between patients developing brain metastases before and after crizotinib treatment (median PFS: 11.0 months vs. 6.4 months, p = 0.469; median OS: 16.5 months vs. not reached, p = 0.605). Among the patients with baseline brain metastases, 6 had received prior brain radiotherapy and 7 had received no prior radiotherapy. A total of 2 patients in the treated group had an event of brain metastases progression, as compared with 4 patients in the untreated group (33.3% vs 57.1%, p = 0.592). There was no significant difference in intracranial PFS in the previously brain treated patients versus the untreated patients before crizotinib treatment (median intracranial PFS: 12.5 months vs. 11.0 months, p = 0.790).
Conclusion:
Brain metastases status before crizotinib treatment was significantly associated with both PFS and OS in crizotinib-treated ROS1-rearranged NSCLC patients. Patients with brain metastases received prior radiotherapy have not prolonged survival compared with the patients treated with crizotinib alone.
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MA 07.05 - Discussant - MA 07.01, MA 07.02, MA 07.03, MA 07.04 (ID 10817)
15:45 - 17:30 | Presenting Author(s): Neal Ready
- Abstract
- Presentation
Abstract not provided
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MA 07.06 - Detection of Mechanisms of Resistance to ALK Inhibitors in Routine Practice: A Retrospective Study (ID 8942)
15:45 - 17:30 | Presenting Author(s): Philippe Jamme | Author(s): C. Descarpentries, M. Wislez, E. Dansin, V. Grégoire, S. Baldacci, F. Escande, N. Mathiot, M. Kyheng, Z. Kherrouche, M.C. Copin, Alexis B Cortot
- Abstract
- Presentation
Background:
Treatment of ALK-rearranged Non-Small Cell Lung Cancer (NSCLC) relies on ALK tyrosine kinase inhibitors (TKI). However, efficacy of ALK TKI is limited by the emergence of drug resistance. ALK molecular alterations (amplification or mutation) account for about 40% of mechanisms of resistance to ALK TKI. Even though clinical and fundamental data suggest variability in drug efficacy according to the mechanism of resistance, these mutations are rarely investigated in routine practice. While targeted next-generation sequencing (t-NGS) is increasingly used for detecting molecular abnormalities, the impact of this tool in routine detection of ALK alterations is unknown.
Method:
We performed a retrospective multicentric study aiming at determining the frequency of ALK alterations using t-NGS in metastatic ALK-rearranged NSCLC patients progressing upon ALK TKI. Clinical, pathological, molecular characteristics, and patients outcome were collected.
Result:
We identified 22 patients with metastatic ALK-rearranged NSCLC who underwent a rebiopsy at progression on first ALK TKI, between January 2012 and May 2017. There were 12 females and 10 males, median age was 55, 18 patients (82%) were never smokers. Crizotinib was the first ALK TKI in 21 patients (95%). 15 patients (68%) received a second-generation ALK inhibitor and 3 patients (14%) received a third generation of ALK inhibitor. t-NGS on rebiopsy was performed in 16 patients. 6 ALK mutations (37.5%) were identified, including 3 G1202R, 1 C1156Y, 1 V1180L and 1 L1196M mutations . An ALK amplification (6%) was detected in a rebiopsy (6%) by FISH, with no concomitant ALK mutation. All ALK mutations were detected in solid biopsy, 2 ALK mutation was also detected in liquid biopsy. Median Overall Survival from first ALK TKI was 797 days (IC 95% 460-1135) and tended to be longer in patients with a known mechanism of resistance (1135 days Vs 543 days p=0.2).
Conclusion:
Targeted NGS is feasible in routine practice for detection of mechanisms of resistance to ALK TKI in ALK-rearranged NSCLC patients and may help selecting the best treatment at progression upon ALK TKI.
