Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 272-272
Author(s):  
Toni K. Choueiri ◽  
Todd Michael Bauer ◽  
David F. McDermott ◽  
Edward Arrowsmith ◽  
Ananya Roy ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Preliminary Analysis ◽  
Phase 1 ◽  
Objective Response ◽  
Phase 2 ◽  
Cell Renal Cell Carcinoma ◽  
Hand Foot Syndrome ◽  
Previously Treated ◽  
Grade 3

272 Background: Belzutifan (MK-6482) inhibits HIF-2α and demonstrated antitumor activity and favorable safety as monotherapy in a phase 1 study of patients (pts) with metastatic ccRCC. Current study (NCT03634540) investigates belzutifan plus cabozantinib for pts with advanced ccRCC who were either treatment naive (cohort 1) or previously treated, including immunotherapy and TKIs (cohort 2). This preliminary analysis presents data from cohort 2. Methods: Pts had metastatic ccRCC and received no more than 2 prior systemic treatment regimens. Initially, 6 pts in either cohort 1 or 2 were treated with belzutifan 120 mg and cabozantinib 60 mg orally once daily for 21 days and a safety review committee performed an initial evaluation. For purpose of this preliminary analysis, efficacy was evaluated in pts who received ≥1 dose of treatment and had an opportunity of ≥6 mo of follow-up. Primary end point: objective response rate (ORR; RECIST v1.1 by investigator review). Secondary end points: progression free survival (PFS), overall survival (OS), and duration of response (DOR). Safety was evaluated for all cohort participants. Results: Evaluation of safety and tolerability of belzutifan 120 mg plus cabozantinib 60 mg was performed in the first 6 pts. Only 1 participant experienced a dose-limiting toxicity of hand-foot syndrome, therefore belzutifan 120 mg plus cabozantinib 60 mg was determined to be the recommended phase 2 dose. 53 pts were included in the safety analysis population. Median age was 64 yrs, 73.6% were male, 54.7% had ECOG PS 1. Twenty-eight (52.8%) received prior first-line and 24 (45.2%) prior second-line therapies. Median (range) time from enrollment to data cutoff was 11.3 mo (5.6-24.0) for pts with ≥6 mo of follow-up (n=41). The confirmed ORR was 22.0% (9 PRs) and 90.2% had any tumor shrinkage. Disease control rate (CR+PR+SD) was 92.7%. Median (range) DOR was not reached (3.7+ to 14.8+ mo); all responses were ongoing. Median (95% CI) PFS was 16.8 mo (9.2-not reached); PFS rate at 6 mo was 78.3%. OS rate at 6 mo was 95.0%. While 52 of 53 (98.1%) pts experienced a treatment-related adverse event (TRAE), 92% of events were grade 1 and 2. Most common (≥30%) TRAEs were anemia (75.5%), fatigue (67.9%), hand-foot syndrome (52.8%), diarrhea (45.3%), hypertension (43.4%), nausea (35.8%), and ALT/AST increase (32-34%). Incidence of grade 3 TRAEs >5% were hypertension (22.4%), anemia (11.3%), fatigue (11.3%), and ALT increase (5.7%). 2 pts experienced grade 3 hypoxia (3.8%). There were no grade 4 TRAEs or deaths. Discontinuations due to TRAEs occurred in 6 pts (11.3%) for belzutifan and 8 pts (15.1%) for cabozantinib. Conclusions: In this preliminary analysis, belzutifan in combination with cabozantinib demonstrated promising antitumor activity in previously treated pts with metastatic ccRCC. Safety was consistent with individual profiles of each agent. Clinical trial information: NCT03634540 .

Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with locally advanced cutaneous squamous cell carcinoma (laCSCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6015-6015 ◽  
Author(s):  
Michael Robert Migden ◽  
Nikhil I. Khushalani ◽  
Anne Lynn S. Chang ◽  
Danny Rischin ◽  
Chrysalyne D. Schmults ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Median Duration ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Phase 2 ◽  
Primary Analysis ◽  
Curative Surgery ◽  
Grade 3

6015 Background: Cemiplimab (REGN2810) produced substantial antitumor activity with durable responses in Phase 1 CSCC expansion cohorts and Phase 2 metastatic (m) CSCC cohort. We now present the primary analysis of the Phase 2 laCSCC cohort (NCT02760498; data cutoff date: Oct 10, 2018). Methods: Pts with laCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 78 pts were enrolled (59 M/ 19 F; median age: 74 years; ECOG PS: 0 in 38 pts, 1 in 40 pts; primary CSCC site: head/neck in 79.5%; prior systemic therapy: 15.4%; prior radiotherapy: 55.1%). Median duration of follow-up was 9.3 months (range: 0.8–27.9). ORR by central review was 43.6% (95% CI: 32.4–55.3; 10 CRs and 24 PRs); investigator-assessed (INV) ORR was 52.6% (95% CI: 40.9–64.0; 13 CRs and 28 PRs). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 24.2 months and was still ongoing. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.8% (95% CI: 51.1–73.5). Median observed time to response was 1.9 months (range: 1.8–8.8). Median progression-free and overall survival have not been reached. Tumor PD-L1 status is available for 48/78 pts, tumor mutational burden analysis (from targeted exome panel) is ongoing for ≥40/78 pts; response correlation analyses are planned. The most common treatment-emergent adverse events (AEs; all grades, Grade ≥3) were fatigue (42.3%, 1.3%), diarrhea and pruritus (both 26.9%, 0%), and nausea (21.8%, 0%). INV grade ≥3 immune-related AEs occurred in 10.3% of pts. One pt died due to an unknown cause that was assessed as treatment-related. Conclusions: Cemiplimab 3 mg/kg Q2W showed substantial antitumor activity, durable responses, and acceptable safety profile in pts with laCSCC. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

Phase 2 study of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with metastatic cutaneous squamous cell carcinoma (mCSCC; Group 1): 12-month follow-up.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9526-9526 ◽  
Author(s):  
Alexander David Guminski ◽  
Annette May Ling Lim ◽  
Nikhil I. Khushalani ◽  
Chrysalyne D. Schmults ◽  
Leonel Fernando Hernandez-Aya ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Adverse Events ◽  
Median Duration ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase 2 ◽  
Primary Analysis ◽  
Phase 2 Study ◽  
Grade 3

9526 Background: Primary analysis (Oct 2017) of cemiplimab (REGN2810) in pts with mCSCC in a Phase 2 study demonstrated substantial antitumor activity, durable responses, and acceptable safety profile. We now report 12-month follow-up data from these pts (NCT02760498; data cutoff date: Sep 20, 2018). Methods: Pts with mCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 59 pts (median age: 71 years) were enrolled. Median duration of follow-up was 16.5 months (range: 1.1–26.6). ORR by central review was 49.2% (95% CI: 35.9–62.5; 10 CRs and 19 PRs [4 CRs and 25 PRs by investigator-assessment (INV)]). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 21.6 months and was still ongoing. Observed DOR exceeded 12 months in 22/29 pts (75.9%) with response. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.7% (95% CI: 49.1–75.0). Median observed time to response was 1.9 months (range: 1.7–9.1). Median progression-free survival was 18.4 months (95% CI: 7.3–not evaluable); median overall survival has not been reached. The most common treatment-emergent adverse events (all grades, Grade ≥3) were diarrhea (28.8%, 1.7%), fatigue (25.4%, 1.7%), and nausea (23.7%, 0%). By INV, grade ≥3 immune-related adverse events occurred in 13.6% of pts. Conclusions: This analysis demonstrates substantial antitumor activity and increasing DOR with cemiplimab 3 mg/kg Q2W in pts with mCSCC. There were no new safety signals. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

Update on KEYNOTE-199, cohorts 1-3: Pembrolizumab (pembro) for docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 104-104 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Josep M. Piulats ◽  
Marine Gross-Goupil ◽  
Jeffrey C. Goh ◽  
Ulka N. Vaishampayan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Response Rate ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

