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D. Ross Camidge
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ES 08 - Molecular Diagnostics and Targeted Therapy (ID 517)
- Event: WCLC 2017
- Type: Educational Session
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:Kwun M Fong, David Planchard
- Coordinates: 10/18/2017, 11:00 - 12:30, Main Hall
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ES 08.03 - Update of the Management of ALK-Positive NSCLC (ID 7616)
11:30 - 11:45 | Presenting Author(s): D. Ross Camidge
- Abstract
- Presentation
Abstract:
ALK positive NSCLC represents 2-7% of advanced NSCLC. Three ALK TKIs have shown positive first line trials against either platinum-doublet chemotherapy (ceritinib and crizotinib) or against crizotinib (alectinib). At least three other first line trials against crizotinib are ongoing (brigatinib, ensartinib and lorlatinib). Activity of different ALK TKIs post crizotinib are characterized by comparable response rates but differing toxicity profiles, durations of benefit and extent of CNS activity. With changes in the first line standard, data post non-crizotinib ALK TKIs continues to emerge with attendant caution re the applicability of both biological and clinical data currently available for clinical decision making. Advances in our understanding of CNS trial endpoints has also helped facilitate cross trial comparisons of CNS activity of these different agents. Chemotherapeutic, radiotherapeutic and immunotherapeutic options other than ALK TKIs have all generated different clinical datasets - defining both some reasonable clinical options and some clearly in need of additional research.
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.10 - Phase I Study of ABBV-399 (Telisotuzumab Vedotin) as Monotherapy and in Combination with Erlotinib in NSCLC (ID 9466)
12:05 - 12:10 | Author(s): D. Ross Camidge
- Abstract
- Presentation
Background:
The c-Met receptor is overexpressed in ~50% of patients (pts) with non-small cell lung cancer (NSCLC). ABBV-399 is a first-in-class antibody-drug conjugate composed of ABT-700, an anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data demonstrate that ABBV-399 can deliver a potent cytotoxin directly to c-Met+ tumor cells.
Method:
ABBV-399 was administered at doses ranging from 2.4 to 3.0 mg/kg (dose expansion and combination cohorts at 2.7 mg/kg) once every 21 days to 29 pts with advanced c-Met+ (immunohistochemistry [IHC] H-score ≥150) NSCLC both as monotherapy (ABBV-399/monotherapy; 16 pts) and in combination with oral erlotinib 150 mg daily (ABBV-399/ERL; 13 pts) (NCT02099058). c-Met expression was assessed by IHC utilizing the SP44 antibody (Ventana; Tucson, AZ, USA).
Result:
As of April 26, 2017, 16 pts with c-Met+ NSCLC received ≥1 dose of ABBV-399/monotherapy. Monotherapy treatment-related adverse events (TRAEs) occurring in ≥10% of pts (all dose levels and all grades) were fatigue (43.8%), nausea (37.5%), neuropathy (25.0%), vomiting (18.8%), anemia, constipation, and diarrhea (12.5% each). Three of 16 (19%) ABBV-399–treated c-Met+ NSCLC pts had a confirmed partial response (PR) with duration of response (DOR) 3.1, 4.8, and 11.1 months. At week 12, 9 of 16 pts (56.3%) had disease control. TRAEs in ABBV-399/ERL occurring in ≥10% of pts (all grades) were neuropathy (46.2%), nausea (23.1%), fatigue, acneiform rash, dry skin, and diarrhea (15.4% each). Four of 13 (31%) evaluable ABBV-399/ERL–treated c-Met+ pts had a PR (3 confirmed, 1 unconfirmed) with DOR 2.8, 5.3, 4.2+, and 9.1+ months. Three of the 4 pts with PR had EGFR-mutated tumor and recently progressed on TKI. At week 12, 10 of 13 pts (76.9%) had disease control. There were no treatment-related deaths as monotherapy or in combination with erlotinib. Responses were seen in both squamous and non-squamous histology.
