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4560 Background: In the multicenter, open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS and OS benefits, and improved ORR vs SUN in first-line advanced RCC. Herein, we explore efficacy according to selected subgroups and the association between pts’ depth of response and OS. Methods: Pts in the CLEAR study were randomly assigned 1:1:1 to 1 of 3 treatment arms: LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + everolimus 5 mg orally QD; or SUN 50 mg orally QD (4 weeks on/2 weeks off). We report PFS, OS, and ORR based on IMDC risk group (favorable and intermediate/poor) and presence of a target kidney lesion at baseline (post hoc analysis). Post hoc 6-month landmark analyses assessed the association between tumor shrinkage and OS. Pts who were alive at 6 months were grouped based on maximum tumor shrinkage from baseline or confirmed complete response (CR) up to 6 months. Tumor assessments were performed by independent review committee per RECIST v1.1. Odds ratios were calculated using the Cochran-Mantel-Haenszel method; HRs were based on stratified Cox proportional hazards model. Results: Among 1069 pts randomized in the CLEAR study, 355 were assigned to LEN + PEMBRO and 357 to SUN. Median follow-up was 27 months for the LEN + PEMBRO group and 26 months for the SUN group. PFS favored LEN + PEMBRO (median 22.1 months, n=243) vs SUN (median 5.9 months, n=229) in the IMDC-intermediate/poor subgroup (HR 0.36 [95% CI 0.28-0.47]); and in the IMDC-favorable subgroup (median 28.1 months, n=110 vs median 12.9 months, n=124; HR 0.41 [95% CI 0.28-0.62]). OS favored LEN + PEMBRO vs SUN in the IMDC-intermediate/poor subgroup (HR 0.58 [95% CI 0.42-0.80]); few events were observed in the IMDC-favorable subgroup thus, it was inadequate to evaluate OS. ORR favored LEN + PEMBRO vs SUN in the IMDC-intermediate/poor subgroup (72.4% vs 28.8%; odds ratio 6.60 [95% CI 4.39-9.90]) and the IMDC-favorable subgroup (68.2% vs 50.8%; odds ratio 2.00 [95% CI 1.17-3.42]). In pts with target kidney lesions, PFS, OS, and ORR were improved with LEN+PEMBRO vs SUN (table). The 6-month landmark analysis in the LEN + PEMBRO group showed that the OS rate at 24 months was 100% (95% CI not estimable [NE]-NE) for pts with confirmed CR per RECIST v1.1 and 91.7% (95% CI 53.9-98.8) both for pts with >75% to

5069 Background: KEYNOTE-427 (NCT02853344), an open-label, single-arm, phase 2 study, showed clinical activity of first-line pembro monotherapy in patients (pts) with ccRCC (cohort A). Previous studies in RCC and immune-oncology suggest depth of response may correlate with long-term benefit. Association between depth of response and OS, along with updated efficacy and safety for cohort A of KEYNOTE-427, are presented. Methods: Pts with histologically confirmed ccRCC, measurable disease (RECIST v1.1), and no prior systemic therapy received pembro 200 mg IV Q3W for 2 y or until progressive disease, unacceptable toxicity, or withdrawal. End points: ORR (primary), DOR, and PFS (RECIST v1.1); OS, and safety. Association between depth of response (maximum reduction from baseline in the sum of target lesions) and OS was evaluated using Cox proportional hazards model with target lesion reduction group as time-varying covariate. Results: 110 pts enrolled; median time from enrollment to data cutoff was 23.1 (range, 16.7-27.5) mo. Overall, 38.2% of pts had favorable and 61.2% had intermediate/poor IMDC risk. ORR was 36.4% (95% CI, 27.4-46.1; 3 CRs, 37 PRs); median (range) DOR was not reached (2.3-23.5+ mo); 64.0% had a DOR ≥12 mo. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached; 18-mo PFS and OS rates were 26.6% and 80.0%, respectively. 69.1% had some reduction in target lesions. Pts with > 60% reduction in target lesions had a greater probability of survival than pts with a ≤60% reduction (Table). ORR observed in IMDC favorable and intermediate/poor risk was 31.0% and 39.7%, respectively; 18-mo OS rate was 95.2% for favorable and 70.5% for intermediate/poor IMDC risk. Treatment-related AEs (TRAEs) occurred in 81.8% of pts, primarily fatigue (29.1%) and pruritus (28.2%). Grade ≥3 TRAEs occurred in 29.1% of pts; 1 pt died of treatment-related pneumonitis. Conclusions: First-line pembro monotherapy was tolerable and showed promising antitumor activity in advanced ccRCC. In general, pts who had greater reductions in target lesions demonstrated a trend toward improved OS; pts with reduction of tumor burden ≥80% had comparable long term outcomes to those who achieved a RECIST 1.1 defined CR. Clinical trial information: NCT02853344 . [Table: see text]