104 Background: The KEYNOTE-199 multicohort phase 2 study (NCT02787005) showed that pembro monotherapy has antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with a next-generation hormonal agent (NHA) and docetaxel in cohort 1 (C1) (RECIST-measurable, PD-L1+ disease), C2 (RECIST-measurable, PD-L1− disease), and C3 (bone-predominant disease, irrespective of PD-L1). Updated results with additional follow-up for C1-3 are presented. Methods: Pts previously received ≥1 NHAs and 1 or 2 chemotherapies, including docetaxel. Pts received pembro 200 mg Q3W for 35 cycles or until progression or intolerable toxicity. Primary end point was ORR. Key secondary end points were DCR, DOR, PSA (≥50%) response rate, rPFS, OS, and safety. Results: Of 258 pts enrolled (C1=133; C2=67; C3=58), 6 completed (C1=4; C3=2) and 252 discontinued (C1=129; C2=67; C3=56) therapy, primarily due to progression (C1=106; C2=61; C3=45). Median follow-up was 9.6 mo (C1, 9.5; C2, 7.9; C3, 14.2). ORR (95% CI) for pts with measurable disease was 6% (2.6-11.5) in C1 and 3% (0.4-10.4) in C2 (Table; includes other efficacy results). Treatment-related AEs of any grade/grade 3-5 occurred in 57%/16% in C1, 60%/15% in C2, and 71%/17% in C3. 1 pt in each cohort died of a treatment-related AE (C1, sepsis; C2, unknown; C3, immune-related pneumonitis). Conclusions: With additional follow-up, pembro monotherapy continued to show antitumor activity and disease control in pts with RECIST-measurable and bone-predominant mCRPC previously treated with both NHA and docetaxel. Pts experienced durable responses. Safety was consistent with the known safety profile of pembro. Clinical trial information: NCT02787005. [Table: see text]

Phase I/II study of sunitinib malate in combination with gefitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5097-5097 ◽  
Author(s):  
P. H. Patel ◽  
G. V. Kondagunta ◽  
B. G. Redman ◽  
G. R. Hudes ◽  
S. T. Kim ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Ejection Fraction ◽  
Dose Level ◽  
Egf Receptor ◽  
Phase 1 ◽  
Objective Response ◽  
Cytokine Therapy ◽  
Phase 2 ◽  
Sunitinib Malate ◽  
Grade 3

5097 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGF- and PDGF- receptors with substantial antitumor activity against mRCC (JAMA 2006;295:2516). This study was conducted to evaluate the safety and efficacy of sunitinib in combination with gefitinib, an EGF-receptor inhibitor. Methods: Eligibility included mRCC with clear cell component. The phase 1 part of the study was conducted to determine the maximum tolerated dose (MTD) of sunitinib in combination with gefitinib, and subsequently pts were enrolled in the phase 2 part to further evaluate safety and antitumor activity. Pts were treated with sunitinib at assigned dose level (37.5 mg or 50 mg) orally daily for 4 weeks on, followed by 2 weeks off (Schedule 4/2) and gefitinib at 250 mg daily. The primary endpoint for the phase 2 part of the study was objective response according to RECIST. Results: Forty-two pts were enrolled; 11 pts in phase 1 and 31 pts in phase 2. Median age was 65 years (range: 29–78) and 35 pts (83%) had =2 metastatic sites. Twenty-eight pts (67%) had prior cytokine therapy, 11 pts (26%) had no prior cytokine therapy, and 3 pts (7%) received prior vaccine therapy. Two dose limiting toxicities (DLTs) were observed at the 50-mg dose level (grade 3 fatigue and grade 2 ejection fraction decline), and 37.5 mg on Schedule 4/2 in combination with gefitinib 250 mg daily was determined to be the MTD. The median duration on treatment was 8.3 months for phase 1. Thirty-six pts are evaluable for response and 6 are too early. Eleven pts (30%) achieved a partial response and 15 pts (42%) stable disease. The most common grade 3 treatment-related adverse events observed in phase 1 were diarrhea and nausea (n=2) and for phase 2 were diarrhea (10%) and gastrointestinal hemorrhage (6%). Two pts from phase 2 were withdrawn from the study due to treatment-related adverse event; ejection fraction decline and cardiac arrhythmia, both of which were reversible after treatment discontinuation. Conclusions: The study established dose and feasibility for sunitinib in combination with gefitinib. Early evaluation of the data suggests tolerability for the combination and relative efficacy data compared to sunitinib monotherapy will be assessed with longer patient follow-up. No significant financial relationships to disclose.