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MA 07.07 - Clinical Outcomes and ALK Resistance Mutations in ALK+ Non-Small Cell Lung Cancer According to EML4-ALK Variant (ID 8255)
15:45 - 17:30 | Presenting Author(s): Jessica Jiyeong Lin | Author(s): Viola Zhu, S. Yoda, B.Y. Yeap, N.A. Jessop, A.B. Schrock, I. Dagogo-Jack, K. Gowen, P.J. Stephens, Jeffrey S. Ross, Siraj M Ali, V.A. Miller, Justin F Gainor, A.N. Hata, A.J. Iafrate, Sai-Hong Ignatius Ou, Alice Shaw
- Abstract
- Presentation
Background:
Advanced ALK+ non-small cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes among patients treated with ALK TKIs vary, and the clinical benefit of TKI therapy is limited due to acquired resistance. To date, emerging data suggest that the specific EML4-ALK variant may impact clinical outcome, but whether variant is associated with mechanisms of TKI resistance is unknown.
Method:
We identified 108 advanced ALK+ NSCLC cases with known ALK fusion variants. Progression-free survival (PFS) on ALK TKIs and resistance mechanisms were retrospectively evaluated according to ALK variant.
Result:
The 108 ALK+ cases consisted of: 42 (39%) EML4-ALK v1 (E13;A20), 8 (7.4%) v2 (E20;A20), 45 (41.7%) v3 (E6;A20), 3 (2.8%) v5 (E2;A20), 4 (3.7%) v5’ (E18;A20), 1 (0.9%) v7 (E14;A20), and 5 (4.6%) non-EML4-ALK variants. Given the small numbers of non-v1/v3 cases, v1 and v3 cases were selected for further analysis. Among the 21 v1 and 25 v3 cases treated with first-line crizotinib, there was no significant difference in PFS (HR = 0.81 [95% CI, 0.42-1.57], p = 0.526). Similarly, there was no difference in PFS on second-generation ALK TKIs among 35 v1 and 35 v3 patients who received ceritinib, alectinib, or brigatinib following first- or later-line crizotinib (HR = 1.32 [95% CI, 0.77-2.26], p = 0.308). Interestingly, among 12 v1 and 17 v3 patients who received the third-generation TKI lorlatinib after failure of a second-generation TKI, v3 was associated with significantly longer PFS than v1 (HR = 0.250 [95% CI, 0.09-0.72], p = 0.006). From our cohort, we identified 11 v3 and 14 v1 post-crizotinib biopsies. No difference was noted in the presence of ALK resistance mutations (27% and 21%, respectively; p = 1.000). In contrast, among 30 v3 and 18 v1 post-second generation TKI biopsies, ALK resistance mutations were more common among v3 vs v1 cases (66% vs 44%, respectively; p = 0.147). Furthermore, the ALK G1202R solvent front mutation occurred more frequently in v3 vs v1 (47% vs 0%, respectively; p = 0.001).
Conclusion:
Our findings suggest that EML4-ALK variants 1 and 3 may not be associated with significantly different PFS outcomes on crizotinib or second-generation ALK TKIs. However, ALK resistance mutations, particularly G1202R, occur more frequently in v3 vs v1 post–second generation TKI. Patients with this variant may therefore derive particular benefit from third-generation, pan-inhibitory ALK TKIs. Larger, prospective studies will be needed to confirm these findings.
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MA 07.08 - Clinical Implications of ALK Resistance Mutations: Institutional Experience and Launch of Remote Participation Study (ID 7931)
15:45 - 17:30 | Presenting Author(s): Pablo Martinez | Author(s): N.R. Mahadevan, T. Nguyen, C.A. Lydon, L.M. Sholl, Pasi A Jänne, Geoffrey R. Oxnard
- Abstract
- Presentation
Background:
ALK resistance mutations are detected in 30-50% of the patients with ALK-positive non-small cell lung cancer (NSCLC) and resistance to ALK tyrosine kinase inhibitors (TKIs). Preliminary data suggests that TKI-resistant patients benefit from further ALK inhibition based on the specific resistant mutations, but clinical data are limited.
