NEXUS: a phase I dose escalation study of selinexor plus nivolumab and ipilimumab in Asian patients with advanced/metastatic solid malignancies

Selinexor (SEL) is a nuclear exportin 1 inhibitor that blocks the transport of nuclear proteins, including tumor suppressors, to the cytoplasm. Preclinical data suggest that the combination of SEL with checkpoint blockade may result in improved response to immunotherapy. NCT02419495 was a multiarm phase IB study of SEL in combination with other standard regimens in patients with advanced malignancies. Arm M utilized twice weekly oral SEL and intravenous nivolumab (NIVO). Arm N utilized weekly oral SEL with NIVO plus ipilimumab (IPI). The primary objective of this study was to evaluate the safety of SEL + NIVO and SEL + NIVO+IPI. Secondary objectives included determining the objective response rate (ORR) and progression-free survival (PFS). Twenty-nine patients were enrolled in the study, of which 26 (90%) had clear cell RCC (ccRCC). Most patients (72%, n = 21) had prior systemic therapies. All patients (100%) developed at least one treatment-emergent adverse event, and 93% had a treatment-related adverse event (TRAE). Grade ≥ 3 TRAE occurred in 31% of patients, including 10% with hyponatremia, 7% with neutropenia, and 7% with thromboembolic events. At a median follow-up of 12.4 months, the ORR in 27 patients evaluable for response was 19% (n = 5). An additional 17 patients (63%) had stable disease (SD) as the best response. The median PFS for the overall cohort was 14.5 months (95% CI 5.2-17.4 months; SEL + NIVO+IPI: 12.2 months, SEL + NIVO: 14.5 months). The median overall survival was 27.8 months (95% CI 15.3-32.5; SEL + NIVO+IPI: unreached, SEL + NIVO: 21.3 months). SEL in combination with NIVO or NIVO+IPI had a potentially favorable safety profile and showed modest clinical activity in patients with advanced renal cell carcinoma. This clinical trial was registered on clinicaltrials.gov (NCT02419495).

4551 Background: SEL is a first-in-class nuclear exportin 1 inhibitor, which blocks the transport of several proteins involved in cancer-cell growth from the nucleus to the cytoplasm. A syngeneic RENCA mouse model showed that SEL combined with checkpoint blockade resulted in increased effector and activated T cells, and NKT cells and reductions in myeloid cells and Tregs. We hypothesized that SEL+NIVO and SEL+NIVO+IPI are well tolerated and improve the overall response rate (ORR) observed with anti-PD1/CTLA-4. Methods: NCT02419495 is an open label, single center phase IB study of SEL with multiple standard chemotherapy or immunotherapy regimens in pts with advanced malignancies using 3 + 3 design in dose escalation. For SEL+NIVO+IPI, SEL was 60 mg (N = 4) or 80 mg (N = 6) given P.O. weekly with NIVO 3 mg/kg x 4 cycles then 480 mg Q4W plus IPI 1 mg/kg Q3W for 4 cycles only. For SEL+NIVO, SEL was 40 mg twice a week (N = 8), or 60 mg twice a week (N = 11) given with NIVO 240 mg Q2W or 480 mg Q4W. Primary objective was to establish the safety and tolerability of SEL+NIVO and SEL+NIVO+IPI. Secondary objectives included ORR and progression free survival (PFS). Results: 29 pts with RCC (25 males) were enrolled (table), including 3 pts with nonclear cell RCC (nccRCC), with a median age of 64 years (IQR 56-69). 21 patients (72%) had prior systemic therapies. Most common SEL or NIVO/IPI treatment-related ≥ grade (G) 3 adverse events (AEs) included endocrine disorders (N = 3), hyponatremia (N = 3), leukopenia (N = 3), transaminitis (N = 3), thromboemobolic events (N = 2), asymptomatic lipase increased (N = 2), anemia (N = 1), pneumonitis (N = 1), nephritis (N = 1), colitis (N = 1), fatigue (N = 1). Two pts discontinued therapy due to AEs (G3 pneumonitis from SEL+NIVO+IPI and G3 transaminitis from SEL+NIVO, respectively). At a median follow up of 17.5 months, 5 (17%) pts achieved a PR, and 17 (59%) achieved a stable disease (SD). The median PFS for the entire cohort was 17.5 months (SEL+NIVO+IPI: 7.2 months, SEL+NIVO: 17.5 months). Among the patients with clear cell RCC who received SEL+NIVO+IPI as first line (1L) therapy (N = 4), all (100%) achieved SD as best overall response. Among the patients with ccRCC who received SEL+NIVO as 1L (N = 2), one patient achieved confirmed PR and the other achieved SD. The median overall survival (OS) was 27.8 months (SEL+NIVO+IPI: unreached, SEL+NIVO: 21.3 months). Conclusions: Treatment with SEL in combination with NIVO or NIVO+IPI is well-tolerated and shows modest clinical activity as compared to historic NIVO or NIVO+IPI activity. Clinical trial information: NCT02419495.