Outcomes of patients (pts) ≥ 65 years of age in ZUMA-1, a pivotal phase 1/2 study of axicabtagene ciloleucel (axi-cel) in refractory large B-cell lymphoma (LBCL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7555-7555
Author(s):  
Sattva Swarup Neelapu ◽  
Caron A. Jacobson ◽  
Olalekan O. Oluwole ◽  
Javier Munoz ◽  
Abhinav Deol ◽  
...  
Keyword(s):  
T Cell ◽  
Phase 1 ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

7555 Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of pts with relapsed or refractory LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%, and 39% of pts were in ongoing response (Locke et al. Lancet Oncol. 2019). Here we report efficacy and safety outcomes by age. Methods: Eligible pts with refractory LBCL underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed ORR. Additional key endpoints were adverse events (AEs), overall survival (OS), and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 pts; safety was evaluated for all treated pts (Phases 1 and 2). Pts were analyzed by ≥ 65 y vs < 65 y of age. Results: As of 8/11/2018, 108 pts were treated. Pts ≥ 65 y (n = 27) vs < 65 y (n = 81) had a median age of 69 y vs 55 y, respectively, were 81% vs 63% male, 70% vs 36% had an IPI score 3-4, 59% vs 57% had ECOG 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm2 vs 3574 mm2. Median follow-up was 27.1 mo for Phase 2 pts (n = 101). The ORR for pts ≥ 65 y (n = 24) and < 65 y (n = 77) was 92% and 81% (CR rate 75% and 53%), respectively, with ongoing responses in 42% and 38% of pts (ongoing CR 42% and 35%). The 24-mo OS rate was 54% for pts ≥ 65 y and 49% for pts < 65 y. Most pts experienced Grade ≥ 3 AEs (100% of pts ≥ 65 y; 98% of pts < 65 y), and 4% of each group (1/27 pts ≥ 65 y and 3/81 pts < 65 y) died due to AEs as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of pts ≥ 65 y vs < 65 y, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μl) or area under the curve (562 vs 448 d × cells/μl) was similar in pts ≥ 65 y vs < 65 y, respectively. Conclusions: The 2-y follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for pts ≥ and < 65 y. Axi-cel offers substantial clinical benefit for older pts with refractory LBCL who otherwise have limited treatment options. Clinical trial information: NCT02348216.

scholarly journals A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4774-4774
Author(s):  
James R. Berenson ◽  
Laura V. Stampleman ◽  
Alberto Bessudo ◽  
Peter J. Rosen ◽  
Leonard M Klein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability–high tumors: A combined analysis of two cohorts in the GARNET study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2564-2564
Author(s):  
Dominique Berton ◽  
Susana N. Banerjee ◽  
Giuseppe Curigliano ◽  
Sara Cresta ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Low Grade ◽  
Open Label ◽  
Tumor Types

2564 Background: Dostarlimab is an investigational, humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the PD-1 ligands, PD-L1 and PD-L2. GARNET (NCT02715284) is a phase 1 study assessing the antitumor activity and safety of dostarlimab monotherapy in patients with solid tumors. Methods: This multicenter, open-label, single-arm study is being conducted in 2 parts: dose escalation and expansion. Here we report on the 2 expansion cohorts that enrolled mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) patients. Cohort A1 enrolled patients with advanced or recurrent dMMR/MSI-H endometrial cancer (EC), and cohort F enrolled patients with advanced or recurrent dMMR/MSI-H or POLε-hypermutated non-EC solid tumors, mainly gastrointestinal (GI) tumors (99 [93.4%] had GI tumors, including 69 [65.1%] with colorectal cancer). Patients received 500 mg IV of dostarlimab every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks until disease progression or discontinuation. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by RECIST v1.1. Here we report ORR and DOR, by individual cohort and as an overall population, in patients with dMMR tumors identified by immunohistochemistry testing. Results: For this interim analysis, an efficacy analysis was performed for the patients who had baseline measurable disease and ≥6 months of follow-up in the study (N = 209). The ORR was 41.6% (95% CI, 34.9%–48.6%) for the combined A1+F dMMR cohorts (Table). Responses were durable, and median DOR has not been reached in either cohort (median follow-up: cohort A1, 16.3 months; cohort F, 12.4 months). A total of 267 patients were included in the safety population (all patients who received ≥1 dose; cohort A1, N = 126; cohort F, N = 141). Treatment-related adverse events (TRAEs) were consistent across tumor types. Overall, the most frequently reported any-grade TRAEs were asthenia (13.9%), diarrhea (13.5%), and fatigue (11.2%). The most common grade ≥3 TRAEs were anemia (2.2%), lipase increased (1.9%), alanine aminotransferase increased (1.1%), and diarrhea (1.1%). No deaths were attributed to dostarlimab. Conclusions: Dostarlimab demonstrated durable antitumor activity in patients with dMMR solid tumors, with consistent antitumor activity seen across endometrial and nonendometrial tumor types. The safety profile was manageable, with no new safety signals detected. Most TRAEs were low grade and were similar across cohorts. Clinical trial information: NCT02715284. [Table: see text]

