Search

PURPOSE Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced BRAF V600–mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453 ). METHODS Patients with locally advanced unresectable or metastatic BRAF V600–mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned. RESULTS Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard. CONCLUSION In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600–mutant melanoma.

TPS1589 Background: The emergence of immune checkpoint inhibitors has improved survival outcomes for patients with advanced melanoma. However, these treatment modalities are also associated with specific immune-related toxicities. These are often reversible after prompt recognition and initiation of appropriate management, but can result in severe morbidity and hamper health-related quality of life (HRQoL) if left undetected. Hence, accurate and regular monitoring of these patients is critical. Recent advances in mHealth technologies and the rapidly expanding armamentarium of wearable devices allow for real-time objective (vital signs and physical activity) data and patient-reported outcome measurement (PROMs) collection and, hence, serve this purpose. We hypothesize that collection of real-time objective data adds to the early detection of disease- and treatment-related adverse events. The primary objective of this study is to determine the feasibility of collecting real-time PROMs, vital signs, and physical activity data in advanced melanoma patients receiving immunotherapy using a comprehensive ambulatory monitoring platform (CAMP) that consists of a smartphone app, activity monitor, digital thermometer, and online dashboard for physicians. Methods: In this prospective multi-center trial, patients (n = 50) with advanced melanoma, scheduled to receive immunotherapy with immune checkpoint inhibitors, and with access to a smartphone are eligible for inclusion. Consenting patients will be asked to wear a FitBit Versa 2.0 during waking hours, collect daily temperature measurements using a Withings Smart Temporal thermometer, and answer weekly toxicity questionnaires (NCI PRO-CTCAE) using the smartphone app for the duration of the study (12 weeks). Primary outcome is feasibility in terms of (i) participation rates, (ii) wear-time, (iii) compliance rates with in-app questionnaires and temperature measurements, and (iv) satisfaction with the platform. Secondary exploratory outcomes include associations between CAMP-derived parameters and clinical outcomes: performance status (PS), HR-QoL scores (EORTC QLQ-C30 questionnaire), unplanned hospitalizations, physician-assessed adverse events, and 1-year survival outcomes. PS and HR-QoL will be rated at baseline, mid-study, and end-of-study. The occurrence of adverse events will be documented up to 12 months from baseline. Survival outcomes will be compared to a propensity score matched group from the Netherlands Cancer Registry. Accrual has started in February 2021. Clinical trial information: NL8827.

10012 Background: Treatment of patients with BRAF V600–mutant melanoma includes BRAF/MEK-inhibitor combinations based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). To better understand the proportion of patients who derive long-lived benefit and their characteristics, we performed an updated analysis of OS and other endpoints from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 patients with advanced/metastatic BRAF V600‒mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to ENCO 450 mg QD + BINI 45 mg BID (COMBO450) vs VEM 960 mg BID (VEM) or ENCO 300 mg QD (ENCO300). An updated analysis including PFS, OS, objective response rate (ORR), and safety was conducted after an additional 24 months’ follow-up from the initial analysis. The study is ongoing. Results: At data cutoff (November 2019, as-is data), events had occurred in 65%, 59%, and 75% of patients in the COMBO450, ENCO300, and VEM treatment arms, respectively. Across arms, median follow-up for OS was 60.6 months (mo), with median OS of 33.6 mo (95% CI, 24.4–39.2) for COMBO450, 23.5 mo (95% CI, 19.6–33.6) for ENCO300, and 16.9 mo (95% CI, 14.0–24.5) for VEM. Compared to VEM, COMBO450 decreased the risk of death by 38% (HR, 0.62 [95% CI, 0.49–0.79]). Updated median PFS was COMBO450, 14.9 mo (95% CI, 11.0–20.2), ENCO300, 9.6 mo (95% CI, 7.4–14.8), and VEM, 7.3 mo (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.52 [95% CI, 0.40–0.67]). A landmark analysis showed a higher rate of OS for COMBO450 at each year analyzed, with OS rates at 4 years of 39%, 37%, and 26% COMBO450, ENCO300, and VEM, respectively. Updated safety analysis confirmed the beneficial long-term tolerability of COMBO450. Conclusions: In the COLUMBUS trial, results for updated PFS and OS with COMBO450 continue to demonstrate long-term benefits in patients with BRAF V600‒mutated melanoma. Clinical trial information: NCT01909453.

