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S.N. Gettinger
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MINI 08 - Prognostic/Predictive Biomarkers (ID 106)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T.E. Stinchcombe, N. Pavlakis
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI08.04 - VeriStrat® and Epidermal Growth Factor Receptor Mutation Status in a Phase 1b/2 Study of Cabozantinib +/- Erlotinib in Non-Small Cell Lung Cancer (ID 552)
16:45 - 18:15 | Author(s): S.N. Gettinger
- Abstract
- Presentation
Background:
VeriStrat is a blood-based multivariate proteomic test that predicts response to second line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy in non-small cell lung cancer (NSCLC). We report a retrospective blinded analysis of VeriStrat classification in plasma samples from a phase 1b/2 trial of cabozantinib (C) +/- erlotinib (E) in metastatic NSCLC patients who had all progressed after benefiting from EGFR TKI therapy. Cabozantinib inhibits the MET/hepatocyte growth factor (HGF) pathway, and VeriStrat may be a surrogate marker for this pathway.
Methods:
Patients enrolled into phase 1b (1A:60 mg C+150 mg E, 2A:60 mg C+100 mg E, 3A:100 mg C+100 mg E, 4A:100 mg C+50 mg E, 2B:40 mg C+150 mg E) and phase 2 (Arm A:100 mg C, Arm B:100 mg C+50 mg E). EGFR mutation (EGFRm) status was tested on archival tissue and/or plasma when available. The primary objective was to determine if pre-treatment VeriStrat (VS) classification, good or poor, was prognostic for patients treated with cabozantinib +/- erlotinib. Kaplan-Meier method and log-rank test was used to compare progression-free survival (PFS) of VS-good v. VS-poor patients. Outcomes were stratified by EGFRm status (mutated v. wild type WT/unknown UNK).
Results:
Of 79 evaluable patients, 71 were classified as VS-good and 8 as VS-poor. 55.7% had an activating EGFRm (majority exon 19 del/exon 21 L858R) and 12.7% had UNK EGFRm status. There were no significant differences in patient characteristics between VeriStrat-groups. VS-good patients had a statistically improved PFS: VS-good 3.7 mo. (95% CI 3.5-5.4) v. VS-poor 1.9 mo. (95% CI 1.1-3.4), p=0.014. This was still true after excluding 14 patients who had received cabozantinib alone (p=0.005). There was no difference in PFS for VS-good patients when stratified by EGFRm status. There was also no difference in PFS for VS-poor patients with WT/UNK EGFR v. VS-good patients irrespective of EGFRm status. However, VS-poor patients with WT/UNK EGFR had improved PFS compared to VS-poor patients with an EGFRm (3.1 mo. v. 1.6 mo., HR 0.15, 95% CI 0.03-0.68).
Conclusion:
VeriStrat is a strong prognostic marker in this study. This study suggests cabozantinib neutralized the worse prognosis of VS-poor patients with WT/UNK EGFR. Given the heterogeneity of treatment dosing, the small number of VS-poor patients, and a high proportion of unknown EGFRm (including T790M) status, this analysis should be considered exploratory.
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MS 21 - Immunotherapy Predictive Biomarkers (ID 39)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:K. Fong, P. Dennis
- Coordinates: 9/09/2015, 14:15 - 15:45, Four Seasons Ballroom F1+F2
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MS21.04 - Search for Genetic/Molecular Predictors of Immune Checkpoint Therapy - Role of KRAS, LKB1, Other Genetic Markers as Predictors for Immunotherapy (ID 1944)
14:15 - 15:45 | Author(s): S.N. Gettinger
- Abstract
- Presentation
Abstract not provided
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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 3
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.05 - Safety and Efficacy of First-Line Nivolumab (NIVO; Anti-Programmed Death-1 [PD-1]) and Ipilimumab in Non-Small Cell Lung Cancer (NSCLC) (ID 786)
10:45 - 12:15 | Author(s): S.N. Gettinger
- Abstract
- Presentation
Background:
Combined blockade of the PD‐1 and cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) immune checkpoint pathways has shown improved responses, encouraging survival rates, and a manageable safety profile in advanced melanoma. NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has activity across NSCLC histologies and is approved in the US for treatment of metastatic squamous (SQ) NSCLC with progression on or after platinum-based chemotherapy. This phase 1 study evaluated the safety and efficacy of first‐line therapy with NIVO plus ipilimumab (IPI), an IgG1 CTLA‐4 checkpoint receptor blocking antibody, in chemotherapy‐naïve patients with advanced NSCLC.
