POLARIS: A phase 2 trial of encorafenib plus binimetinib evaluating high-dose and standard-dose regimens in patients with BRAF V600-mutant melanoma with brain metastasis.

Background: POLARIS (phase 2 [ph2]; NCT03911869) evaluated encorafenib (BRAF inhibitor) in combination with binimetinib (MEK1/2 inhibitor) in BRAF/MEK inhibitor-naïve patients with BRAF V600-mutant melanoma with asymptomatic brain metastases. Methods: The safety lead-in (SLI) assessed tolerability for high-dose encorafenib 300 mg twice daily (BID) plus binimetinib 45 mg BID. If the high dose was tolerable in ph2, patients would be randomized to receive high or standard dose (encorafenib 450 mg once daily [QD] plus binimetinib 45 mg BID). Otherwise, standard dose was evaluated as the recommended ph2 dose (RP2D). Patients who tolerated standard dosing during Cycle 1 could be dose escalated to encorafenib 600 mg QD plus binimetinib 45 mg BID in Cycle 2. Safety, efficacy, and pharmacokinetics were examined. Results: RP2D was standard encorafenib dosing, as >33% of evaluable SLI patients (3/9) had dose-limiting toxicities. Overall, of 13 safety-evaluable patients (10 SLI, 3 ph2), 9 had prior immunotherapy. There were 9 treatment-related adverse events in the SLI and 3 in ph2. Of the SLI efficacy-evaluable patients (n = 10), 1 achieved complete response and 5 achieved partial responses (PR); the brain metastasis response rate (BMRR) was 60% (95% CI: 26.2, 87.8). In ph2, 2 of 3 patients achieved PR (BMRR, 67% [95% CI: 9.4, 99.2]). Repeated encorafenib 300 mg BID dosing did not increase steady-state exposure compared with historical 450 mg QD data. Conclusions: Despite small patient numbers due to early trial termination, BMRR appeared similar between the SLI and ph2, and the ph2 safety profile appeared consistent with previous reports of standard-dose encorafenib in combination with binimetinib.

COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma.

BACKGROUND: Treatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff). METHODS: 577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed. RESULTS: Seven-year PFS and OS rates (95 % CI) were 21.2 % (14.7-28.4 %) and 27.4 % (21.2-33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1-14.0 %) and 18.2 % (12.8-24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7-51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8-25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms. CONCLUSIONS: This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/).

Phase II Study of Erdafitinib in Patients With Tumors With Fibroblast Growth Factor Receptor Mutations or Fusions: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol K2.

PURPOSE: Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions. METHODS: Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], P = .034 against the null rate of 5%). An additional seven patients experienced stable disease as best-confirmed response. Four patients had a prolonged PFS including two with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma. The median PFS and OS were 3.6 months and 11.0 months, respectively. Erdafitinib was manageable with no new safety signals. CONCLUSION: This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.

Phase II Study of Erdafitinib in Patients With Tumors With FGFR Amplifications: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol K1.

PURPOSE: Despite fibroblast growth factor receptor (FGFR) inhibitors being approved in tumor types with select FGFR rearrangements or gene mutations, amplifications of FGFR represent the most common FGFR alteration across malignancies. Subprotocol K1 (EAY131-K1) of the National Cancer Institute-MATCH platform trial was designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 amplification. METHODS: EAY131-K1 was an open-label, single-arm, phase II study with central confirmation of presence of FGFR1-4 amplification in tumors. Patients with urothelial carcinoma were excluded. Enrolled patients received oral erdafitinib at a starting dose of 8 mg once daily continuously with escalation to 9 mg once daily continuously, on the basis of predefined time point assessments of phosphate levels, until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR), with key secondary end points being 6-month progression-free survival (PFS6), PFS, overall survival (OS), and safety. RESULTS: Thirty-five patients were enrolled into this study with 18 included in the prespecified primary efficacy analysis. The median age of the 18 patients was 60 years, and 78% had received ≥3 previous lines of therapy. There were no confirmed responses to erdafitinib; however, five patients experienced stable disease (SD) as best response. One patient with an FGFR1-amplified breast cancer had a prolonged PFS >168 days (5.5 months). The median PFS was 1.7 months (90% CI, 1.1 to 1.8 months) and the median OS was 4.2 months (90% CI, 2.3 to 9.3 months). The estimated PFS6 rate was 13.8% (90% CI, 3.3 to 31.6). The majority of toxicities were grade 1 to 2 in nature, although there was one grade 5 treatment-related adverse event. CONCLUSION: Erdafitinib did not meet its primary end point of efficacy as determined by ORR in treatment-refractory solid tumors harboring FGFR1-4 amplifications. Our findings support that rearrangements and gene mutations, but not amplifications, of FGFR remain the established FGFR alterations with approved indications for FGFR inhibition.