LBA768 Background: Patients (pts) with MSI-H/dMMR mCRC have poor outcomes with standard chemo ± targeted therapies. NIVO ± IPI are approved in previously treated pts with MSI-H/dMMR mCRC in many countries, based on the phase 2 CheckMate 142 study. CheckMate 8HW (NCT04008030) is a randomized phase 3 study comparing NIVO + IPI with NIVO or chemo in pts with MSI-H/dMMR mCRC. We report progression-free survival (PFS) by blinded independent central review (BICR) at a prespecified interim analysis for NIVO + IPI vs chemo in the 1L setting. Methods: Pts ≥ 18 years with recurrent or mCRC not amenable to surgery and MSI-H/dMMR status per local testing were enrolled across different lines of therapy. Previously untreated pts were randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). For pts with BICR-documented progression with chemo, optional crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. Results: In the 1L setting, 303 pts were randomized to NIVO + IPI (n = 202) or chemo (n = 101); of these pts, 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR result by either immunohistochemistry and/or polymerase chain reaction-based tests. With 24.3 months of median follow-up, NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS vs chemo, with a 79% reduction in the risk of disease progression or death (HR 0.21 [95% CI 0.14–0.32]; P < 0.0001) (Table). No new safety signals were identified (Table). Conclusions: NIVO + IPI demonstrated superior PFS vs chemo in previously untreated pts with MSI-H/dMMR mCRC. NIVO + IPI had a different safety profile compared to chemo, with fewer grade 3–4 treatment-related adverse events (TRAEs). These results support 1L NIVO + IPI as a standard-of-care option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . [Table: see text]

122MO Nivolumab (NIVO) + ipilimumab (IPI) as first-line (1L) treatment (tx) for patients (pts) with advanced NSCLC (aNSCLC) and baseline (BL) brain metastases (mets): Intracranial and systemic outcomes from CheckMate 227 Part 1