Conclusion:
ABBV-399 is well tolerated at 2.7 mg/kg once every 21 days and has demonstrated antitumor activity in pts with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Early evidence suggests that ABBV-399 represents a novel treatment paradigm effective against multiple c-Met+ NSCLC molecular subtypes and histologies. Updated efficacy/safety data and c-Met IHC status will be presented. Safety and efficacy data from Q2week dosing of ABBV-399 will also be presented.
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- 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 - 15:50 | Author(s): D. Ross Camidge
- 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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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.05 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial (ID 8027)
16:30 - 16:40 | Author(s): D. Ross Camidge
- Abstract
- Presentation
Background:
Brigatinib, a next-generation ALK inhibitor, recently received accelerated approval in the United States for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. We report updated data from the randomized phase 2 trial (ALTA; NCT02094573), which was designed to investigate the efficacy and safety of 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC.
Method:
Patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib and randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.
Result:
Among 222 patients (n=112/n=110, arm A/B), median age was 51/57 years; 71%/67% had brain metastases. As of February 21, 2017, 17 full months since the last patient enrolled, median follow-up was 16.8/18.6 months and 32%/41% of patients continued to receive brigatinib in A/B. The table shows brigatinib efficacy. Per independent review committee, confirmed ORR was 51%/55% and median PFS was 9.2/16.7 months in A/B. Among patients with measurable baseline brain metastases (n=26/n=18, A/B), confirmed intracranial ORR was 50%/67% as of January 24, 2017; median intracranial DoR was not reached/16.6 months. The most common treatment-emergent adverse events (TEAEs) were: nausea (38%/47%, A/B), diarrhea (28%/44%), cough (28%/40%), headache (30%/35%), and vomiting (36%/30%); the most common grade ≥3 TEAEs were: increased creatine phosphokinase (5%/13%), hypertension (6%/8%), pneumonia (4%/5%), and increased lipase (5%/4%). Dose reduction (9%/30%, A/B) or discontinuation (4%/11%) due to TEAEs was reported.
Conclusion:
In ALTA, brigatinib continues to show substantial efficacy and acceptable safety at both dose levels, with numerically longer PFS and higher intracranial ORR at the recommended dosing regimen of 180 mg qd (with lead-in) vs 90 mg qd.Investigator Assessment Independent Review[a] Arm A (n=112) Arm B (n=110) Arm A (n=112) Arm B (n=110) Confirmed ORR, % 46 (35–57[b]) 55 (44–66[b]) 51 (41–61[c]) 55 (45–64[c]) Median DoR in responders,[d] months 12.0 (9.2–17.7[c]) 13.8 (10.2–17.5[c]) 13.8 (7.4–NR[c]) 14.8 (12.6–NR[c]) Median PFS,[d] months [% of events] 9.2 (7.4–11.1[c]) [65] 15.6 (11.1–19.4[c]) [50] 9.2 (7.4–12.8[c]) [54] 16.7 (11.6–NR[c]) [41] Median OS,[d] months [% of events] NR (20.2–NR[c]) [38] 27.6 (27.6–NR[c]) [29] — — 1-year OS probability,[d ]% 70 (61–78[c]) 80 (71–87[c]) — — DoR, duration of response NR, not reached OS, overall survival PFS, progression-free survival [a]Last scan date: February 28, 2017 [b]97.5% CI for primary endpoint [c]95% CI [d]Kaplan-Meier estimate
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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 12.06 - Plasma Genomic Profiling and Outcomes of Patients with MET Exon 14-Altered NSCLCs Treated with Crizotinib on PROFILE 1001 (ID 9385)
11:50 - 12:00 | Author(s): D. Ross Camidge
- Abstract
- Presentation
Background:
MET exon 14 alterations occur in ~4% of non-squamous non-small cell lung cancers (NSCLCs). Treatment with the MET inhibitor, crizotinib, achieves confirmed and durable responses in patients with MET exon 14-altered NSCLCs, underscoring the need to test for these drivers (as of August 1, 2016, objective response rate was 39% and median duration of response was 9.1 months). Comprehensive molecular tumor profiling is required to detect MET exon 14 alterations that are highly heterogeneous. The utility of plasma profiling to detect these drivers has not previously been explored in a prospective trial.