Method:
Patients with ALK-positive NSCLC were identified from our institutional database with IRB approval. Tumor specimens from patients with TKI-resistance were analyzed using next-generation sequencing (NGS). We aimed to study the relationship between specific ALK-resistant mutations, patient characteristics and clinical outcomes.
Result:
Among 82 ALK-positive NSCLC patients, we identified 29 cases with advanced disease, TKI resistance, and specimens available for NGS. Twenty-two specimens from 19 patients were adequate for genomic analyses. Patients received a median of 4 lines of treatment for advanced disease including a median of 2 ALK TKIs, with a median overall survival (OS) of 3.3 years. In 9 of 22 specimens, crizotinib was the only TKI received. Ten specimens (45.5%) showed an ALK resistance mutation: one G1128A, one L1152R, four I1171N/T, two F1174V and two G1202R. ALK-resistance mutations were more common with EML4-ALK variant 3 (4/5) than variant 1 (1/5). Three cases with sequential biopsies showed features of tumor evolution, such as a compound mutation (I1171N + C1156Y) or a mutational change (L1152R to G1128A). One case initially had an EGFR L858R mutation, then acquired an ALK rearrangement, then acquired a G1202R mutation. OS was longer in 8 patients with secondary ALK mutation (5.5y) compared to 11 patients without (1.8 y). Using these learnings from an institutional cohort of ALK resistant patients, we designed and are launching a prospective study to characterize ALK TKI resistance, which uses remote-participation and plasma NGS to enroll patients from across the US. Patients with systemic progression while on a next-generation ALK TKI submit blood to a central lab for analysis and banking. Plasma NGS results are returned to the patient and their provider, and including expected TKI sensitivities for any identified ALK-resistance mutations. Through monitoring outcomes, this study can assess if molecularly-guided therapy for ALK TKI-resistance is feasible and effective.
Conclusion:
ALK resistance mutations arise in a large portion of patients and are associated with longer survival. The SPACEW-ALK study (Study of Plasma next-generation sequencing for remote Assessment, Characterization, Evaluation of patients With ALK drug resistance) uses plasma NGS and remote consent to assess ALK resistance and the feasibility of precision resistance therapy for these patients.
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- Abstract
- Presentation
Background:
ALK, ROS1 and TRK kinase inhibitors have achieved tremendous success in the treatment of lung cancer patients with abnormal ALK, ROS1 or NTRK gene. However, the emergence of drug resistance limits their long term clinical applications. An ever increasing number of acquired resistance mutations are being reported from the clinic. In addition to the gatekeeper mutations, the solvent front mutations have been recently recognized as common resistance mutations to many kinase inhibitors. For example, the solvent front ALK G1202R mutant conferred resistance to many clinical ALK inhibitors in lung cancer including crizotinib, ceritinib, alectinib, and brigatinib. The same position mutations ROS1 G2032R, TRKA G595R and TRKC G623R rendered resistance to the ROS1 inhibitor crizotinib in lung cancer, pan-TRK inhibitor entrectinib and larotrectinib in colon cancer, and larotrectinib in infantile fibrosarcoma, respectively.
Method:
A conserved glycine residue at the hinge C-terminal forms a hydrophobic sandwich with the kinase beta 1 sheet. Kinase inhibitors often use an aromatic ring or a flat motif to fit through this narrow glycine sandwich to the solvent. Alterations at the conserved glycine or the nearby residues, commonly referred to as solvent-front mutations, clash with the inhibitor motif and induce clinical resistance. Here, we designed TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current ALK, ROS1, and TRK inhibitors in the clinic to avoid the steric clash inside the sandwich.