3501 Background: In the phase 3 CheckMate 8HW study (NCT04008030), both dual primary endpoints of progression-free survival (PFS) for first-line (1L) NIVO + IPI vs chemo (HR 0.21; P < 0.0001) and NIVO + IPI vs NIVO across all lines (HR 0.62; P = 0.0003) in patients (pts) with centrally confirmed MSI-H/dMMR mCRC were met. We report expanded analyses of NIVO + IPI vs NIVO (all lines) and longer follow-up results for NIVO + IPI vs chemo (1L). Methods: The study design was described previously. Pts with MSI-H/dMMR per local testing were enrolled. After randomization, IHC and PCR based tests were used for central confirmation. PFS2 (time from randomization to progression after subsequent systemic therapy, start of second subsequent systemic therapy, or death) was a key exploratory endpoint. Results: In all randomized pts (all lines), 296 of 354 (84%) in the NIVO + IPI arm, 286 of 353 (81%) in the NIVO arm, and 113 of 132 (86%) in the chemo arm had centrally confirmed MSI-H/dMMR. In all randomized 1L pts, 171 of 202 (85%) in the NIVO + IPI arm and 84 of 101 (83%) in the chemo arm had centrally confirmed MSI-H/dMMR. Median follow-up was 47.0 mo (range 16.7–60.5). 1L NIVO + IPI continued to show PFS benefit vs chemo (Table). Subsequent systemic therapy was received by 27 (16%) and 61 (73%) pts after 1L NIVO + IPI and chemo, respectively; 10 (6%) and 21 (25%) received subsequent non-study immunotherapy. In the 1L chemo arm, 39 (46%) pts crossed over to NIVO + IPI on study. PFS2 continued to favor 1L NIVO + IPI vs chemo (Table). Across all lines, NIVO + IPI demonstrated superior PFS vs NIVO (Table). Subsequent systemic therapy was received by 54 (18%) pts in the NIVO + IPI arm and 83 (29%) in the NIVO arm; 20 (7%) and 31 (11%) received subsequent non-study immunotherapy. PFS2 favored NIVO + IPI vs NIVO across all lines of therapy (Table). In all treated pts, grade 3/4 treatment-related adverse events occurred in 78 (22%) and 50 (14%) pts in the NIVO + IPI and NIVO arms, respectively. Additional analyses will be presented. Conclusions: NIVO + IPI demonstrated sustained clinical benefit vs chemo (1L) and NIVO (all lines) despite use of subsequent therapy, as shown by improved PFS2 in pts with centrally confirmed MSI-H/dMMR mCRC. No new safety signals were observed. These results support NIVO + IPI as a standard of care treatment for MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . Centrally confirmed MSI-H/dMMR (1L) NIVO + IPI(n = 171) Chemo(n = 84) Median PFS (95% CI), mo 54.1 (54.1–NE) 5.9 (4.4–7.8) HR (95% CI) 0.21 (0.14–0.31) Median PFS2 (95% CI), mo NR (NE–NE) 30.3 (15.2–NE) HR (95% CI) 0.28 (0.18–0.44) Centrally confirmed MSI-H/dMMR (all lines) NIVO + IPI (n = 296) NIVO (n = 286) Median PFS (95% CI), mo NR (53.8–NE) 39.3 (22.1–NE) HR (95% CI) 0.62 (0.48-0.81); P = 0.0003 Median PFS2 (95% CI), mo NR (NE–NE) NR (NE–NE) HR (95% CI) 0.57 (0.42–0.78) NE, not evaluable; NR, not reached.

LBA71 First-line nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) in patients (pts) with unresectable malignant pleural mesothelioma (uMPM): 4-year update from CheckMate 743