Method:
Patients with advanced NSCLCs harboring MET exon 14 alterations by local tumor profiling performed in a CLIA-certified or equivalent environment were treated with crizotinib at 250 mg twice daily on an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195). Objective response was assessed by RECIST v1.0. Prospective plasma profiling of circulating tumor DNA (ctDNA) for MET exon 14 alterations was performed using the PlasmaSELECT64 targeted gene panel (sequencing and analysis output by Personal Genome Diagnostics, Boston MA).
Result:
Plasma samples were obtained for MET exon 14 alteration analysis after study amendment approval in 20 of 52 crizotinib-treated patients, of which 18 samples were deemed sufficient for analysis. MET exon 14 alterations were detected in ctDNA in 11 of 18 patients (61% agreement of plasma ctDNA testing with tumor testing) mapping to the same exon 14 splice site region in 10 of the 11 cases. Of the 11 patients with ctDNA-positive tumors, all were evaluable for response. Of these evaluable patients, a confirmed partial response and stable disease were observed in 2 and 4 patients, respectively.
Conclusion:
MET exon 14 alterations can be detected in plasma ctDNA in a subset of patients with advanced NSCLCs that harbor MET exon 14 alterations by tumor testing. Responses to crizotinib were observed in patients with ctDNA-positive testing for a MET exon 14 alteration. Plasma profiling should be considered as an adjunct to tumor profiling in screening patients for MET exon 14 alterations, pending further confirmation.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 5
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-001 - Depth of Target Lesion Response to Brigatinib and Its Association With Outcomes in Patients With ALK+ NSCLC in the ALTA Trial (ID 8035)
09:30 - 09:30 | Presenting Author(s): D. Ross Camidge
- Abstract
Background:
Depth of target lesion response to crizotinib has been associated with overall survival (OS) (J Clin Oncol 2016;34:abstract 2590). ALTA (NCT02094573) is an ongoing randomized phase 2 trial of brigatinib, an ALK inhibitor, in crizotinib-refractory advanced ALK+ NSCLC patients. As the ALTA primary endpoint of confirmed objective response rate (cORR), a binary outcome, might not fully capture clinical benefit, we examined the association of maximum decrease in target lesions with progression-free survival (PFS) and OS.
Method:
Patients were randomized to receive brigatinib at 90 mg qd (arm A; n=112) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110). Arms were pooled in this analysis. Patients with any target lesion shrinkage were sorted into 4 groups based on greatest decrease from baseline per RECIST v1.1; outcomes in these groups were compared with outcomes in patients with no shrinkage.
Result:
As of February 21, 2017, cORR in arm A/B (ITT population) was 46%/55% per investigators. 201/222 patients had ≥1 evaluable response assessment with 18.4-month median follow-up. Median age of these patients was 53 years; 57% were female. Patients with target lesion shrinkage (vs none) had numerically longer PFS (hazard ratios [95% CIs]: 0.61 [0.30–1.22], 1%–25% shrinkage; 0.47 [0.24–0.91], 26%–50%; 0.54 [0.28–1.05], 51%–75%; 0.30 [0.15–0.63], 76%–100%) and numerically higher estimated 1-year OS (Table). In a multivariable analysis, 76%–100% shrinkage (vs none) was independently associated with longer PFS/OS (hazard ratios [95% CIs]: 0.37 [0.18–0.76]/0.35 [0.14–0.89]); arm B (vs A) was independently associated with longer PFS.