10021 Background: Continuous combination of MAPK inhibition (MAPKi) and anti-PD-(L)1 has been investigated by several trials to improve outcome of BRAFV600 mutated melanoma patients. A major obstacle for continuous combination is the high frequency (~60%) of grade 3-4 treatment-related adverse events (TRAE) for which many patients need to discontinue (~40%). In a preclinical model we showed that short‐time MAPKi induces T cell infiltration and is synergistic with anti-PD‐1. In patients T cell infiltration increased after short-term MAPKi, while after > 2 weeks this was often diminished. The aim of this phase 2b study was to identify the optimal duration of MAPKi with dabrafenib (BRAFi) + trametinib (MEKi) in combination with pembrolizumab (anti-PD-1) in terms of safety, feasibility and immune-activating capacity. Methods: Treatment-naïve BRAFV600E/K mutant advanced melanoma patients started pembrolizumab (PEM) 200mg Q3W and were randomized in week 6 to continue PEM only (cohort 1) or to receive in addition intermittent dabrafenib (D) 150 mg BID + trametinib (T) 2mg QD for 2 x 1 week (cohort 2), 2 x 2 weeks (cohort 3), or continuous for 6 weeks (cohort 4). All cohorts continued PEM for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR, RECIST 1.1) at week 6, 12, 18 compared to baseline and PFS. Results: Between June 2016 and August 2018, 32 patients have been included; 56% were male, 50% had M1c disease and the majority had a BRAFV600E mutation (81%) and a baseline LDH level > ULN (87%). Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 62% of patients in cohort 1, 2, 3, and 4, respectively. All planned D+T was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. Most patients needed to interrupt or discontinue D+T due to fever or elevated liver enzymes. ORR at week 6, week 12, and week 18 were 38%, 62%, and 62% in cohort 1, 25%, 62%, and 75% in cohort 2, 25%, 50%, and 75% in cohort 3 and 0%, 62%, and 50% in cohort 4. After a median follow-up of 17.4 months, the median PFS of patients treated with PEM monotherapy was 10.6 months compared to 27.0 months for patients treated with PEM and short-term/intermittent D+T (p = 0.13). Conclusions: Combination of PEM plus intermittent D+T seems more feasible and tolerable than continuous triple therapy. Intermittent short-time combination therapy might be equally effective, enables therapy with MAPKi as a second line, and therefore warrants further investigation in a larger patient cohort. Clinical trial information: NCT02625337.

10042 Background: A large proportion of patients with advanced melanoma is not represented in phase III clinical trials, due to ineligibility. Real-world efficacy evidence of immune- and targeted therapies in these patients is lacking. We aimed to provide insight in survival outcomes of systemically treated patients who were not represented in the phase III trials in order to support clinical decision-making. Methods: Systemically treated ineligible patients with advanced melanoma diagnosed between 2014-2017 were analyzed. Prognostic importance of factors associated with overall survival (OS) was assessed by Kaplan Meier method, Cox regression models, predicted OS probabilities of prognostic subgroups and a conditional inference survival (decision) tree. Results: Of 2,536 systemically treated patients with advanced melanoma, 1,004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria most strongly correlated with survival in ineligible systemically treated patients with ECOG Performance Score (PS) ≥2 vs PS 0-1 (HR 1.95 (95%CI: 1.52-2.5)), symptomatic brain metastases (BM) vs absent BM (HR 1.71 (95%CI: 1.34-2.18)) and LDH > 500 U/l vs normal (HR 1.89 (95%CI: 1.49-2.41)). All other factors for ineligibility were not associated with OS. By combining ECOG PS, BM and LDH, 18 subgroups were created. The 3-year survival probability of patients with ECOG PS ≤1, asymptomatic BM and normal LDH was 35.1%. Patients with ECOG PS of ≥2 with or without symptomatic BM had a mOS of 6.5 and 11.3 months and a 3-year survival probability of 9.3% and 23.6% respectively. In the decision tree, the covariate with the strongest predictive distinctive character for survival was LDH, followed by ECOG PS. Prognosis of LDH of > 500 U/L is infaust, although still long-term survival is possible (3-year survival probability of 15.3%). The decision tree showed the prognosis of patients with symptomatic BM can be good if ECOG PS is 0 and patients are aged ≤55 years (mOS of 22.3 months). Conclusions: Patients with advanced melanoma not represented in phase III trials treated with systemic therapy can achieve long term survival. LDH was the strongest predictive factor associated with survival, followed by ECOG PS and symptomatic BM. Other factors for ineligibility were not associated with OS. These results, together with the decision tree, can be used to provide insight in outcomes to facilitate the shared decision-making process when comparative studies are not available.

