Phase I/IIa dose finding study of triplet regimen of relatlimab (RELA), ipilimumab (IPI), and nivolumab (NIVO) in first-line therapy of metastatic melanoma (TRINITY).

Immune checkpoint (IC) proteins are some of the most important factors that tumor cells hijack to escape immune surveillance, and inhibiting ICs to enhance or relieve antitumor immunity has been proven efficient in tumor treatment. Immune checkpoint blockade (ICB) agents such as antibodies blocking programmed death (PD) 1, PD-1 ligand (PD-L) 1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 have been approved by the U.S. Food and Drug Administration (FDA) to treat several types of cancers. Although ICB agents have shown outstanding clinical success, and their application has continued to expand to additional tumor types in the past decade, immune-related adverse events (irAEs) have been observed in a wide range of patients who receive ICB treatment. Numerous studies have focused on the clinical manifestations and pathology of ICB-related irAEs, but the detailed mechanisms underlying irAEs remain largely unknown. Owing to the wide expression of IC molecules on distinct immune cell subpopulations and the fact that ICB agents generally affect IC-expressing cells, the influences of ICB agents on immune cells in irAEs need to be determined. Here, we discuss the expression and functions of IC proteins on distinct immune cells and the potential mechanism(s) related to ICB-targeted immune cell subsets in irAEs.

Introduction: Checkpoint inhibitors have demonstrated activity in brain lesions in several tumor types, including NSCLC. CheckMate 227 Part 1 (NCT02477826) met its two independent co-primary endpoints, including improved overall survival (OS) for NIVO + IPI vs histology-based chemotherapy (chemo) in patients (pts) with tumor programmed death ligand 1 (PD-L1) expression ≥ 1%. Benefit was also observed in pts with PD-L1 < 1%. Eligible pts included those with treated, asymptomatic brain metastases (mets). Here we present a post-hoc analysis of efficacy and safety in pts with and without baseline (BL) brain mets. Methods: Eligible pts were chemo-naive, with stage IV or recurrent NSCLC, no known sensitizing EGFR/ALK alterations, and ECOG PS 0–1. Pts with treated brain mets who were asymptomatic for ≥ 2 wks prior to randomization were eligible; corticosteroids equivalent to ≤ 10 mg of prednisone daily were permitted if stable or decreasing for ≥ 2 wks prior to randomization. Pts with PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W, NIVO 240 mg Q2W, or chemo; pts with PD-L1 < 1% (n = 550) were randomized 1:1:1 to NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W, NIVO 360 mg Q3W + chemo, or chemo. Pts were treated until disease progression, unacceptable toxicity, or ≤ 2 y of immunotherapy. Results: BL characteristics were generally similar between pts with and without BL brain mets, except that a greater proportion of pts with BL brain mets were < 65 years of age and had non-squamous histology. Efficacy data are shown in the Table. Any-grade nervous system adverse events were reported in 46% of pts with BL brain mets treated with NIVO + IPI and 42% of those treated with chemo, most were grade 1–2. Conclusion: In this post-hoc analysis of pts with advanced NSCLC, NIVO + IPI appeared to provide similar benefit in pts with and without BL brain mets. No new safety signals were identified. Table.Efficacy by baseline brain metastases in CheckMate 227 Part 1Patients with baseline brain metastasesPatients without baseline brain metastasesNIVO + IPI (n = 69)Chemo (n = 66)NIVO + IPI (n = 514)Chemo (n = 517)OS, median (95% CI), mo18.8 (9.2-29.4)13.7 (10.5-16.2)17.1 (15.3-19.9)13.9 (11.8-15.3)HR (95% CI)0.57 (0.38-0.85)0.76 (0.66-0.88)1-y rates, %575962542-y rates, %44264030PFS,a median (95% CI), mo5.4 (3.1-8.6)5.8 (4.3-8.0)4.9 (4.1-5.7)5.4 (4.5-5.6)HR (95% CI)0.79 (0.52-1.19)0.81 (0.70-0.93)1-y rates, %382132172-y rates, %227206ORR,a %33263328DOR,a median (95% CI), mo24.9 (11.3-NR)8.4 (4.2-13.9)19.6 (15.5-28.6)5.8 (4.8-6.9)1-y rates, %724065262-y rates, %5384610Minimum follow-up was 29.3 mo.aPer BICR. BICR, blinded independent central review; CI, confidence interval; chemo, chemotherapy; DOR, duration of response; HR, hazard ratio; IPI, ipilimumab; mo, month; NIVO, nivolumab; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; y, year. Citation Format: Hossein Borghaei, Adam Pluzanski, Reyes Bernabe Caro, Mariano Provencio, Sjaak Burgers, Enric Carcereny, Keunchil Park, Aurelia Alexandru, Lorena Lupinacci, Randeep Sangha, Judith Raimbourg, Alain Vergnenegre, Konstantinos Syrigos, Fabrice Barlesi, Norbert Frickhofen, Ang Li, Ravi Kasinathan, Luis Paz-Ares. Nivolumab (NIVO) + ipilimumab (IPI) as first-line (1L) treatment for patients with advanced non-small cell lung cancer (NSCLC) with brain metastases: Results from CheckMate 227 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT221.