Conclusion:
In this exploratory post hoc analysis, brigatinib-treated patients with target lesion shrinkage, including those without confirmed partial response, had improved PFS/OS vs patients without shrinkage. Patients with the deepest response (76%–100% shrinkage) appeared to have the longest PFS and higher estimated 1-year OS.Best Target Lesion Shrinkage n (%)[a] Median PFS,[b,c] Months (95% CI) Median OS,[b ]Months (95% CI) 1-year OS,[b ]% (95% CI) None 18 (9) 3.7 (1.9–11.0) 8.3 (4.7–NR) 48 (22–99) 1%–25% 40 (20) 9.3 (4.0–21.2) NR (14.5–NR) 75 (58–99) 26%–50% 60 (30) 12.8 (9.2–15.7) NR (NR–NR) 82 (70–99) 51%–75% 44 (22) 11.1 (7.4–18.2) 27.6 (20.2–NR) 77 (62–99) 76%–100% 39 (19) 19.5 (12.6–NR) NR (22.3–NR) 92 (78–99) NR, not reached [a]Evaluable patients [b]Kaplan-Meier estimate [c]Per investigator
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P1.01-004 - Hypertension With Brigatinib: Experience in ALTA, a Randomized Phase 2 Trial in Crizotinib-Refractory ALK+ NSCLC (ID 8346)
09:30 - 09:30 | Presenting Author(s): D. Ross Camidge
- Abstract
Background:
The next-generation ALK inhibitor brigatinib received accelerated approval in the United States in April 2017 for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. Hypertension has been identified as an adverse event of interest with brigatinib treatment based on prior clinical data; here, we report incidence, management, and outcomes of hypertension in ALTA (NCT02094573).
Method:
In ALTA, 222 patients were randomized 1:1 to receive brigatinib at 90 mg qd (arm A; n=112 randomized, n=109 treated) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110 randomized and treated). A medical history of hypertension was allowed, but patients with significant, uncontrolled, or active cardiovascular disease were excluded. Blood pressure (BP) was measured at screening, on days 1, 8, and 15 of the first 28-day cycle, and then every 4 weeks (starting on day 1 of cycle 2).
Result:
Median age was 50/57 years in treated patients in A/B; 22%/25% of treated patients in A/B had a history of hypertension at baseline. As of February 21, 2017, hypertension was reported as a treatment-emergent adverse event (TEAE; any grade) in 17%/27% of patients (A/B) and as a grade 3 TEAE in 6%/8%; no grade 4 hypertension was reported. Few patients had dose interruptions (1%/2%, A/B) or reductions (1%/1%) due to hypertension; no patients discontinued brigatinib due to hypertension. Among patients with hypertension, median time to onset of first hypertension TEAE was 5.8 months/2.1 months in A/B. Among patients with baseline systolic BP <120 mmHg (n=50/n=48, A/B), 20%/42% had a maximum shift to 140–159 mmHg postbaseline (6%/10%, <120 mmHg to ≥160 mmHg); among patients with baseline diastolic BP <80 mmHg (n=68/n=72, A/B), 29%/35% had a maximum shift to 90–99 mmHg postbaseline (10%/8%, <80 mmHg to ≥100 mmHg). Among patients with hypertension TEAEs (n=19/n=30, A/B), 84%/80% started a new antihypertensive medication during the study. Among patients with hypertension TEAEs and no medical history of hypertension (n=11/n=20, A/B), 73%/70% started a new antihypertensive medication during the study. Cardiovascular events in patients with hypertension TEAEs included: angina pectoris in 1 patient without a medical history of hypertension and, in patients with a medical history of hypertension, hypertensive retinopathy (n=1), intermittent claudication (n=1), and peripheral artery stenosis (n=1).
Conclusion:
Hypertension was observed frequently with brigatinib, and appeared dose-related, but was managed with antihypertensive therapy and rarely led to dose modification or discontinuation.