Result:
TPX-0005 resides at the center of the highly conserved ATP site without direct contact with the solvent front glycine sandwich. As expected, TPX-0005 potently inhibited WT EML4-ALK and solvent front mutant EML4-ALK G1202R with similar activities in both enzymatic (WT Ki 0.87 nM vs G1202R 0.81 nM) and Ba/F3 cell proliferation assays (WT IC~50~ 21.1 nM vs G1202R 20.5 nM). TPX-0005 showed potent activities against CD74-ROS1 G2032R (IC~50~ 8.4 nM), LMNA-TRKA G595R (IC~50~ 0.4 nM), TEL-TRKB G639R (IC~50~ 1.9 nM) and TEL-TRKC G623R (IC~50~ 0.4 nM) in Ba/F3 cell proliferation assays. In the xenograft tumor model studies, TPX-0005 dramatically caused tumor growth inhibition and tumor regression in the tumors carrying WT and solvent-front mutations of ALK, ROS1 or TRKA fusion genes, respectively.
Conclusion:
Taken together, preclinical results demonstrated that TPX-0005 is a novel ALK/ROS1/TRK inhibitor overcoming the profound solvent front kinase mutations. TPX-0005 will bring new methods for the treatment of resistance patients with solvent front mutations in ALK, ROS1, or TRK fusion genes. A phase 1/2 study of TPX-0005 in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1) is actively pursued (NCT03093116).
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MA 07.10 - Discussant - MA 07.06, MA 07.07, MA 07.08, MA 07.09 (ID 10818)
15:45 - 17:30 | Presenting Author(s): Takashi Seto
- Abstract
- Presentation
Abstract not provided
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MA 07.11 - A Phase II Study of Trastuzumab Emtansine in HER2-positive Non-Small-Cell-Lung Cancer (ID 8453)
15:45 - 17:30 | Presenting Author(s): Daijiro Harada | Author(s): T. Kozuki, N. Nogami, K. Hotta, K. Aoe, K. Ohashi, K. Ninomiya, T. Hirata, S. Hinotsu, Shinichi Toyooka, K. Kiura
- Abstract
- Presentation
Background:
Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with vinca-alkaloid, has been approved for clinical use in HER2-positive breast cancer. HER2-alterations are detected even in non-small-cell lung cancer (NSCLC). We have launched a phase II trial of T-DM1 monotherapy for patients with HER2-positive lung cancer.
Method:
Eligible patients had pathologically diagnosed NSCLC with documented HER2-positivity (immunohistochemistry [IHC] 3+, both IHC 2+ and fluorescence in situ hybridization [FISH] +, or exon 20 insertion mutation) and were previously treated with standard chemotherapy. Thirty patients would receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate (ORR) per RECIST v1.1.
Result:
This study was early terminated due to the limited efficacy, leading that only 16 patients were registered. The demographics of the 15 evaluable patients were as follows: age (median; 67, range: 45-77), sex (male; 47%), performance status (0-1; 80%), histology (non-squamous; 100%), HER2 status (IHC3+; 33%, IHC2+/FISH; 20%, and mutation; 47%) and number of prior chemotherapeutic regimens (median; 4, range: 1-7). Of 15 patients, one, who possessed HER2 mutation achieved a partial response, resulting in ORR of 6.7%. None of the 15 patients experienced treatment-related deaths. Survival data would be presented at the meeting.
Conclusion:
T-DM1 has a limited efficacy for HER2-positive NSCLCs in our cohort. Additional molecular approaches are warranted for the precision medicine in HER2-positive tumors. UMIN registration number 000019446.
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MA 07.12 - Short-Term Culture of Patient Derived Tumor Organoids Identify Neratinib/Trastuzumab as an Effective Combination in HER2 Mutant Lung Cancer (ID 10119)
15:45 - 17:30 | Presenting Author(s): Elena Ivanova | Author(s): M. Bahcall, A.R. Aref, T. Chen, L. Taus, F. Avogadri-Connors, R.E. Cutler Jr., A.S. Lalani, J. Choi, J.J. Haworth, E. Chambers, M. Kuraguchi, M. Xu, A.J. Redig, Kwok-Kin Wong, C.P. Paweletz, Pasi A Jänne
- Abstract
- Presentation
Background:
There are currently no effective targeted therapies for HER2 mutant lung cancer. Both neratinib alone or in combination with temsirolimus both have low response rates. One challenge is the lack of patient derived HER2 mutant cell line models and a platform in which to identify the most effective therapeutic strategy. Patient derived xenografts (PDXs) are emerging as an alternative tool to screen for drug efficacy, but can take months to generate and are impractical for screening of large sets of drug combinations. Here we report on a novel 3D microfluidic platform that allows for evaluating ex vivo responses to targeted therapies or targeted therapy combinations from patient derived tumor spheroids (xDOTS).