540 Background: Ipilimumab (IPI) and nivolumab (NIVO) are standard first-line systemic therapy for patients with metastatic renal cell carcinoma (RCC). The regimen is administered in combination once every 3 weeks for 4 doses, followed by NIVO maintenance. The dose and frequency of IPI appears to correlate with treatment safety and tolerability across cancer types. Further, studies in advanced melanoma have demonstrated that the efficacy of IPI + NIVO is largely driven by the first two doses in many patients (Postow MA et al., J Clin. Oncol. 2022). We assessed outcomes with IPI + NIVO by number of doses given in patients with metastatic RCC. Methods: We conducted a retrospective study of patients with metastatic RCC at Memorial Sloan Kettering Cancer Center treated with first-line IPI + NIVO. Baseline characteristics and treatment outcomes were obtained from electronic health record review. We calculated overall survival (OS) by the Kaplan-Meier method starting at 12 weeks after initiation of combination therapy, including all patients who were still alive and being followed at that time point and excluding those who had disease progression prior to completing 4 doses. We compared survival rates at 12 and 18 months and median OS for patients who received 4 doses versus those who received fewer than 4 doses. Results: Patients with metastatic RCC treated with first-line IPI + NIVO were included (N=222); 77% were male, 85% had clear cell RCC, 48% had sarcomatoid and/or rhabdoid features, and 87% had IMDC intermediate or poor risk disease. Regarding IPI + NIVO, 145 patients (65%) received all 4 doses, 30 (14%) received 3 doses, 21 (9%) received 2 doses, and 26 (12%) received 1 dose. The most common reasons for not completing all 4 doses (77, 35%) were toxicity (57%) and disease progression (21%). All 145 patients who received 4 doses and 44 who received fewer than 4 doses for reasons other than early progression or death were included in the analysis. OS in the 4 dose and <4 dose group at 18 months was 83% (95% CI: 76%, 89%) and 79% (95% CI: 63%, 88%), respectively. Conclusions: In this observational analysis, we found comparable OS rates in those patients who received all 4 doses of IPI + NIVO compared to those who received fewer than 4 doses for reasons other than disease progression, primarily toxicity. Four Doses of IPI + NIVO (N=145) Fewer Than Four Doses of IPI + NIVO, Excluding Early Disease Progression (N=44) 12-month OS (95% CI) 89% (82%, 93%) 86% (72%, 94%) 18-month OS (95% CI) 83% (76%, 89%) 79% (63%, 88%) Median OS, months (95% CI) 67.1 (40.1, NR) 82.5 (27.1, 109.3) Log-rank p value = 0.595

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]

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]

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.