LBA143 Background: The CheckMate 8HW study met its dual primary endpoint with NIVO + IPI demonstrating superior progression-free survival (PFS) by blinded independent central review (BICR) vs chemotherapy (chemo) in patients (pts) with centrally confirmed MSI-H/dMMR mCRC in the first-line (1L) setting (HR 0.21; 95% CI 0.14–0.32; P < 0.0001). We report first results from the other dual primary endpoint of PFS for NIVO + IPI vs NIVO across all lines of therapy in pts with centrally confirmed MSI-H/dMMR mCRC. Methods: Immunotherapy-naive pts with unresectable or mCRC and MSI-H/dMMR status by local testing who had received 0 or 1 prior line of therapy were randomized 2:2:1 to (i) NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), (ii) NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), or (iii) chemo ± targeted therapies. Pts who had received ≥ 2 prior lines of therapy were randomized 1:1 to the NIVO + IPI or NIVO arms. Treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). Results: Across all lines of therapy,707 pts were randomized to NIVO + IPI (n = 354) or NIVO (n = 353); 55% and 52% received study treatment in the 1L setting, respectively. Of all randomized pts, 296 in the NIVO + IPI arm and 286 in the NIVO arm had centrally confirmed MSI-H/dMMR status. With 47.0 months (mo) of median follow-up (range, 16.7–60.5), NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS by BICR vs NIVO (HR 0.62; 95% CI 0.48–0.81; P = 0.0003) and higher 12-, 24-, and 36-mo PFS rates vs NIVO (Table). Objective response rate (ORR) by BICR was significantly higher with NIVO + IPI vs NIVO (71% vs 58%; P = 0.0011; Table); best overall response of progressive disease was reported in 10% and 19% of pts, respectively. No new safety concerns were identified (Table). Conclusions: In the first randomized study to compare dual- vs single-agent immunotherapy in MSI-H/dMMR mCRC, NIVO + IPI demonstrated superior PFS vs NIVO across all lines of therapy, with a manageable safety profile. These results establish NIVO + IPI as the potential new standard-of-care treatment for MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . Efficacy by BICR (all lines; centrally confirmed MSI-H/dMMR by IHC and/or PCR test) NIVO + IPI(n = 296) NIVO(n = 286) Median PFS (95% CI), mo NR (53.8–NE) 39.3 (22.1–NE) HR (95% CI); P value 0.62 (0.48–0.81); 0.0003 PFS rate (12/24/36-mo), % 76/71/68 63/56/51 ORR, n (%); 95% CI, % 209 (71); 65–76 165 (58); 52–64 P value 0.0011 Safety (all lines; all treated), n (%) NIVO + IPI (n = 352) NIVO (n = 351) Any-grade/grade 3–4 TRAEs 285 (81)/78 (22) 249 (71)/50 (14) Any-grade/grade 3–4 TRAEs leading to discontinuation 48 (14)/33 (9) 21 (6)/14 (4) Treatment-related deaths 2 (< 1) 1 (< 1) IHC, immunohistochemistry; NE, not estimable; NR, not reached; PCR, polymerase chain reaction; TRAE, treatment-related adverse event.

Purpose: This phase 1/2 trial evaluates the novel immunotherapy BMS-986253 in combination with immune checkpoint inhibitors (NCT03400332). Interleukin-8 (IL-8) is an immunosuppressive chemokine often elevated in the serum of patients with cancer. High serum IL-8 concentration is associated with poor prognoses and resistance to immunotherapies, including anti-programmed death-1 (PD-1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents (Schalper et al. Nat Med 2020;26:688). The addition of anti-IL-8 therapy to anti-PD-1 nivolumab (NIVO) and anti-CTLA-4 ipilimumab (IPI) may sensitize patients with high serum IL-8 levels to immune checkpoint inhibition. BMS-986253, a fully human IgG1 anti-IL-8 monoclonal antibody, in combination with NIVO ± IPI is under investigation in a phase 1/2 trial of patients with advanced solid tumors. Initial results from part 1 indicate BMS-986253 + NIVO was well tolerated with no dose-limiting toxicities (Davar et al. J Immunother Cancer 2020;8. Abstract 394). Preliminary antitumor activity was observed, including partial responses in 5 of 28 patients with melanoma that had progressed on or after prior anti-PD-(L)1 therapy, a population with high unmet medical need. Part 2 is a randomized, double-blind phase 2 study comparing the efficacy of BMS-986253 in combination with NIVO + IPI vs NIVO + IPI in patients with advanced melanoma that progressed on or after prior anti-PD-(L)1 therapy. Trial Design: Patients eligible for part 2 have histologically confirmed, unresectable, stage III/IV melanoma, have progressed on or after anti-PD-(L)1 treatment, had an anti-PD-(L)1 agent as their most recent therapy, and have not received anti-CTLA-4 treatment. PD-L1 and BRAFV600 mutation status (wild-type and BRAF mutations permitted) must be documented, and serum IL-8 levels will be measured at screening. Patients will be randomized 1:1 to receive BMS-986253 + NIVO + IPI or placebo + NIVO + IPI and stratified by serum IL-8 level, BRAF V600E status, and lactate dehydrogenase level. The dose and frequency of BMS-986253, NIVO, and IPI will be determined by part 1 data. Treatment with BMS-986253 or placebo and NIVO will continue ≤ 3 years or until disease progression or intolerance. The primary objective is to compare progression-free survival (PFS) by blinded independent central review (BICR) per RECIST v1.1 between treatment arms in patients with baseline serum IL-8 levels > 10 pg/mL. Secondary objectives include PFS by BICR in all randomized patients, overall response rates by BICR per RECIST v1.1, overall survival, safety, pharmacokinetic profile, immunogenicity of BMS-986253, and associations of baseline factors with response. Recruitment will continue until ≈170 patients are enrolled. Citation Format: Matteo Simonelli, Emiliano Calvo, Diwakar Davar, Jason Melear, Donald Richards, Matthew Dallos, Martin Gutierrez, Victor Moreno, Thomas Marron, Sylvie Rottey, Angela Orcurto, Susana Barriga, Jessy Fan, Elizabeth Gibson, Santanu Dutta, Vivek Arora, Ignacio Melero. A randomized, double-blind phase 2 evaluation of the anti-IL-8 monoclonal antibody BMS-986253 + nivolumab + ipilimumab vs nivolumab + ipilimumab in patients with advanced melanoma that progressed on/after anti-PD-(L)1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT119.