TPS399 Background: Combination therapy with the PD-1 inhibitor pembrolizumab and the vascular endothelial growth factor (VEGF) inhibitor lenvatinib showed antitumor activity as first-line treatment for advanced clear cell RCC (ccRCC) in the phase 3 KEYNOTE-581/CLEAR study (NCT02811861). Antitumor activity has also been shown with the hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) in ccRCC and with MK-1308A (coformulation of pembrolizumab and the CTLA-4 inhibitor quavonlimab) in non–small cell lung cancer. Therefore, HIF-2α or CTLA-4 inhibition with a PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in ccRCC. This open-label, randomized, phase 3 study (NCT04736706) will compare first-line treatment with the novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) or MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C) for advanced RCC. Methods: Approximately 1,431 adults with metastatic ccRCC, measurable disease per RECIST v1.1, and KPS score ≥70% who had not previously undergone systemic therapy for advanced ccRCC will be enrolled. Patients will be randomly assigned 1:1:1 to arm A (belzutifan 120 mg + lenvatinib 20 mg orally once daily [QD] + pembrolizumab 400 mg IV every 6 weeks [Q6W]), arm B (MK-1308A [quavonlimab 25 mg + pembrolizumab 400 mg] IV [Q6W] and lenvatinib 20 mg orally QD), or arm C (pembrolizumab 400 mg IV [Q6W] + lenvatinib 20 mg orally QD). Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (̃2 years). Stratification factors are International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, Q6W through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival for arm A or arm B versus arm C in patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety. The study is recruiting patients at sites across, Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT04736706.

BackgroundPembrolizumab + vascular endothelial growth factor (VEGF) inhibitor lenvatinib demonstrated antitumor activity as first-line treatment for advanced clear cell renal cell carcinoma (ccRCC) in phase 3 trial KEYNOTE-581/CLEAR (NCT02811861). Hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) showed antitumor activity in ccRCC, and a coformulation of pembrolizumab and CTLA-4 inhibitor quavonlimab (MK-1308A) showed antitumor activity in non–small cell lung cancer. HIF-2α or CTLA-4 inhibition with PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in ccRCC. This open-label, randomized, phase 3 study (NCT04736706) will be conducted to compare novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) and MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C).MethodsApproximately 1431 adults with metastatic ccRCC, measurable disease per RECIST v1.1, and Karnofsky Performance Status Scale score ≥70% who had not previously undergone systemic therapy for advanced ccRCC will be enrolled. Patients will be randomly assigned 1:1:1 to arm A (belzutifan 120 mg + lenvatinib 20 mg oral once daily + pembrolizumab 400 mg IV every 6 weeks), arm B (MK-1308A [quavonlimab 25 mg + pembrolizumab 400 mg] IV every 6 weeks and lenvatinib 20 mg oral once daily), or arm C (pembrolizumab 400 mg IV every 6 weeks + lenvatinib 20 mg oral once daily). Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (approximately 2 years). Patients will be stratified by International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of the world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, every 6 weeks through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival. Primary end points will be assessed in arm A compared with arm C and in arm B compared with arm C for patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety.AcknowledgementsMedical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA,Eisai Inc., Woodcliff Lake, NJ, USA.Trial RegistrationClinicaltrials.gov, NCT04736706Ethics ApprovalThe study and the protocol were approved by the Institutional Review Board or ethics committee at each site.