LBA1 Background: The results of a phase I study in MEL suggested complementary clinical activity with NIVO (a PD-1 checkpoint inhibitor) plus IPI (a CTLA-4 checkpoint inhibitor). Here, we report the results of a randomized, double-blind, phase III trial designed to evaluate NIVO combined with IPI or NIVO alone vs IPI alone in MEL. Methods: Treatment-naïve pts (N = 945) were randomized 1:1:1 to NIVO 1 mg/kg Q2W + IPI 3 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W, NIVO 3 mg/kg Q2W + placebo, or IPI 3 mg/kg Q3W for 4 doses + placebo, until progression or unacceptable toxicity. Pts were stratified by PD-L1 status, BRAF mutation status, and M-stage. Co-primary endpoints are progression-free survival (PFS) (reported here) and overall survival (pts continue to be followed). Secondary endpoints include objective response rate (ORR) by RECIST v1.1 and safety. Results: At a minimum follow-up of 9 months, NIVO + IPI and NIVO alone significantly improved PFS and ORR vs IPI (Table). Grade 3-4 drug-related adverse events (AEs) occurred in 55.0%, 16.3%, and 27.3% of pts in the NIVO + IPI, NIVO, and IPI arms, respectively (most commonly diarrhea [9.3%, 2.2%, 6.1%], increased lipase [8.6%, 3.5%, 3.9%], increased alanine aminotransferase [8.3%, 1.3%, 1.6%], and colitis [7.7%, 0.6%, 8.7%]). Drug-related AEs led to discontinuation in 36.4%, 7.7%, and 14.8% of pts in the NIVO + IPI, NIVO, and IPI arms, with 0, 1, and 1 drug-related deaths, respectively. Efficacy outcomes by PD-L1 status will also be presented. Conclusions: NIVO + IPI and NIVO alone had superior clinical activity vs IPI alone. The results with NIVO + IPI and NIVO alone further suggest complementary activity of the two agents. There were no new safety signals or drug-related deaths observed with the combination. Clinical trial information: NCT01844505. [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]

O-3 Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648

TPS9591 Background: Immunotherapy (IMT) with checkpoint blocking antibodies has led to progress in metastatic melanoma with 3 FDA-approved drugs, including the combination of ipilimumab (IPI), a CTLA-4 antibody, and nivolumab (NIVO), a PD-1 antibody. Although radiotherapy (RT) is primarily used as local palliative therapy in metastatic melanoma, it also possibly affects systemic antitumor immunity. Preclinical data suggest RT alters the tumor microenvironment and renders tumor cells more susceptible to immunologically-mediated disease regression. These preclinical immunologic effects of RT have been shown to vary by RT dose and fractionation. We are now conducting the first clinical trial in patients to evaluate the triple combination of IPI + NIVO + RT using 2 different dose/fractionation schemes of RT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02659540) evaluates safety, efficacy, and immunologic effects of IPI + NIVO + RT in 18 patients with unresectable stage IV melanoma. Patients must have 1 melanoma metastasis that can be safely irradiated for palliative purposes and at least 1 measurable lesion that will not be irradiated. Patients receive concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks (Q3W) x 4, followed by NIVO monotherapy (240 mg Q2W), with RT initiated between the first and second doses of IPI + NIVO. In Cohort A, the irradiated metastasis receives a conventionally fractionated low dose of 30 Gy in 10 fractions of 3 Gy each over 2 weeks. If ≤7 of 9 patients (78%) in Cohort A have Grade 3/4 drug- or radiation-related adverse events, safety is deemed acceptable and Cohort B enrollment opens. In Cohort B, the irradiated metastasis receives a hypofractionated high dose of 27 Gy in 3 fractions of 9 Gy each over 2 weeks. The primary endpoint is safety. Secondary endpoints are objective response rate and disease control rate by RECIST and immune-related RECIST measured at Weeks 12 and 18, duration of response, progression-free survival, and overall survival. Exploratory endpoints include correlative studies of immunological effects. Enrollment opened on 05 Aug 2016. As of 31 Dec 2016, 4 patients are enrolled in Cohort A; enrollment is ongoing. Clinical trial information: NCT02659540.