539 Background: The anatomical location of the primary tumor has been associated with different prognosis and outcomes in mCRC. REG significantly improved overall survival (OS) versus placebo in patients with mCRC who progressed on standard therapies in phase 3 trials. We report the final results of outcomes in patients with mCRC with left-sided (L) or right-sided (R) primary tumors who were treated with REG in the real-world CORRELATE study. Methods: CORRELATE (NCT02042144) was a prospective, observational study designed to characterize the safety and effectiveness of REG in patients previously treated with approved therapies and for whom the decision to treat with REG was made by the treating physician according to the local health authority label. Patients with tumor location unknown or tumors in both regions were excluded (n = 62). OS was analyzed using the Kaplan–Meier method. Results: Overall, 975 patients were included in the analysis: L = 768 (79%) and R = 207 (21%). Most patients were ECOG PS 0–1 (L: 86%; R: 87%). Median time from initial diagnosis and from diagnosis of metastatic disease to REG treatment was slightly longer in L versus R tumors (34 vs 30 months and 27 vs 23 months, respectively). A higher proportion of patients with L versus R tumors, respectively, had prior radiotherapy (34% vs 15%) and a lower proportion had a partial colectomy (44% vs 75%). Both groups received a median of three prior regimens. REG treatment duration was similar in the two groups (median duration: L 2.6 months vs R 2.3 months), as was median progression-free survival (95% CI): 2.8 months (2.6, 2.9) for L tumors versus 2.7 months (2.5, 3.1) for R tumors. Median OS (95% CI) was 7.4 months (6.7, 8.0) for L tumors versus 8.2 months (6.6, 9.3) for R tumors; one-year OS rates were 32% versus 34%, respectively. Conclusions: Results from this observational study suggest that OS is similar in patients with L and R tumors treated with REG. Clinical trial information: NCT02042144.

3553 Background: For selected patients with oligometastatic colorectal cancer (mCRC), local treatment of metastases is standard of care based on retrospective reports showing long term survival rates. Local treatment of metastases is technically feasible in an increasing number of patients with multi-organ mCRC. It is unknown if patients with extensive disease will benefit from tumor debulking when added to first line palliative chemotherapy. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival (OS) benefit from tumor debulking in patients with multi-organ mCRC. Methods: Patients with multi-organ mCRC were eligible if > 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. All patients received oxaliplatin based chemotherapy ± bevacizumab. In case of stable disease or response at first evaluation (9 weeks), patients were randomized to continuation of chemotherapy or tumor debulking followed by chemotherapy. Adverse events were reported. If patient withdrawal after randomization was < 10%, the study was deemed feasible. Study continuation was based on the interim report on safety and feasibility after inclusion of 100 (of 478) patients. Results: Patients were randomized to the standard (N = 43) or intervention arm (N = 45). No patients withdrew after randomization. In 6.8% of patients debulking was not performed due to progressive disease (N = 5) or death (N = 1) prior to local treatment. Two patients had no lesions left to treat, 37 patients underwent tumor debulking. In 15 patients (40%) 21 serious adverse events related to debulking were reported, 83.7% of patients had no SAEs or recovered within 30 days. Postoperative 90-day mortality was 2.7% (N = 1). Chemotherapy was resumed in 86.5% of patients, median time to restart was 12.7 weeks (SD 5.6) and 78.4% completed ≥24 weeks of chemotherapy. Conclusions: Tumor debulking is feasible and safe and does not prohibit administration of palliative chemotherapy in the majority of patients with multi-organ mCRC. The ORCHESTRA trial will continue accrual to determine whether the aim of > 6 months OS benefit from tumor debulking will be achieved. Clinical trial information: NCT01792934.