Method:
We generated xDOTS from DFCI 359, a PDX derived from a HER2 mutant (InsYVMA) NSCLC patient under an IRB approved protocol. Tumor organoids (<100 μm and >40μm) were treated with: HER2 covalent inhibitors (neratinib, afatinib); an EGFR inhibitor (gefitinib), and combinations of HER2 inhibitors and other compounds (neratinib/trastuzumab or neratinib/temsirolimus) at known peak plasma concentrations for 3 days in our 3D microfluidic cell culture device. Live/death quantification was performed by dual labeling de-convolution fluorescence microscopy using acridine orange for live and propidium iodide for dead cells. Cell type characterization was performed by immunofluorescence. The most effective combination was used to treat the DFCI 359 PDX and a HER2 InsYVMA genetically engineered mouse model (GEMM).
Result:
Both neratinib alone and afatinib alone, but not gefitinib, induced high degree of cell death in the DFCI 359 xDOTS. The combinations of neratinib/trastuzumab, and neratinib/temsirolimus enhanced the therapeutic benefit compared to neratinib alone, with the former combination being more effective than the latter. Using fluorescence microscopy we demonstrate that the effects are specific to the tumor cells, rather than the stromal component. We then went on to confirm these findings in a concomitant in-vivo efficacy experiment using the DFCI 359 PDX and the HER2 InsYVMA GEMM. In both in vivo models, the neratinib/trastuzumab combination led to significant tumor regressions and was superior to either single agents or the neratinib/temsirolimus combination.
Conclusion:
Our findings demonstrate the ability to use a 3-D in vivo microfluidic system to identify combination therapies for HER2 mutant NSCLC. Based on our studies, neratinib/trastuzumab is a promising combination for a clinical trial for HER2 mutant lung cancer.
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MA 07.13 - NGS Sequencing Based Liquid / Tissue Biopsy Identified Coexistence of HER2 Amplification and Mutation in Advanced NSCLC Patients (ID 9737)
15:45 - 17:30 | Presenting Author(s): Rongrong Chen | Author(s): J. Zhao, G. Lin, Li Liu, Likun Chen, X. Hu, Xinghao Ai, Z. Fan, Chunwei Xu, W. Wang, Wu Zhuang, Meiyu Fang, Y. Zhu, Gang Chen, Y. Guan, L. Yang, X. Xia, X. Yi
- Abstract
- Presentation
Background:
Human epidermal growth factor 2 (HER2, ERBB2) mutations / amplifications have been identified as oncogenic drivers in 2-5% of lung cancers. It has been reported that hybridization capture-based next-generation sequencing (NGS) could reliably detect HER2 amplification in qualified breast and gastroesophageal tumor tissue samples. However, there is little data in lung cancer, especially for advance NSCLC with only ctDNA samples available.
Method:
We reviewed 2000 consecutive samples from advanced NSCLC patients sequenced in our institute between 2015 and 2016. Tumor biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59 – 1021 genes).