Phase II Study of Osimertinib in Patients With Epidermal Growth Factor Receptor Mutations: Results From the NCI-MATCH ECOG-ACRIN (EAY131) Trial Subprotocol E.

PURPOSE: The National Cancer Institute Molecular Analysis for Therapy Choice trial is a signal-finding genomically driven platform trial that assigns patients with any advanced refractory solid tumor, lymphoma, or myeloma to targeted therapies on the basis of next-generation sequencing results. Subprotocol E evaluated osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with EGFR mutations. METHODS: Eligible patients had EGFR mutations (T790M or rare activating) and received osimertinib 80 mg once daily. Patients with lung cancer with EGFR T790M were excluded. The primary end point was objective response rate (ORR), and the secondary end points were 6-month progression-free survival (PFS), overall survival, and toxicity. RESULTS: A total of 19 patients were enrolled: 17 were evaluable for toxicity and 13 for efficacy. The median age of the 13 included in the efficacy analysis was 63 years, 62% had Eastern Cooperative Oncology Group performance status 1, and 31% received >three previous systemic therapies. The most common tumor type was brain cancers (54%). The ORR was 15.4% (n = 2 of 13; 90% CI, 2.8 to 41.0) and 6-month PFS was 16.7% (90% CI, 0 to 34.4). The two confirmed RECIST responses were observed in a patient with neuroendocrine carcinoma not otherwise specified (EGFR exon 20 S768T and exon 18 G719C mutation) and a patient with low-grade epithelial carcinoma of the paranasal sinus (EGFR D770_N771insSVD). The most common (>20%) treatment-related adverse events were diarrhea, thrombocytopenia, and maculopapular rash. CONCLUSION: In this pretreated cohort, osimertinib did not meet the prespecified end point threshold for efficacy, but responses were seen in a neuroendocrine carcinoma with an EGFR exon 20 S768T and exon 18 G719C mutation and an epithelial carcinoma with an EGFR D770_N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

Benefit, recurrence pattern, and toxicity to adjuvant anti-PD-1 monotherapy varies by ethnicity and melanoma subtype: An international multicenter cohort study.

Background: Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence pattern and toxicity to adjuvant PD-1 between different ethnicities and melanoma subtypes. Objective: We performed a multicenter cohort study incorporating 6 independent institutions in Australia, China, Japan, and the United States. The primary outcomes were recurrence free survival (RFS) and overall survival (OS). Secondary outcomes were disease recurrence patterns and toxicities. Results: In total 534 patients were included. East-Asian/Hispanic/African reported significantly poorer RFS/OS. Nonacral cutaneous or melanoma of unknown primary reported the best RFS/OS, followed by acral, and mucosal was the poorest. Within the nonacral cutaneous or melanoma of unknown primary subtypes, East-Asian/Hispanic/African reported significantly poorer RFS/OS than Caucasian. In the multivariate analysis incorporating ethnicity/melanoma-subtype/age/sex/stage/lactate dehydrogenase/BRAF (v-Raf murine sarcoma viral oncogene homolog B)-mutation/adjuvant radiotherapy, East-Asian/Hispanic/African had independently significantly poorer outcomes (RFS: HR, 1.71; 95% CI, 1.19-2.44 and OS: HR, 2.34; 95% CI, 1.39-3.95), as was mucosal subtype (RFS: HR, 3.25; 95% CI, 2.04-5.17 and OS: HR, 3.20; 95% CI, 1.68-6.08). Mucosal melanoma was an independent risk factor for distant metastasis, especially liver metastasis. East-Asian/Hispanic/African had significantly lower incidence of gastrointestinal/musculoskeletal/respiratory/other-rare-type-toxicities; but higher incidences of liver toxicities. Limitations: A retrospective study. Conclusions: Ethnicity and melanoma subtype are associated with survival and recurrence pattern in melanoma patients treated with adjuvant anti-PD-1. Toxicity profile differs by ethnicity and may require a precision toxicity surveillance strategy.