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P1.01-005 - Overall Survival (OS) After Disease Progression (PD) on Brigatinib in Patients With Crizotinib-Refractory ALK+ NSCLC in ALTA (ID 8546)
09:30 - 09:30 | Author(s): D. Ross Camidge
- Abstract
Background:
Brigatinib, a next-generation ALK inhibitor, has been associated with a median progression-free survival of approximately 16 months in ALTA, a randomized phase 2 trial (NCT02094573) investigating 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC. This post hoc analysis explores the clinical benefit of continuing brigatinib beyond PD in ALTA.
Method:
Patients were randomized to arm A (brigatinib 90 mg qd; n=112) or B (brigatinib 180 mg qd with 7-day lead-in at 90 mg; n=110). Patients in arm A were permitted to escalate to 180 mg qd after RECIST PD. 107 patients who had PD on brigatinib, did not have PD as their best response, and survived ≥21 days post-PD were analyzed here.
Result:
As of February 21, 2017, 84 patients continued and 23 discontinued brigatinib treatment post-PD. Estimated 1-year OS after first PD and OS hazard ratios (HRs; unadjusted and adjusted) are shown in the table. Unadjusted HRs indicated significantly longer OS in patients who continued brigatinib vs those who did not (HR: 0.32 [95% CI, 0.17–0.62]), particularly those who continued at 180 mg. Patients who were more heavily pretreated, had longer duration of brigatinib therapy before PD, did not progress due to new lesions, had confirmed objective response, and had better ECOG performance status at PD were more likely to continue brigatinib post-PD. Adjusted HRs indicated numerically longer OS in patients who continued brigatinib (HR: 0.53 [95% CI, 0.26–1.08]). Number of prior regimens (2 vs ≥3), shorter time to investigator-assessed PD, PD due to new lesions only, and ECOG performance status at PD (≥2 vs 0) were independently associated with worse OS (P<0.05).
Conclusion:
Survival was better among patients who continued vs discontinued brigatinib after PD. Continuing brigatinib, especially at 180 mg, could be one of many factors associated with longer OS after PD in these patients.Patients With PD on Brigatinib (n=107) n 1-Year OS Post-PD,[a] % (95% CI) Unadjusted HR (95% CI) Adjusted HR[b] (95% CI) Continued brigatinib 84 66(53–99) 0.32(0.17–0.62) 0.53(0.26–1.08) At 90 mg qd (arm A without escalation) 23 62(38–99) 0.49(0.22–1.11) 0.61(0.25–1.46) At 180 mg qd 61 68 (51–99) 0.26(0.13–0.54) 0.48(0.21–1.06) Arm A with escalation 23 70(44–99) 0.29(0.12–0.72) 0.51(0.19–1.33) Arm B 38 66(44–99) 0.25(0.11–0.57) 0.45(0.18–1.16) Did not continue brigatinib 23 31(13–100) Reference Reference [a]Kaplan-Meier estimate from time of first PD [b]Adjusted for duration of prior crizotinib exposure, number of prior treatment regimens (1, 2, or ≥3), time to investigator-assessed PD, PD due to new lesions only (yes/no), and ECOG performance status at PD (0, 1, or ≥2)
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P1.01-012 - Ceritinib in Anaplastic Lymphoma Kinase (ALK)+ NSCLC Patients Pretreated With Only Crizotinib: ASCEND-1 Subgroup Analysis (ID 8972)
09:30 - 09:30 | Author(s): D. Ross Camidge
- Abstract
Background:
In phase 1 ASCEND-1 study (NCT01283516), ceritinib 750 mg/day (fasted) demonstrated durable whole-body and intracranial responses in both anaplastic lymphoma kinase inhibitor (ALKi)-naïve and ALKi-pretreated patients with ALK-rearranged non-small cell lung cancer (NSCLC). Here, we report the efficacy and safety of ceritinib in patients who were pretreated with crizotinib only from the ASCEND-1 study.