4562 Background: The multicenter, open-label, randomized, phase 3 CLEAR study showed that LEN + EVE had a significant PFS benefit (HR 0.65, 95% CI 0.53-0.80, P

5034 Background: KEYNOTE-427 (NCT02853344), a single-arm, open-label, phase 2 study, showed antitumor activity with first-line pembro monotherapy in nccRCC (cohort B). Studies of RCC and immune-oncology have shown that depth of tumor response may correlate with long-term benefit. We present the association between depth of response and OS plus updated efficacy and safety data in cohort B. Methods: Pts with histologically confirmed nccRCC, who did not receive prior systemic therapy, and who have measurable disease (RECIST v1.1) received pembro 200 mg IV Q3W for 2 y or until progressive disease, unacceptable toxicity, or withdrawal. End points were ORR (primary), DOR, and PFS (RECIST v1.1); OS; and safety. Association between depth of response, defined as maximum reduction from baseline in sum of target lesions, and OS was evaluated using a Cox proportional hazards model with target lesion reduction group as time-varying covariate. Results: Of 165 pts, 72% had papillary histology, 13% had chromophobe histology, and 16% were unclassified. Median time from enrollment to data cutoff was 18.7 mo (range, 9.9-26.0). ORR was 26.1% (95% CI, 19.5-33.5; 10 CRs, 33 PRs). Median (range) DOR was 15.3 mo (2.8-21.0+); 57.3% had DOR ≥12 mo. At 18-mo, PFS rate was 18.9% and OS rate was 67.0%. Most pts (58.8%) had some reduction in target lesions. Pts with a > 30% reduction in target lesions had an increased probability of survival (Table). ORR (95% CI) was similar for papillary (28.0% [20.1-37.0]) and unclassified (30.8% [14.3-51.8]) histology but lower for chromophobe (9.5% [1.2-30.4]). OS rates at 18 mo were 70.8%, 66.7%, and 50.0 in the papillary, chromophobe, and unclassified groups, respectively. Treatment-related AEs (TRAEs) occurred in 67.9% of all pts, primarily pruritus (19%), hypothyroidism (14%), and fatigue (14%). Grade 3-5 TRAEs occurred in 14% of pts; 2 pts died of TRAEs (pneumonia and cardiac arrest). Conclusions: First-line pembro monotherapy continued to show antitumor activity in nccRCC with no new safety concerns. In general, for pts who had greater reductions in target lesions, the trend was toward improved OS; pts with reduction of tumor burden ≥80% had comparable long term outcomes to those who achieved a RECIST 1.1 defined CR. Clinical trial information: NCT02853344 . [Table: see text]

BACKGROUND New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N=8). We now report updated results following completion of accrual to non-surgical cohorts (N=68). MATERIALS AND METHODS This is an open-label, multicenter, phase 2 study of selinexor monotherapy. Patients (pts) not undergoing surgery for measurable rGBM per response assessment neuro-oncology criteria (RANO) were enrolled in one of 3 arms encompassing different dosing schedules of selinexor (50 mg/m2 [~ 85 mg] BIW, 60 mg BIW, and 80 mg QW). Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan-Meier method. RESULTS 76 pts were enrolled; 24, 14 and 30 pts on doses of ~85 mg BIW, 60 mg BIW, and 80 mg QW, respectively. Median age was 56 years (range 21–78). Median number of prior treatments was 2 (range 1–7) At the end of the 6 cycles, 30.2% pts on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 18.9%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Complete and partial responses were durable: the complete and a partial responder remain on selinexor for 393 and 1093 days respectively, as of the cut-off date. Median duration of response was 10.8 months. The most common related adverse events (all grades) in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/63%), leukopenia (38%/7%/43%), fatigue (71%/71%/47%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). CONCLUSION Selinexor demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, selinexor at a dose of 80 mg QW is recommended for further development in rGBM.

2005 Background: New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor (SEL) is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N = 8). We now report updated results following completion of accrual to non-surgical cohorts (N = 68). Methods: This is an open-label, multicenter, phase 2 study of SEL monotherapy. Patients (pts) not undergoing surgery for measurable rGBM (per RANO) were enrolled in one of 3 arms encompassing different dosing schedules. Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan Meier method. Results: A total of 76 pts were enrolled. Median age was 56 years (range 21-78). Median number of prior treatments was 2 (range 1-7). At the end of the 6 cycles, 30.2% patients on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 15.1%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Median duration of response was 10.8 months. The most common related adverse events in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/60%), leukopenia (38%/7%/43%), fatigue (71%/71%/43%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). Conclusions: SEL demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, SEL at a dose of 80 mg QW is recommended for further development in rGBM. Clinical trial information: NCT01986348. [Table: see text]