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Scott Gettinger



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    IBS15 - Biology and Genetics in ICI Treatments (Ticketed Session) (ID 46)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      IBS15.01 - Current Status of IO in Lung Cancer (Now Available) (ID 3360)

      07:00 - 08:00  |  Presenting Author(s): Scott Gettinger

      • Abstract
      • Presentation
      • Slides

      Abstract

      Only a decade ago, lung cancer was largely considered a non-immunogenic tumor. The focus of most clinical efforts at the time was development of molecularly targeted agents in hopes to personalize the systemic treatment of lung cancer. Although much has been accomplished over the last 15 years, with regulatory approvals of several targeted agents for EGFR, ALK, ROS1, BRAF and NTRK driven tumors, and emerging targeted therapies for other molecularly defined cohorts (e.g. MET, RET, HER2 driven tumors), the majority of patients with lung cancer do not have readily targetable molecular alterations. Arguably, the most impactful advance in the systemic treatment of lung cancer over the last several decades has been the appreciation and utilization of immunotherapy to attack and control typical lung cancer. Indeed, five- year survival rates from the first phase I trials of programmed death (PD)-1 inhibitor trials (BMS-003 and KEYNOTE-001) in patients with pre-treated advanced non-small cell lung cancer (NSCLC) are an unprecedented 16% (n=578, median duration of response 17 - 39 months), with five- year survival rate from one trial (KEYNOTE-001) evaluating chemo naive advanced lung cancer patients of 23% (n=101, median duration of response 17 months) (ref: PMID 29570421, 31154919). Based on subsequent randomized clinical trials, PD-1 axis inhibitor therapy has become standard first line therapy for the majority of patients with advanced NSCLC (those without readily targetable tumor molecular alterations), either alone (pembrolizumab) if tumor PD- ligand 1 (L1) expression is high (> 50%), or with standard platinum doublet chemotherapy if tumor PD-L1 expression is low/ negative/ unknown (pembrolizumab regardless of NSCLC histology; atezolizumab for non-squamous NSCLC) (ref: PMID 30620668, 29658856, 30280635, 2986395). PD-1 axis inhibitor therapy with durvalumab is additionally approved as consolidation therapy for patients with locally advanced NSCLC after receiving definitive concurrent chemoradiation without progression (ref: PMID 30280658). PD-1 axis inhibitor therapy has also shown activity in advanced small cell lung cancer (SCLC), with regulatory approvals of atezolizumab combined with first line etoposide/ platinum chemotherapy, and nivolumab or pembrolizumab as 3rd line therapy (in practice, nivolumab is often combined with ipilimumab after failure of chemotherapy as endorsed by the National Comprehensive Cancer Network) (ref: PMID 30280641, 27269741). Several phase III immunotherapy lung cancer studies are ongoing in the adjuvant and metastatic setting, with additional regulatory approvals anticipated in the coming years.

      Despite the success with PD-1 axis inhibitors, and tremendous impact on treatment paradigms for lung cancer, most treated patients do not clearly benefit from therapy, and most of those who do respond will ultimately develop resistance with recurrence/ progression of their cancer. Little is known about mechanisms of resistance, and coordinated translational efforts across cancer centers will be required to understand both acquired and primary resistance (to date, we are only aware of two published reports describing potential mechanisms of acquired resistance to PD-1 axis inhibitors in lung cancer; one implicating acquired loss of beta-2 microglobulin with resultant lack of MHC1 expression, the other, loss of tumor specific neoantigens through elimination of tumor subclones or chromosomal loss of truncal alterations ) (ref: PMID: 28031159, 29025772). Currently, several trials are evaluating novel immunotherapeutic agents, including other immune checkpoint inhibitors, costimulatory agonists, vaccines, oncolytic viruses and cellular therapies. In most of these trials, patients are not selected by unique molecular/ immunologic characteristics of their tumor. Rather, empiric combinations of therapy (often including a PD-1 axis inhibitor) are generally trialed with tumor biopsies to help understand mechanisms of response and resistance.

      In clinical practice, a handful of unanswered questions repeatedly surface when treating lung cancer patients with immunotherapy. These include:

      What is the optimal duration of PD-1 axis inhibitor therapy? Although there is little data to guide us here, we generally consider treatment holiday after 2 years of therapy without progression. However, PD-1 axis therapy can be continued indefinitely as was done in most registrational trials.