Methods:
Patients (N=49) received NIVO plus IPI at the 1+3 mg/kg or 3+1 mg/kg combination dose, respectively (one SQ and one non‐SQ cohort per dose level), every 3 weeks for 4 cycles, followed by NIVO 3 mg/kg every 2 weeks until progression or unacceptable toxicity. Objective response rate (ORR; RECIST v1.1) was evaluated overall and by baseline tumor PD‐1 ligand 1 (PD‐L1) expression (PD‐L1[+]: ≥5% tumor cells expressing PD‐L1). Response was assessed at weeks 10, 17, and 23, and every 3 months thereafter until progression.
Results:
Median follow‐up for all patients was 50 weeks. Across histologies, confirmed ORR was 13% (3/24) for NIVO1+IPI3 and 20% (5/25) for NIVO3+IPI1. Two of 3 and 4/5 responders in the NIVO1+IPI3 and NIVO3+IPI1 arms, respectively, achieved a response by first scan. Median duration of response was not reached (NR) in either group, and responses were ongoing in 67% (2/3) and 60% (3/5) of patients treated with NIVO1+IPI3 and NIVO3+IPI1, respectively. Two patients in the NIVO3+IPI1 group exhibited an unconventional “immune-related” response with 56% and 64% maximum reductions in target lesions and simultaneous appearance of new lesions. The 24-week progression-free survival (PFS) rates and median PFS were 44% and 16.1 weeks, respectively, for NIVO1+IPI3 and 33% and 14.4 weeks, respectively, for NIVO3+IPI1. One-year overall survival (OS) rates and median OS were 65% and NR, respectively, for NIVO1+IPI3 and 44% and 47.9 weeks, respectively, for NIVO3+IPI1. Thirty-eight of 49 treated patients were evaluable for PD-L1 expression; objective responses were observed in PD‐L1[+] (19%, 3/16) and PD‐L1[-] (14%; 3/22) patients. Across arms, grade 3–4 treatment-related adverse events (AEs) were reported in 25 patients (51%); grade 3 pneumonitis was reported in 3 (6%) patients. Treatment‐related AEs led to discontinuation in 18 patients (37%); 15 (31%) patients discontinued treatment during induction. Treatment‐related deaths (n=3) were due to respiratory failure, bronchopulmonary hemorrhage, and toxic epidermal necrosis.
Conclusion:
Treatment with NIVO plus IPI was associated with durable responses and encouraging survival regardless of tumor PD-L1 expression. The safety profile was managed using established safety guidelines. Updated OS and results from additional doses and schedules will be presented.
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ORAL02.06 - Evaluation of PD-L1 Expression in Metachronous Tumor Samples and FDG-PET as a Predictive Biomarker in Ph2 Study (FIR) of Atezolizumab (MPDL3280A) (ID 2207)
10:45 - 12:15 | Author(s): S.N. Gettinger
- Abstract
- Presentation
Background:
PD-L1 expression on tumor-infiltrating immune cells (IC) and/or tumor cells (TC) can inhibit antitumor immunity. Atezolizumab (MPDL3280A) is an anti-PDL1 antibody that has shown efficacy across multiple tumor types. The efficacy and safety of atezolizumab in the Phase 2 FIR study has been reported previously (Spigel et al, ASCO 2015). Efficacy appeared to correlate with PD-L1 expression on IC and/or TC, with higher ORRs observed in patients with the highest expression of PD-L1, indicating that PD-L1 may be a predictive biomarker for response to atezolizumab. FIR was also designed to address questions of potential heterogeneity and changes in tumor PD-L1 expression in metachronous tissue samples, as well as the utility of using FDG-PET as a biomarker for response to atezolizumab in PD-L1–selected patients with NSCLC.