Method:
Patients with ALK+ NSCLC who were enrolled globally received ceritinib 750 mg/day (fasted). Efficacy and safety were evaluated in a subset of patients who had received prior crizotinib only (no other prior antineoplastic therapy). Data cut-off was May 03, 2016.
Result:
Overall, 246 patients with ALK+ NSCLC (83 ALKi-naïve and 163 ALKi-pretreated) received ≥1 dose of ceritinib, of whom, 26 had received prior crizotinib only. Among the 26 crizotinib-pretreated patients, 11 (42.3%) had baseline brain metastases, of which, 7 received prior radiotherapy, 6 (23.1%) had an ECOG performance status of 0, and 24 (92.3%) patients had stage IV disease. The median time from initial diagnosis to ceritinib initiation was 10.5 months (range, 2.4-33.0). At data cut-off, the median duration of exposure (range) was 41.0 weeks (2.9-180.4). In the 26 crizotinib-pretreated patients, per investigator assessment, the overall response rate was 65.4% (95% confidence interval [CI]: 44.3, 82.8), and the disease control rate was 80.8% (95% CI: 60.6, 93.4) (Table). The most frequently reported grade 3/4 adverse events (AEs), regardless of study drug relationship, were ALT increased (30.8%), AST increased (15.4%), diarrhea (11.5%), nausea (7.7%), fatigue (7.7%), and blood alkaline phosphatase increased (7.7%). All 26 patients discontinued treatment due to disease progression (n=12), consent withdrawal (n=6), AEs (n=2), administrative problems (n=4), or death (n=2).
*Median value derived from summary statistics; **Median value estimated by Kaplan-Meier method.Investigator Assessment N=26 Blinded Independent Review Committee Assessment N=26 Best overall response Complete response (CR), n (%) 1 (3.8%) 1 (3.8%) Partial response (PR), n (%) 16 (61.5%) 15 (57.7%) Stable disease (SD), n (%) 4 (15.4%) 5 (19.2%) Progressive disease (PD), n (%) 2 (7.7%) 1 (3.8%) Unknown, n (%) 3 (11.5%) 4 (15.4%) Overall response rate (ORR), % [95% CI] 65.4% [44.3-82.8] 61.5% [40.6-79.8] Disease control rate (DCR), % [95% CI] 80.8% [60.6-93.4] 80.8% [60.6-93.4] Median time to response*, weeks [95% CI] 6.1 [5.1-23.6] 6.4 [5.1-14.0] Median DOR**, months [95% CI] 8.3 [4.2-11.2] 8.5 [3.0-13.6] Median PFS**, months [95% CI] 8.5 [5.3-9.9] 8.2 [4.4-15.2]
Conclusion:
Ceritinib demonstrated durable efficacy in crizotinib-pretreated patients with ALK-rearranged NSCLC. Safety was consistent with the overall ASCEND-1 study population.
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P1.01-016 - Next-Generation Sequencing Shows Mechanisms of Intrinsic Resistance in ALK-Positive NSCLC Patients Treated with Crizotinib (ID 9514)
09:30 - 09:30 | Author(s): D. Ross Camidge
- Abstract
Background:
Crizotinib (XALKORI®) is a small molecule ALK, ROS1, and c-MET tyrosine kinase inhibitor approved for the treatment of patients with ALK-positive or ROS1-positive metastatic NSCLC. PROFILE 1005 was a single arm phase 2 study of the safety and efficacy of crizotinib in previously treated patients with advanced NSCLC that is ALK-positive as determined by the investigational use only FISH test or on a case-by-case basis using a local FISH, IHC or RT-PCR laboratory developed test. In this study 54.1% of patients exhibited a confirmed complete or partial response to crizotinib (responders) by investigator assessment, while 9.9% had a best overall tumor response of progressive disease (progressors). The objective of this analysis was to investigate mechanisms of intrinsic resistance to crizotinib by comparing progressors with responders through a targeted cancer gene panel of next-generation sequencing (NGS).