Result:
We identified 54 samples from 48 patients with HER2-mutation or amplification in the cohort (54/2000=2.7%). The 54 samples included 14 tissue biopsy samples, 37 ctDNA samples, and 3 pleural effusion samples. Thirty-six samples carried HER2 mutations, and 23 samples carried HER2 amplification with 5 samples have concurrent HER2 mutation and amplification. A 9-base pair (bp) in-frame insertion in exon 20 (Y772_A775dup) was detected in 18 samples (18/36=50%). In addition, there were 5 other insertions in exon 20; eight single bp substitutions (S310F) in exon 8; three exon 17 V659E mutations (from the sample patient with 3 ctDNA samples submitted at different time); one exon 19 D769H mutation; and one exon 21 V842I mutation. Amplification were identified in 23 samples, with copy number range from 3.8 to 19.6 in tissue samples (n=7, medium 11.6); from 4.3 to 51.8 in ctDNA samples (n=16, medium 7.3); 3.2 and 6 in the 2 pleural effusion samples. Interestingly, the allele frequency (AF) of HER2 mutation was the maximal in 4 of the 5 patients with concurrent HER2 mutation and amplification. Two patients were EGFR-TKI resistant with EGFR L858R mutation remaining and HER2 mutation and amplification might be the major reason for the resistance.
Conclusion:
HER2 mutations might coexist with HER2 amplification in advanced NSCLC patients, and it could be detected simultaneously with hybridization capture-based NGS sequencing both in tissue and liquid biopsy samples. Further quantative analysis of HER2 amplification / mutation and anti-HER2 therapeutic effects are underway.
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MA 07.14 - Change in Practice Patterns from an Online NSCLC Treatment Decision Support Tool (ID 11066)
15:45 - 17:30 | Presenting Author(s): David R. Gandara
- Abstract
- Presentation
Abstract not provided
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MA 07.15 - Discussant - MA 07.11, MA 07.12, MA 07.13 (ID 10819)
15:45 - 17:30 | Presenting Author(s): Chia-Chi Lin
- Abstract
- Presentation
Abstract not provided
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MS 25 - Novel Molecular Targets (KRAS/MET/Novel Fusions): Druggable or Not? (ID 547)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:Rafael Rosell, Isamu Okamoto
- Coordinates: 10/18/2017, 14:30 - 16:15, Main Hall
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MS 25.05 - Novel Fusions (ID 7763)
14:30 - 16:15 | Presenting Author(s): Robert C. Doebele
- Abstract
- Presentation
Abstract:
Chromosomal rearrangements or deletions can generate novel gene fusions that lead to the expression of chimeric proteins with oncogenic activity in lung and other cancers. The paradigm for gene fusions in lung cancer is the EML4-ALK gene fusion which is found in approximately 5% of lung adenocarcinomas.[1] Once identified, drug development for this target proceeded rapidly and crizotinib was the first approved tyrosine kinase inhibitor for patients with ALK+ non-small cell lung cancer based on its ability to generate substation objective response rates and prolonged progression free survival (NSCLC).[3,4 ]The development of CNS penetrant and/or next generation ROS1 inhibitors including lorlatinib, entrectinib and TPX-0005 is ongoing. RET gene fusions are also found in 1-2% of NSCLC, but the use of multiple different RET inhibitors have failed to reproduce the success of targeting ALK or ROS1 fusions.[5 ]The development of more selective RET inhibitors such as LOXO-292, BLU-667, and RXDX-105 are currently in clinical trials for RET+ lung and other cancers. NTRK1 fusions were recently identified in NSCLC and homologous NTRK2 and NTRK3 fusions are found in multiple tumor types.[6,7, ]Early clinical trials of larotrectinib showed an impressive objective response rate of 76% for 12 different tumor histologies harboring NTRK1/2/3 fusions and the CNS-penetrant entrectinib is similarly being evaluated in a basket trial. Other rare, novel fusions have recently been identified in NSCLC including EGFR fusions or MET fusions.[7] Early evidence suggests that these fusions may also respond to cognate TKIs. EGFR fusions break the paradigm of ALK and ROS1 fusions in which the 5’ end of ALK or ROS1 is replaced with the 5’ portion of another gene. EGFR fusions retain most of the EGFR gene, with the unrelated gene sequencing fusing at the 3’ end of EGFR. A related oncogenic EGFR mutation in which the kinase domain of EGFR is duplicated in tandem has also been described and appears responsive to EGFR TKIs.