Methods:
FIR is a 3-cohort, single-arm, Phase 2 study of atezolizumab in PD-L1–selected patients with stage IIIB/IV NSCLC. Cohort 1 included chemo-naive patients, Cohort 2 included ≥ 2L patients without a history of brain metastases, and Cohort 3 included ≥ 2L patients with asymptomatic treated brain metastases. PD-L1 expression was centrally assessed by immunohistochemistry (IHC) using the SP142 antibody assay in archival and/or fresh tumor biopsies or resections and scored as IC0, 1, 2 or 3 and TC0, 1, 2 or 3. Patients with PD-L1 IC2/3 or TC2/3 tumors were enrolled and received 1200 mg atezolizumab IV every 3 weeks (last patient entered Jun 27, 2014). Responses were measured by RECIST v1.1, modified RECIST and FDG-PET using EORTC criteria. Exploratory objectives included the evaluation of potential predictive biomarkers, including the comparison of PD-L1 expression in matched archival and fresh tumor specimens, as well as the utility of FDG-PET in assessing response to immune checkpoint blockade.
Results:
From 1009 screened patients, 95 paired archival and fresh tumor samples were obtained. In these samples, the agreement of PD-L1 expression between fresh and archival tissue at the TC3 or IC3 cutoff was 88% when the same type of tissue procurement method was used (resection or biopsy), compared with 65% when different methods of procurement were used. To date, FDG-PET response has been centrally assessed in 71 of the 138 patients enrolled in FIR. Patients with metabolic response by EORTC criteria on 6-week scans had a higher ORR per RECIST v1.1 (72% [13/18]) than metabolic non-responders (ORR 4% [2/53]).
Conclusion:
There was a high agreement in TC3 or IC3 PD-L1 expression between archival and fresh tumor specimens. This work demonstrates that intra-patient heterogeneity in PD-L1 expression is low in metachronous tissues, indicating various types of tumor samples, including fresh or archival, can be reliably used to assess PD-L1 expression. In addition, FDG-PET has potential as an early on-treatment measure of response to atezolizumab. Further analyses will be presented. (NCT01846416)
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ORAL02.07 - Atezolizumab (MPDL3280A) Combined with Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer (NSCLC): A Phase Ib Safety and Efficacy Update (ID 2208)
10:45 - 12:15 | Author(s): S.N. Gettinger
- Abstract
- Presentation
Background:
Despite advances in treatment for NSCLC, the standard first-line treatment for metastatic disease remains platinum-based doublet chemotherapy with historical overall response rates (ORRs) of ≈30%. Preclinical data suggest that chemotherapy treatment can result in antigen release in the tumor microenvironment, potentially enhancing effects of cancer immunotherapy. Atezolizumab (MPDL3280A) is a human monoclonal antibody that targets the PD-L1/PD-1 immune checkpoint, while leaving the PD-L2/B7.1 interaction intact (which may reduce the risk of autoimmune lung toxicity). As atezolizumab has shown promising activity in advanced NSCLC, we investigated atezolizumab in combination with chemotherapy.
Methods:
A Phase Ib study was conducted to evaluate atezolizumab with chemotherapy in locally advanced or metastatic NSCLC patients who had not received chemotherapy for advanced disease. Pts received atezolizumab 15 mg/kg IV q3w with standard chemotherapy (carboplatin plus either paclitaxel [Arm C], pemetrexed [Arm D; nonsquamous] or weekly nab-paclitaxel [Arm E]) for 4-6 cycles followed by atezolizumab maintenance until progression. RECIST v1.1 was used to assess ORRs (unconfirmed) in pts dosed by Jun 29, 2014 (data cutoff: Sep 29, 2014). PD-L1 expression was centrally evaluated using the SP142 IHC antibody assay.
