Intermittent BRAF inhibition in advanced BRAF mutated melanoma results of a phase II randomized trial

Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. Previous preclinical studies suggested that an intermittent dosing of these drugs could delay the emergence of resistance. Contrary to expectations, the first published phase 2 randomized study comparing continuous versus intermittent schedule of dabrafenib (BRAFi) plus trametinib (MEKi) demonstrated a detrimental effect of the “on−off” schedule. Here we report confirmatory data from the Phase II randomized open-label clinical trial comparing the antitumoral activity of the standard schedule versus an intermittent combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF mutant melanoma patients (NCT02583516). The trial did not meet its primary endpoint of progression free survival (PFS) improvement. Our results show that the antitumor activity of the experimental intermittent schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule. Detection of BRAF mutation in cell free tumor DNA has prognostic value for survival and its dynamics has an excellent correlation with clinical response, but not with progression. NGS analysis demonstrated de novo mutations in resistant cases.

A first-in-human phase 1 study of a novel PARP7 inhibitor RBN-2397 in patients with advanced solid tumors.

3000 Background: Targeting cytosolic nucleic acid sensing pathways and the Type I interferon (IFN) response is an emerging therapeutic strategy in oncology. PARP7 is a member of the monoPARP class of enzymes and a newly identified negative regulator of nucleic acid sensing in tumor cells. PARP7 expression is increased by cellular stress and aromatic hydrocarbons, and the PARP7 gene is amplified in multiple cancers. RBN-2397 is a potent, selective inhibitor of PARP7. In preclinical models, RBN-2397 restored Type I IFN signaling in tumors, caused complete tumor regressions, and induced adaptive immunity. Methods: Patients (pts) with advanced solid tumors were treated with RBN-2397 on either a continuous or 14-of-21-day intermittent schedule using a 3+3 dose escalation design. Primary objective: establish MTD and/or RP2D. Secondary obj.: safety, activity, PK of unmicronized/micronized tablets. Exploratory obj.: Pd. Results: As of 4 January 2021, 47 pts were treated: 25 pts in the intermittent schedule (25 to 500 mg BID) and 22 patients in the continuous schedule (100 to 400 mg BID). The most frequent RBN-2397-related AEs (all grades) were dysgeusia (26%), decreased appetite (13%), fatigue (11%), and diarrhea (11%). Gr 3/4 RBN-2397-related AEs all occurred in 7 pts (15%) at doses ≥ 200 mg: diarrhea (2 pts, 4%), increased ALT, AST, and bilirubin (1 pt, 2%), and fatigue, anemia, neutropenia, and thrombocytopenia in 1 pt (2%) each. The 2 DLTs were Gr 3 febrile neutropenia (400 mg continuous schedule) and Gr 4 increase in ALT/AST (500 mg intermittent schedule). Plasma exposures generally increased dose dependently with the majority at or above the projected efficacious range based on animal studies. All evaluable baseline tumor biopsies showed evidence of PARP7 expression as measured by mRNA in situ hybridization (n = 11; Median tumor H score: 128). In 5 evaluable tumor biopsy pairs, increases in interferon-stimulated gene expression were observed post RBN-2397, consistent with activation of Type I IFN. CXCL10 mRNA increased in all evaluable on-treatment biopsies (1.5 to 8-fold). Several on-treatment biopsies showed enrichment for immune response gene sets that was accompanied by an increase in CD8+ T cells and Granzyme B expression, evidence for induction of an adaptive immune response post RBN-2397. This increase in immune response related genes and CD8+ T cells was observed in a pt with metastatic squamous NSCLC who has been on study for 16+ months. 1 pt with HR+, HER2- breast cancer achieved a confirmed PR at 100 mg and 8 pts had SD for ≥18 weeks (RECIST 1.1). Conclusions: To date, RBN-2397 is well tolerated and demonstrates dose dependent increases in plasma exposures, evidence of target inhibition, and preliminary signs of clinical activity. Determination of MTD/RP2D is imminent and study expansion is planned to evaluate safety and efficacy in squamous NSCLC, HNSCC, HR+ breast cancer, and PARP7 amplified tumors. Clinical trial information: NCT04053673.

Results of phase II randomized study of intermittent versus continuous schedule of vemurafenib plus cobimetinib in BRAF-mutated advanced melanoma.

