Intervista a Cesare Gridelli POSTER SESSION Intervista a Cesare Gridelli

Symptom analysis and quality of life (QoL) in patients treated with nivolumab (NIVO) as ≥2nd line therapy for advanced non-small cell lung cancer (aNSCLC) L. Schwartzberg

Background: NIVO, a PD-1 antibody, has demonstrated superior overall survival and tolerability in heavily pretreated aNSCLC pts. In a phase 3 trial (CheckMate 017), squamous (SQ) pts on NIVO experienced symptom and QoL benefit from baseline (BL), while chemotherapy remained stable. Here we explore NIVO-associated symptom change and QoL in a phase 3B/4 trial (NCT02066636) by utilizing 2 patient-reported outcome (PRO) measures, Lung Cancer Symptom Scale (LCSS) and EuroQol Five Dimensions (EQ-5D). Methods: Eligible pts with stage 3B/4 SQ and non-SQ NSCLC who were ≥2nd line received NIVO 3mg/kg IV Q2W and completed PROs at BL and every 6 weeks (Q6W). Radiographic tumor assessments were conducted at wk 9, then Q8W. LCSS average symptom burden index (ASBI) and EQ-5D visual analogue scale (VAS) change from BL, and association with radiographic assessment at wk 9, were analyzed. Results: In this initial database lock, evaluable PRO change scores were available for 557 pts at wk 6 and up to 46 pts at wk 30. Change from BL is shown (Table). LCSS and EQ-5D scores improved over time, with significance observed on ASBI and VAS at wks 12 through 24 (t-test, P<0.05). VAS scores exceeded the minimal important difference (MID) threshold at wks 18 to 30. PRO results analyzed for pts with radiographic data demonstrated association between tumor response and QoL benefit. Partial response (PR) pts had significant VAS improvements at wks 6 and 24 and exceeded MID at wk 6, 18, 24 and 30, while stable disease (SD) pts showed significant VAS improvements at wks 6 through 18, exceeding MID at wk 18 (t-test, P<0.05). VAS scores at wk 6 showed significant worsening for pts who progressed (PD). Conclusions: Overall, these data suggest that pts initiating NIVO experienced continued improvements in QoL and symptoms. Pts with early radiographic PR and SD trended towards improved symptomology and overall health status, which was sustained for wks after radiographic scan. These results, reflective of a real-world community practice setting, are consistent with those observed in CheckMate 017.

Nivolumab (NIVO) safety profile: Summary of findings from trials in patients (pts) with advanced squamous (SQ) non-small cell lung cancer (NSCLC) S.N. Gettinger

Background: NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, has shown survival benefit across NSCLC histologies and is approved in the US for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. To further describe the safety profile of NIVO in SQ NSCLC, a pooled analysis of 2 SQ NSCLC clinical trials was conducted. Methods: A post-hoc review of safety data was performed from a phase 2 trial (CheckMate 063; NCT01721759) and phase 3 trial (CheckMate 017; NCT01642004) in pts with advanced SQ NSCLC. Safety data were pooled from 248 pts treated with NIVO 3mg/kg IV Q2W until disease progression or unacceptable toxicity. Pts who received ≥1 dose of NIVO were included in the analysis. AEs in the following categories were analyzed: all AEs, treatment-related AEs (TRAEs), select TRAEs (immune-related etiology), and serious AEs (SAEs). Results: Most TRAEs were low grade (Table). TRAEs (any grade) reported in ≥5% of pts were fatigue (23.8%), decreased appetite (14.5%), nausea (12.1%), asthenia (10.9%), diarrhea (8.9%), and rash (7.3%). Grade 3–4 TRAEs in ≥1% of pts were fatigue (2.4%), pneumonitis (2.0%), diarrhea (1.2%), and lymphopenia (1.2%). TRAEs resulting in NIVO dose delay in ≥2% of pts included fatigue (2.4%) and pneumonitis (2.0%). TRAEs led to discontinuation in 7.3% (all-grade AEs) of pts; most commonly pneumonitis (2.8%). Select TRAEs (any grade) reported in ≥2% of pts were diarrhea (8.9%), rash (7.3%), pruritus (4.0%), pneumonitis (4.8%), hypothyroidism (3.2%), and increased blood creatinine (2.4%). Select grade 3–4 TRAEs in ≥1% of pts were pneumonitis (2.0%) and diarrhea (1.2%). Of the 12 pts who developed pneumonitis (grade 1–2, n=7; grade 3, n=5), 2 were re-challenged with NIVO; one developed recurrent pneumonitis. Two treatment-related deaths (1 hypoxic pneumonia, 1 ischemic stroke) occurred in pts with multiple comorbidities and concurrent progressive disease. Conclusions: NIVO was well tolerated, with generally low-grade toxicities and manageable immune-related toxicities, including pneumonitis.