Method:
Archival tumor tissue used to screen patients for enrollment was analyzed using the FoundationOne NGS panel (Cambridge, MA). Results of the analyses from tumor tissue positive by ALK FISH were compared for a subgroup of progressors (N=22) with a randomly selected subgroup of responders (N=25).
Result:
There was a higher proportion of patients who were ALK-negative by NGS in progressors (8 of 22; 36%) as compared to responders (3 of 25; 12%) (p=0.083), including 5 patients with oncogenic driver mutations in KRAS (G12S, Q61H, amp), EGFR (L858R) and BRAF (G469A). Among responders, 4 patients (16%) had non-EML4 ALK fusions (KIDINS220, EDC4, DTWD2, AFF2) while no such case was detected in progressors. TP53 mutations were detected in 10 progressors (45%) and 5 responders (20%) (p=0.115). Excluding NGS-negative patients, TP53 mutations were detected in 7 of 14 progressors (50%) and 3 of 22 responders (13%) (p=0.026).
Conclusion:
In the small percentage of patients with ALK-positive NSCLC with a best response of progression upon treatment with crizotinib, a higher proportion are ALK-negative by NGS, representing either a technical false-positive or an accurate FISH result reflecting a non-activating gene rearrangement that is not detected by NGS. TP53 mutations were observed at a higher frequency in progressors than in responders in patients with ALK-positive NSCLC by both FISH and NGS. Both technical and biologic factors thus may contribute to apparent intrinsic resistance in patients with ALK-positive NSCLC treated with crizotinib.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-011 - Clinical and Molecular Features of Lung Cancers with Increased FGFR1 mRNA and/or Gene Copy Number (ID 8825)
09:30 - 09:30 | Author(s): D. Ross Camidge
- Abstract
Background:
Lung cancer cell line data suggest FGFR1 status defined by FGFR1 mRNA levels and FGFR1 gene copy number can predict sensitivity to FGFR tyrosine kinase inhibitors (TKIs).
Method:
A phase II biomarker preselected trial of ponatinib, an FGFR1, FGFR2, and FGFR4 targeted TKI was designed. Patients with metastatic EGFR- and ALK-negative lung cancers (both NSCLC and SCLC) were pre-screened for FGFR1 mRNA levels by in-situ hybridization (ISH) and FGFR1 gene copy number by silver in-situ hybridization (SISH). Positivity criteria for ISH were defined as a score of 3 (Dot clusters seen in 1 to <10% tumor cells; otherwise >10 dots/cell in ≥ 10% tumor cells), or 4 (Dot clusters seen in ≥ 10% of tumor cells). Positivity for SISH was defined as an average of ≥ 4 FGFR1 signal clusters/nucleus or FGFR1/CEN8 ratio ≥ 2.0. Clinical factors including sex, histology, age and sites of metastases at diagnosis of stage IV disease, smoking status, status of other known molecular drivers, and response to initial platinum-doublet therapy for stage IV disease were collected.
Result:
From 11/2013 to 05/2017, the study has pre-screened 163 patient samples for FGFR1 ISH and SISH. Thirty-eight (23.3%) had insufficient tissue; four had incomplete clinical or FGFR1 information. Clinical variables according to FGFR1 ISH/SISH status (n=121) are summarized in Table 1. Impact of alternate positivity cut-points, outcomes of patients treated with ponatinib and survival analysis according to ISH/SISH subgroups will be presented. Figure 1
Conclusion:
Although the numbers were small, the FGFR1 ISH+/SISH+ subgroup had a greater percentage small cell histology, liver metastases at diagnosis and male sex compared to other FGFR1 subgroups. FGFR1 ISH and/or SISH positivity can overlap with other known oncogenic drivers suggesting that the initial cut-points for FGFR1 positivity used may be too low to identify a true FGFR1 addicted state.