520 Background: In the phase 3 CheckMate 9DW study (NCT04039607), 1L NIVO + IPI demonstrated significant overall survival (OS) benefit vs LEN/SOR, higher objective response rate (ORR) with durable responses, and manageable safety in uHCC. We present efficacy by best overall response (BOR) subgroups and baseline characteristics, and additional safety analyses from the preplanned interim analysis. Methods: Patients (pts) with previously untreated HCC not eligible for curative surgical or locoregional therapies, Child-Pugh score 5 or 6, and ECOG performance status 0 or 1 were randomized 1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg Q3W (up to 4 cycles), then NIVO 480 mg Q4W or LEN 8 mg or 12 mg QD or SOR 400 mg BID until disease progression or unacceptable toxicity. NIVO was given for a maximum of 2 years. The primary endpoint was OS; secondary endpoints included ORR and duration of response (DOR) per blinded independent central review (BICR) using RECIST v1.1. Results: A total of 668 pts were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333). At a median follow-up of 35.2 (range 26.8–48.9) months (mo), median OS (95% CI) was 23.7 (18.8–29.4) mo with NIVO + IPI vs 20.6 (17.5–22.5) mo with LEN/SOR (HR 0.79 [95% CI 0.65–0.96]; P = 0.0180). ORR (95% CI) per BICR was significantly higher with NIVO + IPI vs LEN/SOR (36% [31–42] vs 13% [10–17]; P < 0.0001); median DOR (95% CI) was 30.4 (21.2–not estimable [NE]) mo vs 12.9 (10.2–31.2) mo. Survival benefit of NIVO + IPI vs LEN/SOR was observed across BOR subgroups at the 24-week landmark timepoint (Table). In subgroup analyses, ORR (95% CI) per BICR was higher with NIVO + IPI vs LEN/SOR across HCC etiologies (uninfected: 35% [26–44] vs 8% [4–15]; HBV infected: 25% [17–34] vs 17% [10–25]; HCV infected: 50% [39–61] vs 16% [9–25]) and in pts with Barcelona Clinic Liver Cancer stage ≤B (33% [23–43] vs 13% [6–21]) or stage C (37% [31–44] vs 14% [10–19]). Safety data are shown in the Table. Additional exploratory analyses will be presented. Conclusions: These additional analyses from CheckMate 9DW demonstrate the efficacy and manageable safety of 1L NIVO + IPI in uHCC and further support its use as a potential standard-of-care treatment option in this setting. Clinical trial information: NCT04039607 . OS by BOR at week 24 landmark NIVO + IPI LEN/SOR BOR CR + PR (n = 101) SD a (n = 105) PD (n = 47) CR + PR (n = 28) SD a (n = 212) PD (n = 31) Median OS (95% CI), mo NR (44.4–NE) 30.0(23.5–37.8) 16.0(12.0–18.7) 28.3(20.6–NE) 22.5(20.5–24.8) 13.5(8.7–25.3) All treated pts NIVO + IPI (n = 332) LEN/SOR (n = 325) Any-grade/grade 3–4 TRAEs, n (%) 278 (84)/137 (41) 297 (91)/138 (42) Hepatobiliary 44 (13)/35 (11) 15 (5)/10 (3) Cardiovascular 10 (3)/3 (< 1) 138 (42)/39 (12) Hemorrhagic 2 (< 1)/1 (< 1) 20 (6)/5 (2) a Includes non-CR/non-PD. CR, complete response; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease; TRAE, treatment-related adverse event.

PD‐1/PD‐L1 immune checkpoint blockade (ICB) has improved overall survival (OS) in solid tumor trials; however, parallel improvements in Response Evaluation Criteria in Solid Tumors (RECIST)‐based surrogate end points, progression‐free survival (PFS), and objective response rate (ORR), are not always observed. Here, we assess the surrogacy of PFS/ORR for OS with ICB therapy across advanced/metastatic tumors. In a trial‐level analysis (N = 40 randomized trials), PFS, ORR, and OS treatment effects were correlated (Spearman's rho). In a patient‐level analysis, data were extracted from available trials of durvalumab; the correlation of PFS and OS was evaluated (Bayesian normal‐induced‐copula‐estimation model) and the ordinal association between objective response and OS hazard ratio (HR) were assessed with concordance index measures. High correlation was observed between PFS HR and OS HR in intention‐to‐treat (ITT; rho = 0.76) and PD‐L1‐enriched populations (0.74); modest (or limited) benefit in PFS was associated with meaningful improvement in OS. Moderate correlations were observed between ΔORR and OS HR: ITT, −0.63; PD‐L1‐enriched, −0.53. At the patient level, a positive association was observed between PFS and OS in non‐small cell lung cancer (Kendall’s Tau = 0.793; 95% confidence interval, 0.789–0.797), head and neck squamous cell carcinoma (0.794; 0.789–0.798), and bladder cancer (0.872; 0.869–0.875). Objective responders had significantly better OS (concordance index > 0.9) than nonresponders across these tumor types. Modest (or limited) improvement in RECIST‐based end points did not rule out meaningful OS benefit, indicating they are imperfect surrogates and do not fully capture ICB clinical benefit. Therefore, caution is advised when basing early discontinuation of novel ICB agents on these end points.