Trastuzumab and Pertuzumab in Patients with Non-Breast/Gastroesophageal HER2-Amplified Tumors: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol J.

PURPOSE: NCI-MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors. PATIENTS AND METHODS: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31-80), and half of all patients had ≥3 prior therapies (range, 1-11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%-28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0-4.1), and median OS 9.4 months (90% CI 5.0-18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response. CONCLUSIONS: HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors.

Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.

PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy.

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma1,2. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance3. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.

MAESTRO-Pool Enables Highly Parallel and Specific Mutation-Enrichment Sequencing for Minimal Residual Disease Detection in Cohort Studies.

BACKGROUND: Tracing patient-specific tumor mutations in cell-free DNA (cfDNA) for minimal residual disease (MRD) detection is promising but challenging. Assaying more mutations and cfDNA stands to improve MRD detection but requires highly accurate, efficient sequencing methods and proper calibration to prevent false detection with bespoke tests. METHODS: MAESTRO (Minor Allele Enriched Sequencing Through Recognition Oligonucleotides) uses mutation-specific oligonucleotide probes to enrich cfDNA libraries for tumor mutations and enable their accurate detection with minimal sequencing. A new approach, MAESTRO-Pool, which entails pooling MAESTRO probes for all patients and applying these to all samples from all patients, was used to screen for 22 333 tumor mutations from 9 melanoma patients in 98 plasma samples. This enabled quantification of MRD detection in patient-matched samples and false detection in unmatched samples from other patients. To detect MRD, a new dynamic MRD caller was used that computes a probability for MRD detection based on the number of mutations and cfDNA molecules sequenced, thereby calibrating for variations in each bespoke test. RESULTS: MAESTRO-Pool enabled sensitive detection of MRD down to 0.78 parts per million (ppm), reflecting a 10- to 100-fold improvement over existing tests. Of the 8 MRD positive samples with ultra-low tumor fractions <10 ppm, 7 were either in upward-trend preceding recurrence or downward-trend aligning with response. Of 784 patient-unmatched tests, only one was found as MRD positive (tumor fraction = 2.7 ppm), suggesting high specificity. CONCLUSIONS: MAESTRO-Pool enables massively parallel, tumor-informed MRD testing with concurrent benchmarking of bespoke MRD tests. Meanwhile, our new MRD caller enables more mutations and cfDNA molecules to be tested without compromising specificity. These improve the ability for detecting traces of MRD from blood.

Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study.

Background: Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. Methods: This multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1 between Jul 2015 and Oct 2022. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity. Findings: We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n = 393 [66%]) or PD-1 (n = 205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21-43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50-0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39-0.86, P = 0.007), with comparable OS with PD-1 (multivariate, HR 0.90, 95% CI 0.48-1.70, P = 0.75). Similar findings were observed using a restricted-mean-survival-time model. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs. Interpretation: In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T seems to provide a better outcome compared with PD-1, but a longer follow-up and ideally a large prospective trial are needed. Funding: Dr. Xue Bai was supported by the Beijing Hospitals Authority Youth Programme (QMS20211101) for her efforts devoted to this study. Dr. Keith T. Flaherty was funded by Adelson Medical Research Foundation for the efforts devoted to this study.

A twenty year perspective on melanoma therapy.