Results:
37 NSCLC pts were safety evaluable (8 in Arm C; 14 in Arm D; 15 in Arm E). Across these arms, 54% of pts were male, with a median age of 65 y (range, 40-82 y). 81% had non-squamous NSCLC, and 19% had squamous NSCLC. Median safety follow-up was 22.0 wks (range, 0.1-49.4 wks). Across arms, all-Grade AEs regardless of attribution included those commonly associated with chemotherapy, such as nausea (Arms C & D, 50%; Arm E, 73%), fatigue (Arm C, 38%; Arm D, 36%; Arm E, 73%) and constipation (Arm C, 25%; Arm D, 71%; Arm E, 27%). The most common Grade 3-4 atezolizumab-related AEs included anemia (Arms D & E, 7%), neutropenia (Arm C, 13%; Arm D, 7%) and thrombocytopenia (Arms D & E, 7%), with no pneumonitis or autoimmune renal toxicity observed. One potentially atezolizumab-related Grade 5 AE was observed in Arm D (candidemia after prolonged neutropenia). 30 pts were efficacy evaluable, and responses were observed in all arms regardless of PD-L1 expression (Table). Updated clinical data will be presented.Table. RECIST v1.1 Responses in Patients with NSCLC
Arm C: carboplatin + paclitaxel (n = 5) Arm D: carboplatin + pemetrexed (n = 12) Arm E: carboplatin + nab-paclitaxel (n = 13) All Indicated Arms (n = 30) ORR, % 60% 75% 62% 67% 95% CI, % 19%-92% 45%-93% 33%-83% 48%-82% CR, n 0 0 2 2 PR, n 3 9 6 18
Conclusion:
Atezolizumab plus standard first-line chemotherapy was well tolerated in advanced NSCLC pts, with no unexpected toxicities. Clinical activity was promising and supportive of a potential synergy of atezolizumab with chemotherapy. Based on these results, several Phase III studies have been initiated.
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ORAL 13 - Immunotherapy Biomarkers (ID 104)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Kim, D. Grunenwald
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL13.04 - Discussant for ORAL13.01, ORAL13.02, ORAL13.03 (ID 3403)
16:45 - 18:15 | Author(s): S.N. Gettinger
- Abstract
- Presentation
Abstract not provided
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ORAL 31 - PD1 Axis Inhibition (ID 143)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:J. Weiss, B. Luey
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL31.07 - A Phase II Trial of Pembrolizumab for Untreated Brain Metastases from Non-Small Cell Lung Cancer (ID 824)
16:45 - 18:15 | Author(s): S.N. Gettinger
- Abstract
- Presentation
Background:
Patients with advanced non-small cell lung cancer (NSCLC) often develop brain metastases (BrMs), and standard therapy such as surgery or radiation can cause toxicity and delay systemic treatment. Pembrolizumab is a PD-1 inhibitor with promising clinical activity and a favorable toxicity profile in patients with advanced NSCLC, however the efficacy of pembrolizumab in the central nervous system (CNS) is unknown. This trial aims to determine the safety and activity of pembrolizumab in patients with advanced NSCLC and untreated brain metastases.
Methods:
Eligibility for patients with NSCLC in this Phase II trial includes the presence of at least 1 BrM between 5 and 20 mm that is asymptomatic, untreated or progressing after prior local therapy, and not requiring urgent local therapy. PD-L1 expression in tumor obtained since the most recent systemic therapy is required. Patients are treated with pembrolizumab 10mg/kg every 2 weeks. Systemic response is determined by RECIST 1.1, and BrM response is determined by modified RECIST (mRECIST) in which brain lesions ≥ 5mm are considered measurable and up to 5 target lesions are allowed. The primary endpoint of this trial is BrM response rate.
Results:
Fifteen patients with NSCLC and untreated BrMs were treated with pembrolizumab, none of whom had a drug-related Grade ≥ 3 adverse event (AE) or any grade AE attributed to BrMs. Of the 10 patients evaluable for response, 5 (50% with 95% CI: 0.24-0.76) had a BrM response (4 partial and 1 complete) and 5 had a systemic response. Only one patient who responded in the body had progressive disease in the brain; all other patients who had a systemic response also had a CNS response. The duration of response in the brain was at least 12 weeks for 4 of the 5 responders, and all responses are ongoing at the time of data analysis.