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

High tumor mutational burden assessed in tissue biopsies (tTMB-H) or blood (bTMB-H) is associated with clinical efficacy in patients treated with immunotherapies. CheckMate 848 (NCT03668119) is a prospective phase 2 study of nivolumab (NIVO) with or without ipilimumab (IPI) in patients with advanced or metastatic solid tumors that are tTMB-H or bTMB-H (≥ 10 mutations/megabase) who were immunotherapy-naive and refractory to standard local therapies. The primary endpoint was objective response rate (ORR) in patients with tTMB-H or bTMB-H, assessed by FoundationOne® CDx-based and Clinical Trial Assays (Foundation Medicine), respectively. The study was not powered to compare NIVO + IPI vs NIVO. We present the interim and final analyses for the tTMB-H and bTMB-H cohorts, respectively (≥ 12 months follow-up, database lock June 2021). Of 1954 screened patients, 212 were randomized 2:1 to NIVO 240 mg Q2W + IPI 1 mg/kg Q6W or NIVO 480 mg Q4W for ≤ 24 months, and 201 (135 tTMB-H; 147 bTMB-H) were refractory to standard therapies. Of > 40 tumor types, colorectal (10.8%), small-cell lung (7.5%), breast (7.1%), and uterine (7.1%) were the most common. ORR and survival outcomes with NIVO + IPI were improved in patients with tTMB-H. The responses were independent of bTMB-H status in the tTMB-H cohort but improved with tTMB-H status in the bTMB-H cohort (Table). The safety profile of NIVO + IPI was manageable, and clinical outcomes with NIVO were comparable with previous studies. The impact of TMB cutoff, PD-L1 expression, and microsatellite instability were explored. In conclusion, NIVO + IPI demonstrated clinical efficacy with a manageable safety profile in patients with advanced or metastatic solid tumors that are tTMB-H or bTMB-H and refractory to standard therapies, with increased efficacy observed in patients with tTMB-H. NIVO + IPI tTMB-H cohort bTMB-H cohorta Patients, n (%)b,c 68 (32.1) 80 (37.7) Number of prior treatments, median (range) 2 (0–7) 2 (1–9) ORR, n (%)c, 95% CI 24 (35.3), 24.1–47.8 18 (22.5), 13.9–33.2 ORR in patients with bTMB-H by tTMBc: < 10 mut/Mb (n = 31), n (%), 95% CI NA 3 (9.7), 2.0–25.8 ≥ 10 mut/Mb (n = 39), n (%), 95% CI NA 13 (33.3), 19.1–50.2 ≥ 10 to < 16 mut/Mb (n = 18), n (%), 95% CI NA 3 (16.7), 3.6–41.4 ≥ 16 mut/Mb (n = 21), n (%), 95% CI NA 10 (47.6), 25.7–70.2 ORR in patients with tTMB-H by bTMBc: < 10 mut/Mb (n = 20), n (%), 95% CI 7 (35.0), 15.4–59.2 NA ≥ 10 mut/Mb (n = 43), n (%), 95% CI 16 (37.2), 23.0–53.3 NA ≥ 10 to < 16 mut/Mb (n = 12), n (%), 95% CI 3 (25.0), 5.5–57.2 NA ≥ 16 mut/Mb (n = 31), n (%), 95% CI 13 (41.9), 24.5–60.9 NA Percentage of responders (≥ 9 months) (95% CI) 91 (68–98) 88 (61–97) Median PFS, months (95% CI)c 4.1 (2.8–11.3) 2.8 (2.3–3.0) Median OS, months (95% CI)c 14.5 (7.7–NE) 8.5 (5.8–10.5) aThe bTMB cohort was randomized prior to December 20, 2019. bOut of 212 randomized patients; data presented in this table are from patients who were refractory to standard therapies. cMinimum follow-up 12 months. bTMB, blood tumor mutational burden; NA, not applicable; NE, not evaluable; PFS, progression-free survival; OS, overall survival; tTMB, tissue tumor mutational burden. Citation Format: Michael Schenker, Mauricio Burotto, Martin Richardet, Tudor Ciuleanu, Anthony Goncalves, Neeltje Steeghs, Patrick Schöffski, Paolo A. Ascierto, Michele Maio, Iwona Lugowska, Lorena Lupinacci, Alexandra Leary, Jean-Pierre Delord, Julieta Grasselli, David S. Tan, Jennifer E. Friedmann, Jacqueline Vuky, Marina Tschaika, Ruta Slepetis, Georgia D. Kollia, Misena Pacius, Ning Huang, Parul Doshi, Jonathan Baden, Massimo Di Nicola. CheckMate 848: A randomized, open-label, phase 2 study of nivolumab in combination with ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden [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 CT022.