[7] Additional fusions involving the receptor tyrosine kinase (RTK) encoding genes AXL, PDGFRA, and ERBB4 fusions have been described, but little is known about the true incidence in lung cancer.[8,9] The fusions described thus far all involve genes that encode RTKs, but additional gene fusions have also been identified in lung cancer including BRAF fusions.[7,9 ]BRAF fusions replace the 5’ region of BRAF, including the Ras-binding domain (RBD), with sequences from another gene. Anecdotal evidence suggest that these alterations may be responsive to MEK inhibition. Analogous splice alteration which remove a region including the RBD have also been described in cancer and are oncogenic. Finally, gene fusions involving NRG1, which encodes the HER3/4 ligand neuregulin-1, have been described, mostly in invasive mucinous adenocarcinomas of the lung.[9,10 ]Several challenges exist to the development of targeted therapies for these novel fusions. Even in the era of next-generation sequencing tests these alterations may go undetected due to limited testing of genes to those with approved therapies (ALK, ROS1, EGFR, and BRAF) and not all assays are designed to detect all of these alterations. Furthermore, the rarity of some of these alterations may make clinical trials for these novel fusions less appealing, although amalgamating some of these alterations with analogous mutations, e.g., MET gene fusions with MET exon 14 splice alterations or MET gene amplification, may allow for a more rapid path to approval. References 1. Chia PL, Mitchell P, Dobrovic A, et al: Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin Epidemiol 6:423-32, 2014 2. Camidge DR, Bang YJ, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. The lancet oncology 13:1011-9, 2012 3. Davies KD, Le AT, Theodoro MF, et al: Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 18:4570-9, 2012 4. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963-71, 2014 5. Gautschi O, Milia J, Filleron T, et al: Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry. J Clin Oncol 35:1403-1410, 2017 6. Vaishnavi A, Capelletti M, Le AT, et al: Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nature medicine 19:1469-72, 2013 7. Stransky N, Cerami E, Schalm S, et al: The landscape of kinase fusions in cancer. Nat Commun 5:4846, 2014 8. Seo JS, Ju YS, Lee WC, et al: The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22:2109-19, 2012 9. Nakaoku T, Tsuta K, Ichikawa H, et al: Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res 20:3087-93, 2014 10. Fernandez-Cuesta L, Plenker D, Osada H, et al: CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4:415-22, 2014
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.01 - The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC (ID 10369)
11:00 - 12:30 | Author(s): Robert C. Doebele
- Abstract
- Presentation
Background:
Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.
Method:
We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).
Result:
In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.
Conclusion:
Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.06 - Entrectinib in Patients with Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC) (ID 8564)
11:00 - 12:30 | Author(s): Robert C. Doebele
- Abstract
- Presentation
Background:
Entrectinib is a potent, investigational, CNS-active, oral inhibitor of ROS1 with a biochemical IC~50~ (0.2 nM) ~30 times more potent than crizotinib, the only agent approved for the treatment of ROS1-positive NSCLC. Previously, we reported an objective response rate of 85% in 13 ROS1 inhibitor-naïve NSCLC patients who were treated in Phase 1 studies (Drilon and Siena et al, Cancer Discov 2017), including 2 of 3 (67%) patients with CNS disease. Responses were durable, with 1 patient remaining on study for more than 3 years. Entrectinib was well tolerated, with predominantly Grades 1 or 2 adverse events that were reversible with dose modification.
Method:
Patients with ROS1 inhibitor-naïve NSCLC were enrolled across Phase 1 and 2 studies of entrectinib. Patients were screened for ROS1 gene fusions either locally or centrally at Ignyta’s diagnostic laboratory using next generation sequencing. Entrectinib was administered orally at 600 mg once-daily in 4-week cycles. Safety was assessed by monitoring adverse events, laboratory tests, and clinic visits. Tumor assessments were performed at the end of Cycle 1 and every 8 weeks thereafter. All scans were read locally (INV) and by blinded independent central review (BICR) using RECIST v1.1. INV results will be presented except where noted.
