Search

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]