Conclusion:
To our knowledge this is the first study to demonstrate that the PD-1 inhibitor pembrolizumab has activity in the CNS in patients with NSCLC and untreated brain metastases. To date there have been no drug-related neurologic or significant toxicity identified. Patient enrollment and biomarker analysis are ongoing.
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.06 - Brigatinib (AP26113) Efficacy and Safety in ALK+ NSCLC: Phase 1/2 Trial Results (ID 2125)
16:45 - 18:15 | Author(s): S.N. Gettinger
- Abstract
- Presentation
Background:
Brigatinib (AP26113), an investigational oral tyrosine kinase inhibitor with FDA breakthrough therapy designation for the treatment of patients with crizotinib-resistant advanced ALK+ NSCLC, has preclinical activity against both rearranged ALK and clinically identified crizotinib-resistant mutant ALK.
Methods:
This is an ongoing phase 1/2, single-arm, open-label, multicenter study in patients with advanced malignancies (N=137; NCT01449461). Patients received escalating total daily doses of brigatinib from 30–300 mg during phase 1. Daily regimens of 90 mg, 180 mg, or 90 mg for 7 days followed by 180 mg were evaluated in phase 2. Safety is reported for all treated patients; antitumor efficacy (ORR and PFS per RECIST v1.1) is reported for ALK+ NSCLC patients.
Results:
Seventy-nine (58%) patients had ALK+ NSCLC. Median age was 54 (29–83) years, 49% were female, 90% had prior crizotinib, and 47% had ≥2 prior chemotherapy regimens. As of February 17, 2015, 45/79 (57%) ALK+ NSCLC patients remained on study, with median time on treatment of 12.6 months (1 day to 35.5 months; n=79); ORR/PFS for evaluable ALK+ NSCLC patients was 74%/13.4 months (additional data shown in Table). In a post hoc independent radiological review of patients with brain metastases at baseline (as of January 19, 2015), 8/15 (53%) patients with measurable brain lesions ≥10 mm had an intracranial response (≥30% decrease in sum of longest diameters of target lesions) and 9/30 (30%) patients with only nonmeasurable lesions had disappearance of all lesions. Treatment-emergent AEs in ≥30% of total patients, generally grade 1/2, included nausea (52%), fatigue (42%), diarrhea (40%), headache (33%), and cough (32%). Early-onset pulmonary events, which occurred ≤7 days after treatment initiation and included dyspnea, hypoxia, and new pulmonary opacities on chest CT consistent with pneumonia or pneumonitis, were reported in 13/137 (9%) patients overall (6/44 [14%] at 180 mg qd; 2/50 [4%] at 90 mg qd [maintained or escalated to 180 mg qd after 7 days]).Response and PFS With Brigatinib All Evaluable ALK+ NSCLC Patients n=78 Prior Crizotinib n=70 No Prior Crizotinib n=8 Response, n(%) OR (CR+PR) 58(74) 50(71) 8(100) [95% CI] [63–84] [59–82] [63–100] CR 7(9) 4(6) 3(38) PR 51(65) 46(66) 5(63) SD 11(14)[a] 11(16)[a] 0 PD 6(8) 6(9) 0 Termination before scan 3(4) 3(4) 0 Median duration of response,[b] mo 11.2[c] 9.9[d] Not reached[e] Median PFS,[b] mo 13.4 13.4 Not reached [a]Includes non-CR/non-PD for 4 patients with no measurable disease at baseline [b]Kaplan-Meier estimate [c]n=55 evaluable [d]n=48 evaluable [e]n=7 evaluable
Conclusion:
Brigatinib has promising antitumor activity in ALK+ NSCLC patients with (71% ORR; PFS 13.4 months) or without (100% ORR) prior crizotinib, including patients with brain metastases (53% ORR in patients with measurable brain lesions). Early-onset pulmonary events were less frequent when starting at 90 vs 180 mg qd. A pivotal global phase 2 trial (ALTA) of brigatinib 90 mg qd vs 90 mg qd for 7 days followed by 180 mg qd in crizotinib-resistant ALK+ NSCLC is ongoing.
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