A phase Ib/II trial of lenvatinib plus pembrolizumab in non-small cell lung cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 16-16 ◽  
Author(s):  
Marcia S. Brose ◽  
Nicholas J. Vogelzang ◽  
Christopher DiSimone ◽  
Sharad K. Jain ◽  
Donald A. Richards ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Small Cell ◽  
Clinical Activity ◽  
Phase 2 ◽  
Small Cell Lung ◽  
Previously Treated ◽  
Grade 3

16 Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is an approved monotherapy for previously treated patients (pts) with PD-L1 (+) (tumor proportion score ≥1%) metastatic non-small cell lung cancer (mNSCLC; objective response rate [ORR] 18%). We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in pts with solid tumors, focusing on the mNSCLC cohort. Methods: In this multicenter, open-label study (NCT02501096), pts with measurable, confirmed mNSCLC, ECOG PS ≤1, ≤ 2 prior systemic therapies (phase 2 only) received oral LEN (20 mg/day) and PEM (200 mg Q3W, IV). Pts were not preselected by PD-L1 status. The phase 2 primary end point was ORR at 24 weeks (ORRWK24) by investigator-assessed immune-related RECIST (irRECIST). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 9 (43%) PD-L1(+), 5 (24%) PD-L1(-), and 7 (33%) not tested. Pts were treatment-naïve (14%); or had 1 (33%), 2 (48%), or ≥3 (5%) prior lines of systemic therapy. ORRWK24 was 33.3% (95% CI, 14.6–57.0); other efficacy outcomes are summarized in the table. Grade 3 and 4 treatment-related adverse events (TRAEs) occurred in 48% and 5% (increased aspartate aminotransferase) of pts. There was 1 fatal TRAE (exsanguination; “possibly related” to study treatment). The most common grade 3 TRAEs were hypertension (24%), fatigue (14%), diarrhea (14%), proteinuria (10%), and arthralgia (10%). Conclusions: LEN + PEM showed promising clinical activity and a manageable safety profile in previously treated pts with mNSCLC who were not preselected for PD-L1 status. Further study is warranted.[Table: see text]

Safety and clinical activity of durvalumab monotherapy in patients with microsatellite instability–high (MSI-H) tumors.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 670-670 ◽  
Author(s):  
Neil Howard Segal ◽  
Zev A. Wainberg ◽  
Michael J. Overman ◽  
Paolo Antonio Ascierto ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Median Duration ◽  
Multicenter Study ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Single Center ◽  
Single Center Study ◽  
Center Study