Melanoma had long been considered to be particularly addressable with immunotherapy, but that reputation was built on modestly effective cytokine-based immunotherapy. CTLA-4 antibody therapy reinforced this legacy, but PD-1 antibodies transformed the melanoma treatment landscape and lead the way for immunotherapy to become standard treatment for more than half of the advanced cancer population. BRAF mutations were discovered in 8% of all cancer and nearly 50% of melanomas. Successful development of BRAF inhibitors and BRAF/MEK combination therapy in melanoma preceded regulatory approval across all cancer types. No cancer type saw outcomes improved by the same margin as melanoma in the decade of the 2010s.

Sponsor Perspectives on the Impact of the COVID-19 Pandemic on Interventional Cancer Clinical Trial Protocols and Data Quality.

PURPOSE: The onset of the COVID-19 pandemic created major disruptions in the conduct of cancer clinical trials. In response, regulators and sponsors allowed modifications to traditional trial processes to enable clinical research and care to continue. We systematically evaluated how these mitigation strategies affected data quality and overall trial conduct. METHODS: This study used surveys and live interviews. Forty-one major industry and National Cancer Institute Network groups (sponsors) overseeing anticancer treatment trials open in the United States from January 2015 to May 2022 were invited to participate. Descriptive statistics were used for survey data summaries. Key themes from interviews were identified. RESULTS: Twenty sponsors (48.8%; 15 industry and five Network groups) completed the survey; 11/20 (55.0%) participated in interviews. Sponsors predominantly (n = 12; 60.0%) reported large (≥11 trials) portfolios of phase II and/or phase III trials. The proportion of sponsors reporting a moderate (9) or substantial (8) increase in protocol deviations in the initial pandemic wave versus the pre-pandemic period was 89.5% (17/19); the proportion reporting a substantial increased dropped from 42.1% (n = 8/19) in the initial wave to 15.8% (n = 3/19) thereafter. The most commonly adopted mitigation strategies were remote distribution of oral anticancer therapies (70.0%), remote adverse event monitoring (65.0%), and remote consenting (65.0%). Most respondents (15/18; 83.3%) reported that the pandemic had minimal (n = 14) or no impact (n = 1) on overall data integrity. CONCLUSION: Despite nearly all sponsors observing a temporary increase in protocol deviations, most reported the pandemic had minimal/no impact on overall data integrity. The COVID-19 pandemic accelerated an emerging trend toward greater flexibility in trial conduct, with potential benefits of reduced burden on trial participants and sites and improved patient access to research.

Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial.

PURPOSE: In COLUMBUS part 1, patients with advanced BRAFV600-mutant melanoma were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice a day (COMBO450), vemurafenib 960 mg twice a day, or encorafenib 300 mg once daily (ENCO300). As previously reported, COMBO450 improved progression-free survival (PFS) versus vemurafenib (part 1 primary end point) and ENCO300 (part 1 key secondary end point; not statistically significant). Part 2, requested by the US Food and Drug Administration, evaluated the contribution of binimetinib by maintaining the same encorafenib dosage in the combination (encorafenib 300 mg once daily plus binimetinib 45 mg twice daily [COMBO300]) and ENCO300 arms. METHODS: In part 2, patients were randomly assigned 3:1 to COMBO300 or ENCO300. ENCO300 (parts 1 and 2) data were combined, per protocol, for PFS analysis (key secondary end point) by a blinded independent review committee (BIRC). Other analyses included overall response rate (ORR), overall survival, and safety. RESULTS: Two hundred fifty-eight patients received COMBO300, and 86 received ENCO300. Per protocol, ENCO300 arms (parts 1 and 2 combined) were also evaluated (n = 280). The median follow-up for ENCO300 was 40.8 months (part 1) and 57.1 months (part 2). The median PFS (95% CI) was 12.9 months (10.9 to 14.9) for COMBO300 versus 9.2 months (7.4 to 11.1) for ENCO300 (parts 1 and 2) and 7.4 months (5.6 to 9.2) for ENCO300 (part 2). The hazard ratio (95% CI) for COMBO300 was 0.74 (0.60 to 0.92; two-sided P = .003) versus ENCO300 (parts 1 and 2). The ORR by BIRC (95% CI) was 68% (62 to 74) and 51% (45 to 57) for COMBO300 and ENCO300 (parts 1 and 2), respectively. COMBO300 had greater relative dose intensity and fewer grade 3/4 adverse events than ENCO300. CONCLUSION: COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.