9506 Background: In the phase 3 CheckMate 067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) + ipilimumab (IPI) and NIVO alone vs IPI at 5-y of follow-up (overall survival [OS] and progression-free survival [PFS] rates: 52%, 44%, 26% and 36%, 29%, 8%, respectively). Here we report 6.5-y efficacy and safety outcomes. Methods: Eligible pts with previously untreated unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio and stratified by PD-L1 status, BRAF mutation status, and metastasis stage. Pts received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W (n = 314), NIVO 3 mg/kg Q2W + placebo (n = 316), or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were PFS and OS with NIVO + IPI or NIVO vs IPI. Secondary endpoints included objective response rate (ORR), descriptive efficacy assessments of NIVO + IPI vs NIVO alone, and safety. Results: With a minimum follow-up of 6.5 y, median OS was 72.1 mo with NIVO + IPI, 36.9 mo with NIVO, and 19.9 mo with IPI (table). Median time from randomization to subsequent systemic therapy was not reached (NR; 95% CI, 59.6–NR) with NIVO + IPI, 25.2 mo (95% CI, 16.0–43.2) with NIVO, and 8.0 mo (95% CI, 6.5–8.7) with IPI; 36%, 49%, and 66% of pts, respectively, received any subsequent systemic therapy. Median treatment-free interval (which excluded pts who discontinued follow-up prior to initiation of subsequent systemic therapy) was 27.6 mo (range, 0–83.0), 2.3 mo (range, 0.2–81.6), and 1.9 mo (range, 0.1–81.9) with NIVO + IPI, NIVO, and IPI, respectively. Of the pts alive and in follow-up, 112/138 (81%; NIVO + IPI), 84/114 (74%; NIVO), and 27/63 (43%; IPI) were off treatment and never received subsequent systemic therapy; 7, 8, and 0 pts, respectively, were still on treatment. Grade 3/4 treatment-related adverse events were reported in 59% of NIVO + IPI-treated pts, 24% of NIVO-treated pts, and 28% of IPI-treated pts. Since the 5-y analysis, no new safety signals were observed and no additional treatment-related deaths occurred. Conclusions: This 6.5-y analysis represents the longest follow-up from a phase 3 melanoma trial in the modern checkpoint inhibitor combination therapy and targeted therapy era. The results show durable improved outcomes with NIVO + IPI and NIVO vs IPI in pts with advanced melanoma. We observed improvement in OS, PFS, and ORR with NIVO + IPI over NIVO alone. Clinical trial information: NCT01844505. [Table: see text]