First-Line monotherapy with nivolumab (NIVO) in advanced non-small cell lung cancer (NSCLC): Safety, efficacy, and biomarker analyses S.N. Gettinger

Background: NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has activity across NSCLC histologies and is FDA-approved for treatment of metastatic squamous (SQ) NSCLC with progression on or after platinum-based chemotherapy. This phase 1 study evaluated the efficacy and safety of NIVO monotherapy in patients (pts) with chemotherapy-naïve advanced NSCLC.Methods: Pts (N=52) with SQ or non-SQ advanced NSCLC received NIVO 3mg/kg IV Q2W until progression or unacceptable toxicity. Response (per RECIST v1.1) was evaluated overall and by histology, tumor PD-L1 expression (PD-L1+: ≥5% tumor cells expressing PD-L1), and smoking history (smoking status [current, former, never], smoking exposure [≤5 pack-years [pk-yrs], >5 pk-yrs], and time since quitting [≤15yrs, >15yrs]). Results: Across histologies, objective response rate (ORR) was 23% (12/52); 9/12 (75%) responders had response by first scan (wk 11). Median duration of response was not reached (range, 18.1, 112.3+ wks); 8 (67%) pts had ongoing responses at last tumor assessment (median follow-up, 62.2 wks). Three patients had complete responses which were ongoing at 41.4+, 97.6+, and 112.3+ wks, respectively. An additional three pts had unconventional immune-pattern responses, with 35%, 43%, and 46% maximum reductions in target lesions, respectively, and simultaneous appearance of new lesions (not reported as responders). Median overall survival was 22.6 mos (range, 0.2, 30.1+); median progression-free survival (mPFS) was 15.6 wks (range, 0.1+, 121.6+). ORR for PD-L1+ and PD-L1− pts was 31% (8/26) and 15% (3/20), respectively. ORR and mPFS were higher among pts with a history of smoking (Table). Ten pts (19%) experienced grade 3–4 treatment-related adverse events, including rash (n=2), increased amylase/lipase, increased AST/ALT, hyperglycemia, cardiac failure, lung infection, pneumonitis, dehydration/diarrhea, and hyponatremia (n=1 each). Additional subgroup analyses, including efficacy by PD-L1 status according to histology, will be presented. Conclusions: First-line NIVO demonstrated durable responses and encouraging survival. Smoking history was associated with response to NIVO. NIVO monotherapy was associated with a tolerable safety profile that was consistent with prior studies.

Safety and efficacy of first-line nivolumab (NIVO) and ipilimumab (IPI) in non-small cell lung cancer (NSCLC) M.D. Hellmann

