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Joel W Neal
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.08 - Cabozantinib Plus Atezolizumab in NSCLC Patients Previously Treated with a Checkpoint Inhibitor: Results from COSMIC 021 (ID 1966)
00:00 - 00:00 | Presenting Author(s): Joel W Neal
- Abstract
Introduction
First-line immunotherapy with/without chemotherapy is standard of care for patients with advanced NSCLC; however, there is a need for effective treatment options after progression on a prior immune checkpoint inhibitor (ICI). Cabozantinib may augment response to ICI by inhibiting kinases implicated in suppressing immune cell responses and has shown encouraging clinical activity in combination with ICI in other tumor types including RCC and HCC. COSMIC-021, a multicenter phase 1b study, is evaluating the combination of cabozantinib with atezolizumab in various solid tumors (NCT03170960). We report results from expansion cohort 7 in NSCLC patients with prior ICI therapy.
Methods
Eligible patients had ECOG performance status (PS) 0-1 and radiographic progression after one prior anti–PD-1/PD-L1 ICI given alone or in combination with chemotherapy for metastatic non-squamous NSCLC. Up to 2 lines of prior systemic anticancer therapies were permitted. Patients received cabozantinib 40 mg PO QD and atezolizumab 1200 mg IV Q3W. CT/MRI scans were performed Q6W for the first year and Q12W thereafter. The primary endpoint is ORR per RECIST 1.1 by investigator. Other endpoints include safety, duration of response (DOR), progression-free survival, and overall survival.
Results
Thirty patients with advanced NSCLC were enrolled. Median age was 67 years (range 41, 81), 43% were male, 57% had ECOG PS 1, and 23% had liver metastases. Median duration of prior ICI therapy was 4.8 months (mo; range 0.8, 29), and 15 (50%) patients were refractory to prior ICI (progressive disease as best response). As of December 20, 2019, the median follow-up was 8.9 mo (range 5, 20) with 9 (30%) patients continuing study treatment. The most common treatment related adverse events (TRAEs) of any grade were diarrhea (53%), fatigue (37%), nausea (23%), decreased appetite (20%), palmar-plantar erythrodysesthesia (20%), and vomiting (20%). Grade 3/4 TRAEs occurred in 14 (47%) patients, and 1 (3.3%) had grade 5 TRAEs of myocarditis and pneumonitis. Confirmed ORR per RECIST 1.1 was 23% (7 of 30 patients; all partial responses including 3 patients refractory to prior ICI). Median time to response was 1.4 mo (range 1, 3), and median DOR was 5.6 mo (range 2.6, 6.9). DCR (CR+PR+SD) was 83%.
Conclusion
The combination of cabozantinib and atezolizumab had an acceptable safety profile and showed encouraging clinical activity in patients with advanced NSCLC who had progressed after prior ICI therapy. The response rate was greater than previously observed with cabozantinib monotherapy. Due to the promising data, enrollment in this cohort has been expanded and is ongoing.
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OA01 - Established Drugs in Special Populations and New Drugs in Established Populations (ID 226)
- Event: WCLC 2020
- Type: Oral
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 09:15 - 10:15, Scientific Program Auditorium
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OA01.04 - Tumor Mutation Burden (TMB) by Next Generation Sequencing (NGS) Associates with Survival (OS) in Lung-MAP Immunotherapy Trials S1400I and S1400A (ID 3229)
09:15 - 10:15 | Author(s): Joel W Neal
- Abstract
- Presentation
Introduction
TMB is an emerging biomarker for efficacy of immune checkpoint inhibitors (ICI). Lung-MAP is a master protocol for biomarker-driven trials in advanced NSCLC. Two sub-studies in previously treated ICI naïve advanced squamous cell lung cancer (sqNSCLC), S1400I, a phase III trial randomizing patients to nivolumab plus ipilimumab (N/I) versus nivolumab (N), and S1400A, a phase II trial evaluating durvalumab (D), provided the opportunity to evaluate TMB and related biomarkers by NGS and to determine associations with clinical outcomes.