The NCI-MATCH trial: lessons for precision oncology.

The NCI-MATCH (Molecular Analysis for Therapy Choice) trial ( NCT02465060 ) was launched in 2015 as a genomically driven, signal-seeking precision medicine platform trial-largely for patients with treatment-refractory, malignant solid tumors. Having completed in 2023, it remains one of the largest tumor-agnostic, precision oncology trials undertaken to date. Nearly 6,000 patients underwent screening and molecular testing, with a total of 1,593 patients (inclusive of continued accrual from standard next-generation sequencing) being assigned to one of 38 substudies. Each substudy was a phase 2 trial of a therapy matched to a genomic alteration, with a primary endpoint of objective tumor response by RECIST criteria. In this Perspective, we summarize the outcomes of the initial 27 substudies in NCI-MATCH, which met its signal-seeking objective with 7/27 positive substudies (25.9%). We discuss key aspects of the design and operational conduct of the trial, highlighting important lessons for future precision medicine studies.

COLUMBUS 5-year update: a randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF.

WHAT IS THIS SUMMARY ABOUT?: Here, we summarize the 5-year results from part 1 of the COLUMBUS clinical study, which looked at the combination treatment of encorafenib plus binimetinib in people with a specific type of skin cancer called melanoma. Encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®) are medicines used to treat a type of melanoma that has a change in the BRAF gene, called advanced or metastatic BRAF V600-mutant melanoma. Participants with advanced or metastatic BRAF V600-mutant melanoma took either encorafenib plus binimetinib together (COMBO group), compared with encorafenib alone (ENCO group) or vemurafenib (ZELBORAF®) alone (VEMU group). WHAT WERE THE RESULTS?: In this 5-year update, more participants in the COMBO group were alive for longer without their disease getting worse after 5 years than those in the VEMU and ENCO groups. Patients in the COMBO group were alive for longer without their disease getting worse when they: Had less advanced cancer Were able to do more daily activities Had normal lactate dehydrogenase (LDH) levels Had fewer organs with tumors before treatment After treatment, fewer participants in the COMBO group received additional anticancer treatment than participants in the VEMU and ENCO groups. The number of participants who reported severe side effects was similar for each treatment. The side effects caused by the drugs in the COMBO group decreased over time. WHAT DO THE RESULTS MEAN?: Overall, this 5-year update confirmed that people with BRAF V600-mutant melanoma that has spread to other parts of the body and who took encorafenib plus binimetinib were alive for longer without their disease getting worse than those who took vemurafenib or encorafenib alone. Clinical Trial Registration: NCT01909453 (ClinicalTrials.gov).

Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma.

Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce tolerance to MEK inhibitors, likely by decreasing the levels of cell death. Mechanistically, cIAP2 is upregulated at the transcript level in SOX10-deficient cells and the AP-1 complex protein, JUND, is required for its expression. Using a patient-derived xenograft model, we demonstrate that treatment with the cIAP1/2 inhibitor, birinapant, during the MRD phase delays the onset of resistance to BRAF inhibitor and MEK inhibitor combination therapy. Together, our data suggest that cIAP2 upregulation in SOX10-deficient subpopulations of melanoma cells induces drug tolerance to MAPK targeting agents and provides a rationale to test a novel therapeutical approach to target MRD.

Trametinib in Patients With NF1-, GNAQ-, or GNA11-Mutant Tumors: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols S1 and S2.

PURPOSE: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 (NF1[S1] or GNA11/Q [S2]) altered tumors. METHODS: Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss. RESULTS: Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common. CONCLUSION: Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.