Background: Combined blockade of the PD-1 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) immune checkpoint pathways has shown improved responses, encouraging survival, 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 FDA-approved for treatment of metastatic squamous (SQ) NSCLC with progression on or after platinum-based chemotherapy. This phase 1 study evaluated efficacy and safety of first-line therapy with NIVO plus IPI, an IgG1 CTLA-4 checkpoint receptor blocking antibody, in chemotherapy-naïve patients (pts) with advanced NSCLC. Methods: Pts (N=49) received NIVO plus IPI at the 1+3mg/kg or 3+1mg/kg combination dose, respectively (one SQ and one non-SQ cohort per dose level), Q3W for 4 cycles, followed by NIVO 3mg/kg Q2W until progression or unacceptable toxicity. ORR (per RECIST v1.1) was evaluated overall and by baseline tumor PD-L1 expression (PD-L1+: ≥5% tumor cells expressing PD-L1). Response was assessed at wks 10, 17, and 23, and every 3 mos thereafter until progression. Results: Median follow-up for all pts was 50 wks. 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; 67% (2/3) and 60% (3/5) of NIVO1+IPI3 and NIVO3+IPI1 responders, respectively, are ongoing. Two pts in the NIVO3+IPI1 group exhibited an unconventional “immune-related” response, with 56% and 64% maximum reductions in target lesions, respectively, and simultaneous appearance of new lesions. PFS and OS by combination dose are shown below (Table). Thirty-eight of 49 treated pts were evaluable for PD-L1 expression; ORR was 19% (3/16) for PD-L1+ pts and 14% (3/22) for PD-L1− pts. Across arms, grade 3–4 treatment-related AEs were reported in 25 (51%) pts; grade 3 pneumonitis was reported in 3 (6%) pts. Treatment-related AEs led to discontinuation in 18 (37%) pts; 15 (31%) pts discontinued during induction. Treatment-related deaths (n=3) were due to respiratory failure, bronchopulmonary hemorrhage, and toxic epidermal necrosis. Conclusions: 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. Additional treatment schedules are under evaluation to further optimize safety and efficacy of NIVO plus IPI.

Nivolumab (NIVO) monotherapy or in combination with ipilimumab (IPI) for treatment of recurrent small cell lung cancer (SCLC) E. Calvo

Background: Treatment options for limited and extensive stage SCLC after failing platinum-based (PLT) chemotherapy (CT) are limited. Blockade of immune checkpoint programmed death-1 (PD-1) or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have shown anti-tumor activity as monotherapy or in combination in multiple solid tumors, with manageable safety profiles. NIVO is a fully human IgG4 PD-1 immune checkpoint inhibitor approved for melanoma and squamous NSCLC in the US. IPI is a fully human IgG4 CTLA-4 checkpoint inhibitor approved for melanoma in the EU and US. We report updated results of a phase 1/2 study of NIVO ± IPI in pretreated SCLC patients (pts). Methods: Pts were assigned to NIVO 3mg/kg IV Q2W or NIVO+IPI (1+1mg/kg or 1+3mg/kg) IV Q3W for 4 cycles followed by NIVO 3mg/kg Q2W. Pts who had PD were eligible, regardless of platinum sensitivity, tumor PD-L1 expression, or number of prior CT regimens. The primary objective was ORR. Additional objectives included safety, PFS, OS, and biomarker analysis. Results: 90 pts were enrolled (NIVO, n=40; NIVO1+IPI1, n=3; NIVO1+IPI3, n=47); 53% had ≥2 prior regimens. Results for evaluable pts are shown (Table). 8 pts (20%) in the NIVO monotherapy arm, 1 pt (33%) in the NIVO1+IPI1 arm, and 20 pts (43%) in the NIVO1+IPI3 arm continue treatment. Discontinuations due to treatment-related (TR) AEs were observed in 3 pts (8%) with NIVO; no patients with NIVO1+IPI1, and 5 pts (11%) with NIVO1+IPI3. Grade 3–4 TRAEs occurred in 6 pts (15%) with NIVO (stomatitis, fatigue, amylase increase, gamma-gt increase, hyperglycemia, encephalitis in 1 pt each), no pts (0%) with NIVO1+IPI1, and 16 pts (34%) with NIVO1+IPI3 (in ≥2 pts [4%]: diarrhea 8.5%, lipase increased 6.4%, vomiting 4.3%, rash 4.3%, rash maculo-papular 4.3%, and dermatitis 4.3%). TR pneumonitis occurred in 2 pts (grade 1–2) in the NIVO arm and 1 pt (grade 3–4) in the NIVO1+IPI3 arm. One fatal case of TR myasthenia gravis was reported in the NIVO1+IPI3 arm. Conclusions: NIVO monotherapy or in combination with IPI has clinical activity and is associated with durable response in SCLC patients after progression on PLT-based therapy. The safety profile is consistent with that observed in other tumors, and was managed with established safety guidelines.