Methods
NGS was performed on DNA from formalin-fixed paraffin-embedded tumor specimens using the FoundationOne T5 platform. TMB was defined as the total number of nonsynonymous mutations per megabase (Mb) of coding sequence. In S1400I, PD-L1 expression was assessed by the 22C3 antibody. A Cox model was used to evaluate associations between TMB (continuous and dichotomized at 10 Mb/mt), PD-L1 (continuous and dichotomized at 0% versus > 0%), overall survival (OS) and progression-free survival (PFS), summarized by hazard ratios (HRs) and 95% confidence intervals (CI). Associations between TMB and genetic alterations were evaluated by Wald test, with false discovery rate (FDR) ≤ 5% scored as positive. Unsupervised hierarchical clustering was performed using combined data from S1400I+S1400A.
Results
Conclusion
252 patients on N/I or N and 68 patients on D were included in the analysis. Higher TMB (per 10-unit difference in TMB value) was significantly associated with better OS and PFS (OS HR(CI): 0.80 (0.67–0.94), P = 0.008 and PFS HR(CI): 0.80 (0.69–0.93), P = 0.004). In S1400I, PD-L1 expression levels were not significantly associated with OS or PFS (N=161, P > 0.05), alone or in combination with TMB. In S1400I+S1400A, no genetic variants were significantly associated with OS or PFS. Genes whose alterations were significantly associated with TMB are shown in the volcano plot. Unsupervised hierarchical clustering suggested a variant-defined subgroup conferred better PFS (HR (CI): 0.41 (0.19–0.88), P = 0.022) but not OS; notably, this subgroup showed 3.8-fold higher TMB and more frequent alterations of genes shown in the plot, compared to other subgroups.
Several different methodologies have been employed to measure TMB. TMB by FoundationOne NGS is an analytically and clinically validated assay correlating well with WES and predicted neoantigen load. Here we report that high TMB, but not PD-L1, is associated with improved OS and PFS in patients treated with ICI on S1400I/S1400A. How genetic alterations associated with high TMB may biologically contribute to clinical outcomes from ICI warrants further consideration.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.70 - Afatinib After Progression on Osimertinib in Patients with EGFR-Mutated Lung Adenocarcinoma (ID 3354)
00:00 - 00:00 | Author(s): Joel W Neal
- Abstract
Introduction
Osimertinib is FDA-approved for frontline treatment of EGFR-mutated non-small cell lung cancer (NSCLC) and for EGFR T790M+ tumors after progression on first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). However, acquired resistance to osimertinib eventually occurs and the standard-of-care treatment after resistance is chemotherapy. Afatinib combined with cetuximab is active in treating EGFR-mutated NSCLC with acquired resistance to first-generation EGFR TKIs, though afatinib monotherapy has minimal activity in this setting. Whether afatinib-containing therapy is active after acquired resistance to the third-generation EGFR TKI osimertinib remains unknown.
Methods
We conducted a single-institution retrospective analysis on patients with stage IV EGFR-mutated lung adenocarcinoma who received afatinib-containing therapies after progression on osimertinib from 03/2017 to 07/2020. Kaplan-Meier curves were generated for survival analyses from the date of afatinib initiation. Response was assessed with RECIST v1.1 criteria. Adverse events were graded according to CTCAE v5.0 criteria.
Results
After progression on osimertinib (N=1 frontline, N=10 2nd-5thline), 11 patients (3 exon19del, 6 L858R, 1 L861Q, 1 exons 18-25 duplication) received afatinib monotherapy (N=2), afatinib + cetuximab (N=7), or afatinib + bevacizumab (N=2). Median number of interval lines of therapy was 1 (range 0-2) and median time from osimertinib discontinuation to afatinib-containing therapy was 6.4 months (range 0.1-11.3). Median progression-free survival (PFS) on afatinib-containing therapy was 2.9 months (95% CI 1.9-not reached [NR]), and median overall survival (OS) was 8.7 months (95% CI 5.7-NR). A PFS ≥ 6 months on osimertinib (N=5) was associated with a significantly greater PFS on afatinib-containing therapy compared to a PFS < 6 months on osimertinib (N=6; median 4.9 versus 1.9 months, log-rank P=0.009). Similar results were observed when excluding the two patients who received afatinib monotherapy. The 6-month PFS threshold on prior osimertinib was not associated with differences in OS on afatinib (median 8.7 versus 8.7 months, log-rank P=0.516). The objective response rate for afatinib was 9.1% (95% CI 0.2-41.3) and the disease control rate was 63.6% (95% CI 30.8-89.1). The most common all-grade adverse events with afatinib were acneiform rash (81.8%), diarrhea (72.7%), dry skin (63.6%), and anorexia (63.6%).
