28 research outputs found
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Results from a phase I expansion cohort of the first-in-class oral HIF-2α inhibitor PT2385 in combination with nivolumab in patients with previously treated advanced RCC
558 Background: The transcription factor hypoxia-inducible factor (HIF)-2α has been established as an oncogenic driver in clear cell renal cell carcinoma (ccRCC) due to underlying VHL deficiency. Activation of HIF-2α can also promote immunosuppression. In preclinical models, HIF-2α inhibition demonstrated increased efficacy in combination with checkpoint inhibitors (Han et al. AACR 2016). In a Phase 1 dose escalation/expansion trial in heavily pre-treated advanced ccRCC patients, PT2385 monotherapy was associated with variability in drug exposure with higher therapeutic exposure associated with improved anti-tumor activity (Courtney et al. JCO 2018). Methods: In the current Phase 1 expansion cohort, patients with advanced ccRCC who had received 1-3 prior therapies (including at least one VEGF(R)-targeting agent) were treated with PT2385 (800 mg PO BID) in combination with nivolumab (3 mg/kg IV Q2Weeks) to evaluate safety, efficacy, and pharmacokinetics. Results: 50 patients were enrolled. Median age was 62 with 58% ECOG 1 and 42% ECOG 2. Median number of prior therapies was 1; 42% of patients received ≥2 prior lines of therapy. The most common all-grade AEs were anemia (46%), fatigue (46%), nausea (36%), and arthralgia (30%). The most common Grade 3 AE’s were anemia (4%), fatigue (4%), and hypoxia (4%). Two Grade 4 events of elevated ALT and increased lipase/amylase were observed. As of August 31, 2018, ORR = 22% (1 CR, 10 PR). At a median follow up of 12.4 months (m), median PFS was 7.3 m for all patients. Patients who had sub-therapeutic exposures ( < 300 ng/ml) of PT2385 (n = 17) had a median PFS of 4.7 m compared to patients with therapeutic exposures of PT2385 (n = 33), who had a median PFS of 10.0 m. Conclusions: The combination of PT2385 + nivolumab was well tolerated and demonstrated promising anti-tumor activity in advanced ccRCC patients, most notably in patients who achieved therapeutic exposure of PT2385. Single agent and combination studies with PT2977, a second-generation HIF-2α inhibitor with an improved PK profile, are ongoing. Clinical trial information: NCT02293980
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Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC)
611 Background: Hypoxia-inducible factor (HIF)-2α is a transcription factor that is a key oncogenic driver in RCC. MK-6482 is a first-in-class small molecule HIF-2α inhibitor that blocks the heterodimerization of HIF-2α with HIF-1β and induces regression in mouse xenograft RCC models. Methods: Pts with advanced ccRCC who had received at least 1 prior therapy were enrolled in an expansion cohort from the first-in-human phase 1/2 study of MK-6482 in advanced solid tumors (NCT02974738). Pts were administered 120 mg of MK-6482 orally once daily. Primary end point: safety. Key secondary end points: ORR, duration of response (DOR), and PFS. Results: Fifty-five pts were enrolled in the dose expansion cohort. Median (range) number of prior therapies was 3 (1-9); 67% received anti–PD-1 and anti-VEGF agents. Five pts (9%) were favorable risk, 40 (73%) were intermediate risk, and 10 (18%) were poor risk by IMDC criteria. With a median follow-up of 13 mo the most common all-grade, all-cause AEs > 30% were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), and cough (31%). Anemia (26%) and hypoxia (15%) were the most common grade 3 AEs. No grade 4/5 drug-related AEs were observed. ORR was 24% with 13 confirmed PRs. Thirty-one pts (56%) had SD, with a disease control rate (CR+PR+SD) of 80%. Thirty-five of 52 (67%) pts with baseline and postbaseline assessments had tumor shrinkage. Median DOR was not reached; 81% of pts had response ≥6 mo per Kaplan-Meier estimate. Sixteen pts (29%) continued treatment beyond 12 mo. By IMDC risk, 2/5 pts with favorable risk had PR (ORR = 40%), 10/40 with intermediate risk had PR (ORR = 25%), and 1/10 with poor risk had PR (ORR = 10%); disease control rate was 100%, 80%, and 70%, respectively. Median PFS for the total population was 11.0 mo; the 12 mo PFS rate was 49%. Median PFS for favorable, intermediate, and poor IMDC risk was 16.5, 11.0, and 6.9 mo, respectively. As of May 15, 2019, 30 pts (55%) discontinued due to PD, 2 (4%) due to AEs. Sixteen pts (29%) had treatment ongoing. Conclusions: MK-6482 is well tolerated with a favorable safety profile and demonstrated promising single-agent activity in heavily pretreated pts with ccRCC across IMDC risk groups. A phase 3 trial in a similar population is planned. Clinical trial information: NCT02974738
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Phase 1 LITESPARK-001 (MK-6482-001) study of belzutifan in advanced solid tumors: Update of the clear cell renal cell carcinoma (ccRCC) cohort with more than 3 years of total follow-up