9528 Background: Combination of vemurafenib plus cobimetinib is approved for the treatment of BRAF-mutated advanced melanoma. Although patients initially respond to treatment, resistance emerges before 18 months in most cases. One of the key pre-clinical observations that supported an intermittent schedule was that resistant tumors suffer a fitness deficit in the absence of the drug, so modulation of the drug pressure through an intermittent dosing could delay the emergence of resistance. Methods: GEM1501 is a randomized phase 2 study comparing the activity of the combination of vemurafenib 960 mg every 12 h/d plus cobimetinib 60 mg/d in a standard (arm A) versus intermittent schedule (arm B). Arm A: four-week (w) cycles of daily vemurafenib for 4w plus cobimetinib for 3w-on and 1w-off-treatment. Arm B: first three cycles according to the standard schedule, followed by 6w-cycle with 2w-off vemurafenib & 3w-off cobimetinib. Primary endpoint was progression free survival (PFS) and secondary were objective response (OR) and treatment-related adverse events (TAEs). Results: 70 treatment-naïve patients were included. Results in arms A and B: median PFS 16.2 (95%CI 9.5, 24.1) vs 6.9 months (95%CI 5.2, 9.3) (p = 0.079); OR in 25 (71.4%) (8 complete -23%-) vs 21 (60%) patients (5 complete -14%-); G3-4 TAEs 42.8% vs 40.0%, respectively. Analysis of BRAFV600 mutation in tumoral cell free DNA (cfDNA) was performed in serial plasma samples in 41 patients. Twenty-one (51%) patients had detectable BRAFV600 mutation in pretreatment cfDNA (preBRAF+). Significant differences in PFS were found according to preBRAF V600: 8.2 months (95%CI 5.2, 13.6) in preBRAF+ vs non-reached (NR) (95%CI 2.8, NR) in preBRAF- (p = 0.017). In arm A, median PFS was 13.3 months (95% CI 4.6, NR) in preBRAF+ vs NR (95% CI 2.3, NR) in preBRAF-. In arm B, median PFS was 6.2 months (95% CI 0.3-8.3) in preBRAF+ vs NR (95%CI 2.8, NR) in preBRAF- (p = 0.003). BRAFV600 mutation became undetectable in cfDNA after treatment initiation in all preBRAF+ patients. Different kinetic of BRAFV600 mutation in cfDNA was found according to treatment arm. At progression, BRAFV600 reappeared in cfDNA in all (5/5) cases treated in arm B, but only in 50% (3/6) of cases in arm A. NGS analysis of cfDNA at progression suggested different resistance mechanisms. Conclusions: The results of this study do not support the use of an intermittent schedule of vemurafenib plus cobimetinib in advanced melanoma. BRAFV600 detection in pretreatment cfDNA is a prognostic factor of poor survival that it is independent of treatment schedule, although most striking differences favoring continuous arm vs intermittent arm were found in patients with detectable BRAFV600 mutation on pretreatment cfDNA. Further research is required to determine the clinical value of the analysis of resistance mechanisms in cfDNA. Clinical trial information: 2014-005277-36.

Tolerability and durable respones of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies.

8016 Background: ME-401, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study, and previously demonstrated a high objective response rate (ORR) in FL and chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) when given on a continuous (CS) or an intermittent schedule (IS). IS appeared to significantly reduce the incidence of immune-mediated adverse events of special interest (AESI) associated with PI3kδ inhibitors (diarrhea, rash, transaminase elevation, pneumonitis). We report maturing data from patients treated on the IS in this study. Methods: Eligible patients (pts) had FL, CLL/SLL, marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL), at least 1 prior therapy, adequate bone marrow and organs function, ECOG status ≤2, and no prior PI3K therapy. IS dosing: ME-401 at 60 mg/day for two 28-day cycles, followed by 7 days of therapy every 28-day cycle until disease progression or intolerance. Pts received ME-401 monotherapy (n = 21) or a combination with rituximab (n = 36) given at 375 mg/m2 for 8 doses in Cycles 1-6. Results: Total of 57 pts treated with IS: 35 FL, 10 CLL/SLL, 4 MZL, and 8 DLBCL with 38 (67%) currently still ongoing. Median age: 66 years (range 38-94) and median prior therapies: 2 (range 1-8). As of January 2020, median follow-up = 9.7 mo (range 0.6-25.4+). Grade 3 AESI reported in 7 pts: 2 diarrhea (3.5%), 2 colitis (3.5%), 1 rash (2%), 1 ALT increased (2%), and 1 pneumonitis (2%). No Grade 3 AESI reported beyond Cycle 3. Discontinuation for AE in 3 pts (5%). There were no discernable safety differences between the monotherapy and rituximab combination groups. ORR was 83% in FL (76% in monotherapy group, 88% in combination group) and 89 % in CLL/SLL (100%, 83%), with median duration of response not reached. Median PFS was not reached in all patients with FL and CLL (combined analysis of both single agent and with rituximab). ORR was 100% (4/4) in MZL and 25 % (2/8) in DLBCL (in combination group only). Conclusions: ME-401 administered on an IS was well-tolerated, with a low-rate of Grade 3 class-related AESI and achieved a high-rate of durable objective responses in R/R indolent B-cell malignancies. These results may differentiate ME-401 and support further evaluation as a single-agent and in combination regimens. An ongoing global trial is evaluating ME-401 by IS in pts with FL after failure of ≥2 prior therapies (NCT03768505). Clinical trial information: NCT02914938 .