Conclusion
Afatinib-containing therapies have modest activity in treating patients with EGFR-mutated lung adenocarcinoma after progression on osimertinib, with greater activity in patients who achieved a PFS ≥ 6 months on prior osimertinib. Further investigations of afatinib combinations after progression on osimertinib are ongoing, with mechanisms of resistance (i.e., on-target versus bypass tract) being potentially important for this strategy.
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P76.85 - Afatinib and Necitumumab in EGFR mutant NSCLC with Acquired Resistance to 1st or 3rd Generation EGFR Tyrosine Kinase Inhibitors (ID 3547)
00:00 - 00:00 | Author(s): Joel W Neal
- Abstract
Introduction
There are no approved targeted therapies for patients (pts) with EGFR mutated NSCLC who develop acquired resistance to frontline 3rd generation (gen) tyrosine kinase inhibitors (TKI) osimertinib (osi), 2nd line osi (T790MPOS after 1st/2nd gen TKI), or frontline 1st/2nd gen TKI and T790MNEG. Dual EGFR blockade with TKI (afatinib) and monoclonal antibody (necitumumab) may overcome resistance in these scenarios.
Methods
This was a phase I 3+3 dose escalation of afatinib plus necitumumab in pts with EGFR mutated NSCLC who progressed on 1st gen TKI (T790MNEG), 1st line osi, and subsequent line osi (T790MPOS after 1st/2nd gen TKI). Afatinib was dosed oral daily and necitumumab dosed IV day 1 and 15 of a 28-day cycle. Dose levels (DL) included: DL1 Afatinib 30 mg, Necitumumab 400 mg; DL2 Afatinib 40 mg, Necitumumab 400 mg; DL3 Afatinib 40 mg, Necitumumab 600 mg; DL4 Afatinib 40 mg, Necitumumab 800 mg. Three dose expansion cohorts (15 pts each in above scenarios) are enrolling at the maximum tolerated dose (MTD).
Results
Enrollment completed in the phase I portion (07/2017-07/2019): 3 DL1, 3 DL2, 3 DL3, and 4 DL4. Four pts progressed on 1st gen TKI (T790MNEG), 1 pt on 1st line osi, and 8 pts on subsequent line osi (T790MPOS after 1st/2nd gen TKI). Two dose limiting toxicities were observed in DL4, including grade (G) 3 diarrhea and symptomatic G3 rash (delayed DLT given occurrence after first 28 days); therefore, DL3 was the MTD. At the time of data cutoff (Aug 26, 2020), 3 pts have enrolled in dose expansion; 1 pt progressed on 1st line osi, 1 pt progressed on 1st gen TKI (T790MNEG), and 1 pt on subsequent line osi (T790MPOS after 1st/2nd gen TKI). The most common treatment-related adverse events of all grades included rash (88%; 2 G3), diarrhea (56%; 1 G3), paronychia (38%; 0 G3), mucositis (31%; 1 G3), fatigue and vomiting (25% each; 0 G3), fever, headache, nausea, and pruritus (23% each; 0 G3). There was no pneumonitis; 1 pt had G1 hypomagnesemia. Six patients required dose reductions, median of 2. While no objective responses were observed in this heavily pre-treated population (median 4 prior lines of therapy), the disease control rate was 38% (6/16) and all pts with stable disease were on treatment ≥15 weeks. Reasons for treatment discontinuation included disease progression (n=14), toxicity (n=1) and pt decision (n=1).
Conclusion
The combination of afatinib and necitumumab had expected toxicities of rash and diarrhea. Trial is ongoing, and the MTD of afatinib 40 mg and necitumumab 600 mg is being tested in 3 dose expansion cohorts.