4509 Background: Hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in RCC. Antitumor activity of the HIF-2α inhibitor belzutifan has been observed in RCC and is approved for treatment in patients (pts) with VHL disease who require therapy for associated RCC, CNS hemangioblastomas, or pNETs not requiring immediate surgery. Previous data from the phase 1 LITESPARK-001 trial (NCT02974738) designed to evaluate belzutifan in heavily pretreated RCC showed durable antitumor activity and an acceptable safety profile. After more than 3 years of follow-up for pts with ccRCC still receiving treatment, updated data are presented. Methods: Pts enrolled in the ccRCC cohort were previously treated with ≥1 therapy, had RECIST-measurable disease, ECOG PS score of 0 or 1, adequate organ function, and life expectancy of ≥6 months. Pts received oral belzutifan 120 mg once daily. The primary end point was safety. Secondary end points were ORR, DCR (CR + PR + SD), PFS, and DOR per RECIST v1.1 by investigator. The data cutoff date was July 15, 2021. Results: Of 55 pts enrolled in the ccRCC cohort, 9 (16%) remain on treatment as of the data cutoff date of July 15, 2021; the primary reason for discontinuation was progressive disease (n = 34; 62%). Pts received a median of 3 prior therapies (range, 1-9); 39 (71%) received prior VEGF and immunotherapy. Pts were followed while on treatment and for 30 days after the last dose for a median of 41.2 months (range, 38.2-47.7). Twenty-two pts (40%) experienced grade 3 TRAEs. The most common (≥10%) grade 3 TRAEs were anemia (n = 13; 24%) and hypoxia (n = 7; 13%). There were no grade 4 or 5 TRAEs. ORR was 25%, with 1 confirmed CR (2%) and 13 PRs (24%); DCR was 80%. Median DOR was not reached (range, 3.1+ to 37.9+ months); 8 of 14 responding pts (57%) remain in response as of the data cutoff date. Per IMDC risk, 4 of 13 pts with favorable risk achieved response (ORR = 31%; all PRs) and 10 of 42 pts with intermediate/poor risk achieved response (ORR = 24%; 1 CR, 9 PRs). DCR was 92% for pts with favorable risk and 76% for pts with intermediate/poor risk. For pts who received prior VEGF and immunotherapy, 8 of 39 pts achieved response (ORR = 21%; 1 CR; 7 PR); DCR was 74%. For the 16 pts who did not receive prior VEGF/immunotherapy, 6 achieved response (ORR = 38%; all PRs); DCR was 94%. Median PFS for the total cohort was 14.5 months (95% CI, 7.3-22.1); PFS rate at 156 weeks (̃36 months) was 34%. Conclusions: As seen after a median follow-up of > 3 years for pts still receiving treatment, belzutifan monotherapy continued to show a high rate of disease control and durable responses in previously treated pts with advanced ccRCC. Belzutifan exhibited a favorable safety profile, and no new safety signals were observed. In several phase 3 studies, belzutifan is being evaluated as monotherapy and combined therapy for ccRCC. Clinical trial information: NCT02974738
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The oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC): Updated follow-up of a phase I/II study
273 Background: Clear cell RCC (ccRCC) accounts for ~70% of kidney cancer cases in the US. Several first-line therapies are approved for ccRCC, but few patients respond completely and most progress within 5-11 mo. A key oncogenic driver in RCC is the transcription factor hypoxia-inducible factor 2α (HIF-2α). MK-6482 is a small molecule HIF-2α inhibitor that blocks the heterodimerization of HIF-2α with HIF-1β, inducing tumor regression in mouse xenograft RCC models. Updated data presented here include additional follow-up from the expansion cohort of patients with ccRCC from the first-in-human phase 1/2 study of MK-6482 in advanced solid tumors (NCT02974738). Methods: Patients were aged ≥18 y with advanced ccRCC, received ≥1 prior therapy, and had RECIST v1.1 measurable disease, ECOG status 0 or 1, adequate organ function, and life expectancy ≥6 mo. They received 120 mg of MK-6482 orally once daily. Tumors were assessed at baseline, within 7 days before week 9, and then every 8 weeks; response was assessed using RECIST v1.1. The primary end point was safety. Secondary end points included ORR, duration of response (DOR), and PFS. Results: Fifty-five patients with ccRCC were treated with MK-6482 120 mg (52 in expansion and 3 in dose-escalation cohorts). The median number of prior therapies was 3 (range 1-9). Forty-two patients (81%) previously received PD-1/L1 inhibitors and 48 (92%) previously received VEGF inhibitors. Thirteen patients (24%) were classified as favorable risk and 42 (76%) as intermediate or poor risk per IMDC criteria. With a median follow-up of 28 mo, the most common all-grade, all-cause AEs >30% were anemia (76%), fatigue (71%), dyspnea (49%), nausea (36%), cough (31%), and hypoxia (31%). Anemia (27%) and hypoxia (16%) were the most common grade 3 AEs. Two patients (4%) experienced grade 4 AEs, and 4 patients (7%) experienced grade 5 AEs. No grade 4 or 5 AEs were related to treatment. ORR was 25%, with 14 confirmed PRs. Thirty patients (55%) had SD, with a disease control rate (CR+PR+SD) of 80%. Median DOR was not reached; 77% had a response ≥6 mo. By IMDC risk, 4 of 13 patients with favorable risk had PR (ORR = 31%) and 10 of 42 with intermediate or poor risk had PR (ORR = 24%); disease control rate was 92% and 76%, respectively. Median PFS for the total population was 14.5 mo; 51% had a PFS of 12 mo. As of June 1, 2020, 33 patients (60%) discontinued because of PD and 2 (4%) because of AEs; 11 patients (20%) had ongoing treatment. Conclusions: MK-6482 remained well tolerated with a favorable safety profile and promising single-agent activity in patients with ccRCC for all IMDC risk groups after further follow-up. A phase III trial in a similar population is underway. Clinical trial information: NCT02974738