9542 Background: NIVO + IPI has demonstrated durable clinical benefit at 7.5 y in pts with advanced melanoma in the phase 3 CheckMate 067 study. PFS curves plateaued at ~3 y in this study, suggesting that being alive and progression-free for ≥ 3 y (PFS ≥ 3y) may be a good surrogate for long-term clinical benefit. We conducted analyses to quantify this association. Methods: Pts with treatment (tx)-naive, unresectable stage III/IV melanoma (stratified by PD-L1 expression, BRAF mutation status, and metastasis stage) received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314); NIVO 3 mg/kg Q2W + placebo (n = 316); or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Exploratory post hoc analysis was performed in pts with PFS ≥ 3y. Results: In the NIVO + IPI, NIVO, and IPI arms, respectively, 99 (32%), 78 (25%), and 21 (7%) pts had PFS ≥ 3y. Objective response rates (ORRs) in these pts were ≥ 95% (table). The majority of responses were complete responses (CRs; table); in almost all pts with partial responses (PRs) on NIVO + IPI or NIVO, target-lesion size decreased by ≥ 50%. At 7.5 y of follow-up among pts alive and progression-free at 3 y, PFS rates were ≥ 68%, overall survival (OS) rates were ≥ 85%, and melanoma-specific survival (MSS) rates were ≥ 95% in the 3 tx groups (table). Among pts in this group who died after 3 y on study, the majority of deaths were unrelated to disease (table). The majority of pts with PFS ≥ 3y who were alive and in follow-up were tx-free at the 7.5-y data cutoff (77/84, 57/64, and 13/16). Pts who received NIVO + IPI were off tx (median) for 75.5 mo (NIVO, 55.7 mo; IPI, 59.2 mo). Among pts with PFS ≥ 3y in the 3 tx groups, 4%, 5%, and 19% received subsequent systemic tx (table). No new safety signals were observed in pts with PFS ≥ 3y. Conclusions: This exploratory post hoc analysis suggested that PFS ≥ 3y may be a good surrogate for long-term MSS with NIVO + IPI or NIVO, with very few occurrences of progression or death due to melanoma in this population through 7.5 y. Most pts were tx-free without having received subsequent systemic tx after demonstrating PFS ≥ 3y. Further study of pts with PFS ≥ 3y may allow the burden of imaging and follow-up visits to be reduced in this group. Clinical trial information: NCT01844505 . [Table: see text]

3510 Background: NIVO ± IPI is approved in previously treated pts with MSI-H/dMMR mCRC in the US, EU, and Japan, based on findings from the phase 2 CheckMate 142 study (NCT02060188). NCCN guidelines include NIVO + IPI as an initial therapy option for pts with MSI-H/dMMR mCRC. Results from a ~5-year follow-up from CheckMate 142 cohorts 1–3 (C1–3) are reported here. Methods: In this non-randomized, multicohort study, pts with MSI-H/dMMR mCRC were treated as follows: C1 (2L+; NIVO 3 mg/kg Q2W), C2 (2L+; NIVO 3 mg/kg + IPI 1 mg/kg Q3W [4 doses], followed by NIVO 3 mg/kg Q2W) and C3 (1L; NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by investigator assessment (INV) per RECIST v1.1. Other key endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all by INV and blinded independent central review; overall survival (OS), and safety. Results: In C1 (N = 74), C2 (N = 119), and C3 (N = 45), median (range) follow-up (time from first dose to data cutoff) was 70.0 (66.2–88.7), 64.0 (60.0–75.8), and 52.4 (47.6–57.1) months (mo), respectively. ORR (95% CI) by INV was 39% (28–51), 65% (55–73), and 71% (56–84; Table) and progressive disease (PD) rates were 26%, 12%, and 16% in C1, C2, and C3, respectively. Median DOR was not reached in the 3 cohorts. The 48-mo PFS rates were 36%, 54%, and 51% and 48-mo OS rates were 49%, 71%, and 72% in C1, C2, and C3, respectively (Table). PFS and OS rates with up to 60 mo of follow-up will be presented. Safety data are shown in the table. Conclusions: With extended follow-up of ~5 years, NIVO ± IPI continued to demonstrate durable OS and PFS benefit, with no new safety signals. These updated data further support current treatment recommendations for 2L+ NIVO ± IPI and 1L NIVO + IPI for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]