Result:
As of 24 May 2017, a total of 32 patients were evaluable for response (median age 52 years, 72% female). At a median follow-up of 12 months, objective responses were observed in 24 of 32 (75% [95% CI: 56.6, 88.5]; 3 complete responses) patients, including 7 of 11 (64% [95% CI: 30.8, 89.1]) patients with CNS disease at baseline. Five of 7 patients with evaluable CNS lesions by BICR experienced confirmed RECIST intracranial responses, for a CNS response rate of 71% (95% CI: 29.0, 96.3). With 19 (59%) patients remaining on study, the median duration of response was 17.2 months (95% CI: 6.5, 36.0) and progression-free survival was 19.1 months (95% CI: 6.5, 36.6). The most common (>15%) treatment-related adverse events were fatigue/asthenia (34%), dysgeusia (34%), dizziness (24%), weight increase (21%), paresthesia (19%), nausea (18%), constipation (18%), and diarrhea (16%). All data will be updated at the time of presentation.
Conclusion:
Entrectinib is well tolerated and has shown promising antitumor activity in ROS1 inhibitor-naïve NSCLC, including patients with CNS disease. Patients with ROS1+ NSCLC and other tumor types continue to be enrolled in STARTRK-2 (NCT02568267) in order to support a potential regulatory filing for entrectinib in this population.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-057 - Comparison of Molecular Testing Modalities for Detection of ROS1 Rearrangements in a Cohort of Positive Patient Samples (ID 10110)
09:30 - 16:00 | Author(s): Robert C. Doebele
- Abstract
Background:
Targeting oncogenic gene fusions with small molecules has proven to be a highly successful treatment strategy in lung cancer. For ALK and ROS1 rearrangement/fusion positive cases, fusion directed therapy is now considered standard of care for advanced disease. Consequently, the accurate clinical detection of rearrangements/fusions is of critical clinical importance. Multiple distinct methodologies are employed in the clinical setting for rearrangement/fusion detection. In this study, we compare the performance of several of these methodologies on a large cohort of ROS1 rearrangement/fusion-positive patient samples.
Method:
Eighteen ROS1 rearrangement/fusion-positive clinical samples were assessed by at least two of the following molecular testing methodologies: break-apart fluorescence in situ hybridization (FISH), DNA-based hybrid capture library preparation followed by next-generation sequencing (NGS), and RNA-based anchored multiplex PCR library preparation followed by NGS.
Result:
None of the testing methodologies demonstrated 100% sensitivity in detection of ROS1 rearrangements/fusions. FISH results were negative in 2/18 tested clinical samples. One of these demonstrated an atypical staining pattern, suggestive of a complex rearrangement. The other occurred in a case of GOPC-ROS1 fusion in which the genes are in close proximity on chromosome 6. The DNA-based NGS assay was negative in 3/11 tested clinical samples. This assay suffered from poor bait coverage in intronic regions containing repetitive sequences, and false negatives were likely due to this deficiency. The RNA-based NGS assay did not identify ROS1 fusions in 3/15 tested clinical samples. However, this assay is highly reliant on RNA quality, and missed calls were associated with metrics derived from the assay suggestive of degraded RNA (and thus the results would have been deemed uninformative). Additionally, we report cases in which the detected fusion at the transcript level (via RNA-based NGS) occurred between exons not predicted by proximal exons bordering the detected genomic breakpoint (via DNA-based NGS), likely due to exon removal via mRNA splicing. For these cases, the detected genomic DNA breakpoint may have resulted in a non-call due to the prediction of an out-of-frame fusion transcript.
Conclusion:
Rearrangement/fusion detection in the clinical setting is complex and all methodologies have inherent limitations that users must be aware of. Consequently, careful scrutiny of negative results must be performed, particularly in cases negative for other known oncogenic drivers (pan-negative cases). Ideally, orthogonal rearrangement/fusion testing methodologies should be employed for such cases.