670 Background: MSI-H tumors have shown to be responsive to PD-1 inhibitor therapy. We evaluated the anti-PD-L1 mAb durvalumab in patients with MSI-H tumors, in two ongoing studies: a phase 1/2, multicenter, open-label study in patients with advanced solid tumors, and a phase 2 single-center study in patients with advanced colorectal cancer (CRC). Methods: Patients with MSI-H tumors (determined locally by immunohistochemistry or sequencing) received durvalumab 10 mg/kg IV every 2 weeks for 12 months or until confirmed progressive disease, whichever was first. Objectives were to evaluate safety and antitumor activity (per investigator-assessed RECIST v1.1). Results: As of Oct 16, 2017, 62 MSI-H patients (97% with prior anti-cancer therapy) received treatment in the multicenter study; median duration of follow-up was 29 months. Treatment-related adverse events (TRAEs) occurred in 37 patients (60%), most commonly diarrhea (15%), asthenia (11%), fatigue (11%), nausea (10%), and hypothyroidism (10%). Grade 3/4 TRAEs occurred in 2 patients (3%). There were no deaths or treatment discontinuations due to TRAEs. Objective response rates (ORR) were 23% for the total population and 22% for patients with CRC; 9 of 14 responders were ongoing at data cutoff. As of Sep 13, 2018, 11 patients with MSI-H CRC were treated in the single-center study; median duration of follow-up was 30 months. One patient discontinued treatment due to treatment-related aseptic meningitis (resolved with steroids); response rate and survival were similar to the multicenter study (Table). Conclusions: Durvalumab had a tolerable safety profile, and showed promising antitumor activity and overall survival in patients with MSI-H tumors. Clinical trial information: NCT01693562 and NCT02227667. [Table: see text]

FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 108-108 ◽  
Author(s):  
Lipika Goyal ◽  
Funda Meric-Bernstam ◽  
Antoine Hollebecque ◽  
Juan W. Valle ◽  
Chigusa Morizane ◽  
...  
Keyword(s):  
Disease Progression ◽  
Intrahepatic Cholangiocarcinoma ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Gene Fusions ◽  
Phase 2 ◽  
Fgfr2 Gene ◽  
Platinum Based Chemotherapy ◽  
Grade 3

108 Background: Patients (pts) with intrahepatic cholangiocarcinoma (iCCA) have a 5-year survival rate of 24%. There is no standard treatment for advanced disease after first-line chemotherapy. Fibroblast growth factor receptor-2 ( FGFR2) gene fusions occur in 10% to 20% of pts with iCCA, offering a promising therapeutic avenue for this disease. Futibatinib is a highly selective irreversible FGFR1-4 inhibitor given as a continuous once-daily (QD) oral regimen. This phase 2 registrational trial was initiated because of results from a phase 1 dose escalation/expansion study showing tolerability and preliminary efficacy of futibatinib in pts with iCCA with FGFR2 fusions. Methods: FOENIX-CCA2 (NCT02052778), a single-arm multicenter phase 2 study, enrolled pts with locally advanced/metastatic unresectable iCCA harboring FGFR2 gene fusions or other rearrangements, disease progression after ≥1 line of systemic therapy (including gemcitabine plus platinum-based chemotherapy), no prior FGFR inhibitor treatment, and an ECOG performance status of 0 or 1. Pts received futibatinib 20 mg QD until disease progression/unacceptable toxicity. The primary endpoint is objective response rate (ORR) based on independent central radiology review. Secondary endpoints include disease control rate (DCR), duration of response (DOR), and safety. Results: A total of 103 pts were enrolled. For this interim analysis, data are reported for the 67 pts (65%) with ≥6 months of follow-up. Of these, 82.1% of pts had tumors harboring an FGFR2 fusion. One, 2, or ≥3 prior therapies were received by 44.8%, 28.4%, and 26.9% of pts, respectively. ORR was 34.3% (all partial response, n = 23), and DCR was 76.1%; assessment was pending for 8 pts. Median time to response was 1.6 months (range, 1.0-4.9), and median DOR was 6.2 months (range, 2.1-14.2). The most common treatment-related adverse events (AEs; all grade, grade ≥3) were hyperphosphatemia (79.1%, 25.4%), diarrhea (37.3%, 0%), and dry mouth (32.8%, 0%). Any-cause grade ≥3 AEs were reported in 73.1% of pts. Dose delay or dose reduction was required in 65.7% and 53.7% of pts, respectively; 6.0% of pts discontinued treatment because of AEs. Conclusions: Preliminary assessment of these phase 2 data indicate efficacy and tolerability of futibatinib for treatment of pts with iCCA harboring FGFR2 fusions or other rearrangements who have progressed after chemotherapy. Continued analysis of the study population is underway. Clinical trial information: NCT02052778.

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