Preliminary Safety and Efficacy Results with an Intermittent Schedule of the PI3kδ Inhibitor ME-401 Alone or in Combination with Rituximab for B-Cell Malignancies

Background: ME-401, a potent and selective oral PI3kδ inhibitor, achieved a high rate of early and durable responses in patients with follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) when administered once daily in 28-day cycles on a continuous schedule (CS) in a dose escalation Phase 1b study (Soumerai et al, ASCO 2018:#7519). The most common adverse events (AEs) were the delayed onset (beyond Cycle 2) of grade 3 diarrhea and rash, which were reversible with drug interruption and/or corticosteroids. These delayed AEs were thought to be due to pathway inhibition in regulatory T cells (Treg) leading to a disruption in immune homeostasis. We hypothesized that an intermittent schedule (IS) beyond Cycle 2 might mitigate or reduce the incidence of significant delayed AEs. The IS tested was selected based on the kinetics of Treg repopulation, and consists of ME-401 administered on days 1-7 of a 28-day cycle. We report preliminary results of this strategy. Methods: Group 1 included 31 patients with relapsed FL (n = 22) or CLL/SLL (n = 9) who received ME-401 on a CS at doses ≥60 mg per day. 11/29 patients (38%) who received >2 cycles of therapy had developed delayed grade 3 AEs on CS and could be re-challenged with either the CS or IS (from December 2017 onward) following recovery from toxicity. The other 18/29 patients (62%) had not developed a grade 3 AEs of interest on CS and, beginning in December 2017, were switched to IS after a median of 26 weeks (range, 8-49) of daily dosing. Group 2 included 15 patients with relapsed FL (n = 9), diffuse large B-cell lymphoma (n = 4), marginal zone lymphoma (MZL, n = 1), and CLL (n = 1) who received rituximab 375 mg/m2 x 8 doses over 6 months and ME-401 at 60 mg daily x 2 cycles then switched to the IS. Group 3 includes 30 patients with relapsed FL/CLL/SLL enrolling in an expansion cohort of ME-401 alone at 60 mg daily x 2 cycles then switching to IS. Results: Group 1: Of the 11 patients who developed a delayed grade 3 AE on CS, 6 were never re-challenged, 2 were re-challenged with CS with recurrence of their AE, and 3 were re-challenged with IS without recurrence of their AE. Of the 18 patients switched to the IS, and with a median follow-up of 5.2 months (range, 2.3-6.6) on IS, 3 developed grade 3 diarrhea on IS, 2 in the first cycle and 1 in the second cycle after the switch to IS, of whom 2 have been re-treated with IS for 1+ and 5+ months without recurrence of the AE. One patient was not evaluable for response due to discontinuation on Day 28 for personal reasons and 27/30 (90%) evaluable patients achieved an objective response. With a median follow-up of 9.4 months (range, 2.2-17.5) from enrollment, only 2/27 (7%) responders had disease progression (PD) on CS and were discontinued. Of the 18 patients who were switched to IS, only 1 SLL patient with a partial response (PR) achieved on CS developed PD on IS and was successfully rescued with switch back to CS. Another CLL patient in PR on CS had 10% increase in SPD from nadir in Cycle 5 on the IS and was switched back to CS. Group 2: 10/15 patients have completed 2 cycles of daily dosing at the time of analysis and were systematically switched to IS. With a median follow-up of 3.4 months (range, 1.5-5.7) on IS, only 1/10 patients developed delayed grade 3 diarrhea in the first cycle after switch to IS. 7/10 patients (70%) with FL/MZL achieved an objective response and no PD was reported with a median follow-up of 5.2 months (range, 3.1-7.5) from enrollment. Conclusions: Preliminary data suggest that switching to an intermittent schedule consisting of ME-401 administered on days 1-7 of a 28-day cycle following 2 cycles of continuous daily dosing was associated with a low rate of delayed grade 3 AEs and was associated with preservation of response in the vast majority of patients. All delayed grade 3 AEs of interest on IS occurred within 1-2 cycles of switching from CS to IS, suggesting that these might have represented a delayed effect of daily dosing. IS may also be a suitable re-treatment strategy in patients with delayed AEs on CS. Safety and efficacy data for the expansion cohort of 30 patients treated with ME-401 at 60 mg for 2 cycles then switched to IS will be presented at the meeting. A randomized study comparing CS and IS in FL is planned. Disclosures Zelenetz: Abbvie: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; Novartis/Sandoz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Reddy:MEI Pharma: Research Funding. Stathis:Oncology Therapeutic Development: Research Funding. Ghalie:MEI Pharma: Employment, Equity Ownership; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.