      What is the role of immunotherapy in never smokers and those with targetable molecular alterations driving their disease? There remains pessimism about use of immunotherapy in these populations, with the belief that tumors in such patients are less immunogenic (lower mutational burden with less neoantigens). However, there are limited numbers of patients who do respond, and efforts are underway to understand these responses. Novel immunotherapeutic approaches are also being developed. Currently, many thoracic oncologists will reserve PD-1 axis inhibitor therapy until no other standard targeted therapies (or trials evaluating novel targeted therapy) or chemotherapy remain.

      When should we concede that a patient’s tumor is primarily resistant to PD-1 axis inhibitor therapy. i.e., how much time on therapy should be allowed to exclude delayed response or pseudo-progression. Generally, if a patient’s performance status has not deteriorated at the first tumor assessment on immunotherapy (6-8 weeks), many thoracic oncologists will continue therapy for another 6 weeks. If assessment at that time shows further progression, therapy is discontinued.

      Should immunotherapy ever be continued with addition of other systemic therapy on progression of disease? Generally, this is not recommended, unless a patient is having a mixed response or acquired resistance with oligo-progressive disease. That said, there is some rationale here, as PD-L1 may be induced in tumors by subsequent therapy.

      Is there any role for consolidation durvalumab in patients with locally advanced NSCLC after concurrent chemoradiation followed by lung resection? The PACIFIC trial leading to approval of consolidation durvalumab did not include such patients; currently, durvalumab is not indicated after surgery.

      Should salvage nivolumab combined with ipilimumab be considered in patients with extensive stage small cell lung cancer after progression on standard chemotherapy plus/ minus atezolizumab. Although nivolumab plus ipilimumab is not approved for use in the United States as salvage therapy for SCLC, it is occasionally prescribed as endorsed by the NCCN. It is unclear if the combination would have any activity in a patient who failed prior atezolizumab in combination with etoposide/ platinum.

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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.01 - A Phase III Randomized Study of Nivolumab/Ipilimumab vs Nivolumab for Previously Treated Stage IV Squamous Cell Lung Cancer (Now Available) (ID 872)

      15:15 - 16:45  |  Author(s): Scott Gettinger

      • Abstract
      • Presentation
      • Slides

      Background

      Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. (Lung-MAP Sub-Study S1400I, NCT02785952)

      Method

      S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity.

      Result

      From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). Median follow up for patients still alive was 17.4 months. The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. The response rate was 18% (12-25) in N+I and 17 % (11, 24) in N. Outcomes were similar across TMB subgroups and PD-L1 expression levels. Most AE were low grade. There were 5 grade 5 AE in N+I arm and 1 in N arm. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% of pts on N+I and 16% of pts on N.

      OS and PFS based on TMB and PD-L1

      N+I

      Median in months

      N

      Median in months
      HR p
      OS PD-L1 ≥5 14.1 (5.8-17.5) 12.0 (8.2-19.8) 1.06 (0.58-1.92) 0.86
      OS PD-L1 <5 8.3 (6.0-10.7) 10.3 (6.3-13.5) 1.01 (0.62-1.65) 0.97
      OS TMB ≥10 13.1 (9.3-17.0) 11.4 (8.2-16.1) 0.86 (0.56-1.32) 0.48
      OS TMB <10 7.6 (5.7-10.2) 10.0 (6.3-15.2) 1.08 (0.68-1.71) 0.74
      PFS PD-L1 ≥ 5 3.9 (1.7-7.1) 2.9 (1.8-4.7) 0.65 (0.38-1.08) 0.10
      PFS PD-L1 <5 4.4 (2.1-6.0) 1.6 (1.5-3.0) 0.64 (0.41-1.01) 0.06
      PFS TMB ≥ 10 4.2 (3.4-5.9) 3.4 (1.8-5.3) 0.75 (0.52-1.10) 0.15
      PFS TMB < 10 1.9 (1.5-4.1) 2.7 (1.6-3.3) 0.92 (0.62-1.39) 0.70

      Conclusion

      S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Molecular correlates will be presented at the meeting.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Presenting Author(s): Scott Gettinger

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    PR04 - Press Conference (ID 95)

    • Event: WCLC 2019
    • Type: Press Conference
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/10/2019, 10:45 - 11:30, CC7.1 A&B
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      PR04.03 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (Now Available) (ID 3621)

      10:45 - 11:30  |  Presenting Author(s): Scott Gettinger

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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