9560 Background: In Part 1 of the phase II CheckMate 568 study (NCT02659059), NIVO + IPI was active and tolerable in patients (pts) with advanced NSCLC. The addition of chemo to dual immune checkpoint inhibitor therapy may further improve initial disease control. We report results from Part 2 of CheckMate 568, which evaluates NIVO + IPI combined with 2 cycles of chemo in pts with advanced treatment-naive NSCLC. Methods: Adult pts with untreated stage IV NSCLC received NIVO 360 mg Q3W + IPI 1 mg/kg Q6W combined with 2 cycles of histology-based platinum-doublet chemo, followed by NIVO + IPI without chemo until disease progression/unacceptable toxicity for ≤ 2 years. The primary endpoints were dose-limiting toxicity (DLT) within the first 9 weeks and safety/tolerability. Treatment was considered safe if ≤ 25% of at least 22 evaluable pts had a DLT. DLTs included but were not limited to: uncontrolled grade 3 non-skin treatment-related adverse events (TRAEs), grade 4 TRAEs, grade 2 treatment-related pneumonitis not resolved within 14 days, and treatment-related hepatic function abnormalities. Results: In total, 36 pts received treatment; 97% of pts completed 2 cycles of chemo combined with NIVO + IPI. Three pts discontinued IPI while continuing NIVO. Minimum follow-up was 14.9 months. Only 1 (3%) pt experienced a DLT (transient, asymptomatic grade 3 AST and ALT elevation) within the first 9 weeks. The elevation occurred on cycle 1, day 21 and resolved 2 weeks later with discontinuation of IPI, delay of NIVO, and treatment with prednisone; chemo was continued throughout and NIVO was restarted thereafter without recurrent toxicity. Grade 3–4 TRAEs occurred in 21 (58%) pts. Eight (22%) pts experienced a TRAE leading to discontinuation, most commonly colitis, encephalopathy, pneumonitis, and arthralgia (each in 2 [6%] pts); these events occurred outside of the 9-week window for DLT assessment. The most common select TRAEs (defined as AEs of potential immunologic causes) were skin related (18 [50%] pts); the most common grade 3–4 select TRAEs were endocrine (3 [8%] pts), skin related, gastrointestinal, and pulmonary (each in 2 [6%] pts). No treatment-related deaths occurred. Updated safety in addition to efficacy data will be presented. Conclusions: In pts with untreated advanced NSCLC, the addition of 2 cycles of platinum-doublet chemo to NIVO + tumor-optimized IPI was tolerable. No unexpected safety signals were observed. Clinical trial information: NCT02659059 .

LBA4_PR - Nivolumab (NIVO) + low-dose ipilimumab (IPI) vs platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate 227 part 1 final analysis

9506 Background: MCC is a rare and aggressive skin cancer. Programmed death-ligand 1 (PD-L1) is often upregulated in MCC and blockade of PD-L1 or its receptor, PD-1, has improved survival for patients with metastatic MCC. Anti–PD-1 combined with anti–CTLA-4 has been reported to improve outcomes over anti–PD-1 monotherapy (NCT03071406; Kim S et al., Lancet 2022), however further investigation is needed. CheckMate 358 (NCT02488759) assessed NIVO ± IPI in 2 non-randomized MCC cohorts. Methods: Eligible pts had recurrent or metastatic MCC, ≤ 2 prior therapies, ECOG performance status (PS) 0–1, and no prior immune checkpoint inhibitor (ICI) therapy. Pts were eligible regardless of PD-(L)1 status. Pts received NIVO 240 mg Q2W or NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W for ≤ 24 months (m) or until disease progression, unacceptable toxicity, or consent withdrawal. Imaging was conducted Q8W in year 1 and Q12W thereafter. Planned sample sizes were 23 pts for NIVO and 40 pts for NIVO + IPI. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included duration of response (DOR), investigator-assessed progression-free survival (PFS), and overall survival (OS). Results: 68 pts received NIVO (n = 25) or NIVO + IPI (n = 43) with ≥ 24 m follow-up (median: NIVO, 62.5 m; NIVO + IPI, 24.4 m). In the NIVO arm, median age was 66 yrs (range, 27–88), 10 (40.0%) pts had ECOG PS of 1, and 15 (60.0%) were treatment-naive. In the NIVO + IPI arm, median age was 70 yrs (range, 48–85), 27 (62.8%) pts had ECOG PS of 1, and 33 (76.7%) were treatment-naive. Treatment duration was 15.8 m in the NIVO arm, and 7.9 m for NIVO and 6.0 m for IPI in the NIVO + IPI arm. Efficacy and safety outcomes are summarized in the table. ORR was 60.0% (95% CI, 38.7–78.9) in the NIVO arm and 58.1% (95% CI, 42.1–73.0) in the NIVO + IPI arm. The most common reasons for treatment discontinuation were disease progression (NIVO, 28.0%; NIVO + IPI, 32.6%) or study-drug toxicity (NIVO, 20.0%; NIVO + IPI, 25.6%). There was 1 study drug-related death in each arm (NIVO, pneumonitis; NIVO + IPI, gastrointestinal motility disorder). Conclusions: Both NIVO and NIVO + IPI show durable clinical efficacy in advanced MCC. While the non-randomized trial design limits comparisons between the arms, results do not suggest additional efficacy benefit with IPI added to NIVO. Higher incidence of grade 3/4 TRAEs observed in the combination arm could have resulted in shorter treatment duration. Clinical trial information: NCT02488759 . [Table: see text]