3567 Background: The anatomical location of the primary tumor has been associated with outcomes in mCRC, with left-sided (L) tumors having a better prognosis than right-sided (R) tumors and location predicting response to treatment. REG significantly improved overall survival (OS) vs placebo in patients with mCRC who progressed on available treatments in 2 randomized, phase 3 trials (CORRECT, CONCUR). This exploratory analysis evaluated outcomes by primary tumor location in patients with mCRC treated with REG in the CORRELATE study. Methods: CORRELATE is an observational study designed to characterize the safety and effectiveness of REG in unselected patients for whom the decision to treat with REG has been made by the treating physician according to the local health authority label. Primary L tumors were located in the rectum, splenic flexure, recto-sigmoid, descending, or sigmoid colon; R tumors were in the appendix, hepatic flexure, cecum, or ascending colon. OS was analyzed by the Kaplan–Meier method and comparisons were by a 2-sided log-rank test. Results: Primary tumor location was available for 474 patients (L, n = 375 [79%]; R, n = 99 [21%]). Median time from initial diagnosis and from diagnosis of metastatic disease to treatment was slightly longer in L vs R tumors (32 vs 28 months and 25 vs 22 months, respectively). A higher proportion of patients with L vs R tumors, respectively, had prior radiotherapy (34% vs 13%) and a lower proportion had a partial colectomy (40% vs 70%). Best response to prior systemic therapy (partial response + stable disease) was 72% for L tumors and 68% for R tumors with a median duration of treatment of 26 and 22 months, respectively. REG treatment duration was similar in the 2 groups. Median OS (95% CI) was 6.7 months (6.1, 7.7) for L tumors vs 6.3 months (4.9, 8.1) for R tumors (P = 0.3); median progression-free survival (95% CI) was 2.8 months (2.6, 3.0) vs 2.6 months (2.4, 3.0) (P = 0.5), respectively. Conclusions: Interim results from this observational study suggest that OS is similar in patients with R and L tumors treated with REG. Clinical trial information: NCT02042144.

700 Background: REG significantly improved overall survival (OS) vs placebo in patients with mCRC who progressed on available treatments in the randomized, double-blind, phase 3 trials CORRECT and CONCUR. CORRELATE aims to characterize the safety and effectiveness of REG for the treatment of mCRC in an unselected real-world patient population treated in routine clinical practice. Here we report the results of a planned IA. Methods: This global study aims to recruit 1000 patients with mCRC previously treated with approved therapies and for whom the decision to treat with REG has been made by the treating physician according to the local health authority approved label. Dose interruptions and reductions are permitted for the management of adverse events (AEs). The primary endpoint is the incidence of treatment-emergent AEs (TEAE; NCI-CTCAE v4.03). Secondary endpoints include OS, progression-free survival, and the disease control rate. The first planned interim analysis includes the first 500 patients observed for at least 3 months. Here, we report an IA of safety. Results: Median age was 65 years (range: 29–89) and 61% of patients were male. Most patients had a baseline ECOG PS 0/1 vs 2–4 (41%/43% vs 8%) and 50% had KRAS mutations. Most common metastatic sites at study entry were liver (52%) and lung (43%). The median treatment duration was 2.4 months (range: 0.1–10.6). The daily starting REG dose was 160 mg, 120 mg, and 80 mg in 53%, 34%, and 12% of patients, respectively; 26% of patients had dose reductions, 21% due to TEAEs. TEAEs of any grade occurred in 91% of patients, and in 76% TEAEs were considered REG related. Grade ≥ 3 TEAEs occurred in 55% of patients. In 31%, grade ≥ 3 TEAEs were REG related, with fatigue (7%), hand-foot skin reaction (5%), and hypertension (5%) being most common. Grade 5 TEAEs occurred in 13% of patients and were REG related in < 1%. Conclusions: In this observational study, the planned IA showed that the rate of REG-related grade ≥ 3 TEAEs appeared to be somewhat lower than rates observed in the phase 3 trials in patients with mCRC. The starting dose for approximately half the patients was less than 160 mg/day. Clinical trial information: NCT02042144.

e15596Background: Cholangiocarcinoma is an uncommon cancer, often treated in a palliative setting, with an unfavorable prognosis. Since 2010, the standard of care for patients with advanced cholang...