LBA9025 Background: In CheckMate 227 part 1 (NCT02477826), 1L NIVO + IPI demonstrated long-term, durable survival benefit vs platinum-doublet chemo in patients (pts) with metastatic NSCLC regardless of tumor programmed death ligand 1 (PD-L1) expression level. Here we present the longest reported follow-up (5 y) of a phase 3 trial of 1L combination immunotherapy in metastatic NSCLC. Methods: Adults with previously untreated stage IV or recurrent NSCLC, no known EGFR/ ALK alterations , and an ECOG performance status ≤ 1 were enrolled and stratified by histology. Pts with tumor PD-L1 ≥ 1% were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W), or chemo. Pts with tumor PD-L1 < 1% were randomized 1:1:1 to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Pts were treated until progression, toxicity, or ≤ 2 y for immunotherapy. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and a novel efficacy endpoint, treatment-free interval. Treatment-free interval was measured in pts who discontinued study therapy (for any reason including treatment completion) and was defined as the time from last study dose to start of subsequent systemic therapy or death, whichever occurred first. Results: Minimum follow-up was 61.3 mo (database lock, Feb 15, 2022). In pts with tumor PD-L1 ≥ 1% (N = 1189), continued long-term OS benefit was seen with NIVO + IPI vs chemo (HR, 0.77 [95% CI, 0.66–0.91]); 5-y OS rates were 24% (NIVO + IPI), 17% (NIVO), and 14% (chemo). OS benefit also continued in pts with tumor PD-L1 < 1% (N = 550) for NIVO + IPI vs chemo (HR, 0.65 [95% CI, 0.52–0.81]); 5-y OS rates were 19% (NIVO + IPI), 10% (NIVO + chemo), and 7% (chemo). Clinical benefit with NIVO + IPI vs chemo was observed across additional efficacy endpoints in the overall population and in pts alive at 5 y (table). PFS, ORR, and DOR with NIVO and NIVO + chemo will be presented. Among pts alive at 5 y in the NIVO + IPI group, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) remained treatment-free ≥ 3 y after discontinuing study therapy; median (range) duration of NIVO ± IPI therapy was 17.7 (0-25.5) mo (PD-L1 ≥ 1%) and 9.5 (0-25.1) mo (PD-L1 < 1%). No new safety signals were observed. Conclusions: With a 5-y minimum follow-up, NIVO + IPI continues to provide long-term, durable clinical benefit vs chemo in previously untreated pts with metastatic NSCLC, regardless of PD-L1 expression. NIVO + IPI led to increased 5-y survivorship; the majority of these pts were treatment-free for ≥ 3 y post-treatment discontinuation. Clinical trial information: NCT02477826. [Table: see text]