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Background: Dabrafenib plus trametinib has demonstrated clinical benefit across multiple BRAF-mutant tumours, leading to approval for resected stage III and metastatic melanoma, non-small-cell lung cancer (NSCLC) and anaplastic thyroid cancer. Pyrexia is a common adverse event in patients treated with dabrafenib plus trametinib. Here, we characterise the incidence, patterns and management of pyrexia in patients receiving dabrafenib plus trametinib in clinical trials. Methods: Patients (N = 1076) included in the analysis received dabrafenib plus trametinib in the following clinical trials: phase II registration trial in advanced NSCLC (N = 82), phase III COMBI-AD study in resectable stage III melanoma (N = 435) and phase III COMBI-d and COMBI-v studies in unresectable or metastatic melanoma (N = 209 and N = 350, respectively). Results: Among the 1076 patients enrolled in the clinical trials, 61.3% developed pyrexia, 5.7% developed grade 3/4 pyrexia and 15.6% developed a protocol-defined serious pyrexia event. Among the 660 patients with pyrexia, 33.0% had 1 occurrence, 19.8% had 2 occurrences and 47.1% had ≥3 occurrences. The incidence of pyrexia was highest early in treatment and decreased with time on treatment. Temporary dose interruption of dabrafenib or trametinib was the most common and effective management strategy. Conclusions: Pyrexia is the most common adverse event associated with dabrafenib plus trametinib but is manageable with dose interruption. Trial registration: ClinicalTrials.gov (Phase II NSCLC, NCT01336634; COMBI-AD, NCT01682083; COMBI-d, NCT01584648; COMBI-v, NCT01597908). Keywords: Adverse event; BRAF V600–mutant melanoma; BRAF inhibitor; MEK inhibitor; Pyrexia.

In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.

Given the approval of dabrafenib in patients with BRAF-mutant metastatic melanoma, a better understanding of treatment patterns and clinical outcomes with dabrafenib in a clinical setting is warranted. We performed a retrospective chart review of patients who received dabrafenib in a compassionate use setting through the Named Patient Program (DESCRIBE I study) during December 2010-August 2013 in Europe, New Zealand and Australia. Of the 331 Named Patient Program patients included, the majority (95.8%) had stage IV disease at dabrafenib initiation and 39.9% had brain metastases (BMs). Dabrafenib was used first line in 67.7% of patients, and median treatment duration was 6.4 months. Dabrafenib was well tolerated. Common grade 2/3 adverse events were hyperkeratosis (7.6%), pyrexia/fever (6.6%), fatigue (5.1%), hand-foot syndrome (5.4%) and nausea (3.6%). Overall response rate was 45.9%, median progression-free survival was 5.2 months (95% confidence interval, 4.2-6.1 months), and median overall survival was 12.4 months (95% confidence interval, 10.2-15.0 months). In patients with known brain metastases (n = 132) versus patients without (n = 199), overall response rate was 42.4% versus 48.2%, progression-free survival was 3.9 months (95% confidence interval, 3.8-5.5 months) versus 5.9 months (95% confidence interval, 4.8-7.8 months) and overall survival was 9.5 months (95% confidence interval, 6.7-12.4 months) versus 15 months (95% confidence interval, 11.1-20.5 months), respectively. Safety and effectiveness of dabrafenib in patients with unresectable advanced BRAF V600-mutant melanoma treated in an Named Patient Program was similar to the clinical trial experience, demonstrating effectiveness of dabrafenib in a nontrial setting.

9560 Background: First-line DabTram has shown long-term efficacy in pts with BRAF V600–mutant unresectable or metastatic melanoma in the Phase III COMBI-d and COMBI-v trials. Data from the Phase III COMBI-i trial comparing spartalizumab plus DabTram vs placebo plus DabTram (pbo-DabTram) demonstrated efficacy in the pbo-DabTram arm, consistent with historical data. Pyrexia (single preferred term [PT]) is the most common adverse event (AE) reported with DabTram (pooled COMBI-d [data cutoff: Jan 12, 2015] and COMBI-v [data cutoff: Apr 17, 2014]: any grade, 54.2%; grade ≥ 3, 5.4%; serious pyrexia AEs leading to hospitalization, 11.8%). A new pyrexia management algorithm was implemented in the COMBI-i trial to improve pyrexia-related outcomes. We report pyrexia-related outcomes in pts treated with pbo-DabTram in the control arm of COMBI-i part 3. Methods: COMBI-i (NCT02967692) part 3 is a double-blind, Phase III trial in which pts with previously untreated BRAF V600–mutant unresectable or metastatic melanoma were randomized 1:1 to receive spartalizumab (400 mg intravenously every 4 weeks) plus Dab (150 mg orally twice daily) and Tram (2 mg orally once daily) vs pbo-DabTram. In the adapted pyrexia management algorithm, both Dab and Tram are interrupted promptly at the first symptom of pyrexia or its associated prodrome (ie, chills, rigors, night sweats, or influenza-like symptoms). Treatment at the same dose level is restarted upon the improvement of symptoms if pts are symptom free for ≥ 24 hours. Pyrexia incidence rates presented are for the single PT of pyrexia. Results: At data cutoff (July 1, 2020), median follow-up was 27.2 mo for all pts enrolled in COMBI-i part 3 (N = 532). In the DabTram control arm, 52.7% (139/264) and 3.0% (8/264) of pts had any-grade and grade ≥ 3 pyrexia, respectively. Serious pyrexia AEs were reported in 6.1% (16/264), which led to hospitalization in 5.3% (14/264). Pyrexia led to dose interruption of both Dab and Tram in 39.0% (103/264), with 1.5% (4/264) permanently discontinuing both agents. Median relative dose intensity was 97.8% for Dab and 97.7% for Tram. Conclusions: Pyrexia-related outcomes, including grade ≥ 3 pyrexia (3.0% vs 5.4%) and serious pyrexia AEs leading to hospitalization (5.3% vs 11.8%), were improved in pts treated with DabTram in COMBI-i part 3 compared with historical data from COMBI-d/v. The adapted algorithm offers a simplified approach for managing pyrexia, thereby reducing the incidence of severe pyrexia while maintaining consistent efficacy with DabTram. Clinical trial information: NCT02967692.

9525 Background: The long-term benefit of adjuvant dab + tram in pts with resected stage III BRAF V600E/K–mutant melanoma was demonstrated in COMBI-AD where AEs led to permanent discontinuation of dab + tram in 26% of pts, most often due to pyrexia (9%). The COMBI-APlus trial (NCT03551626) is designed to evaluate whether an adapted pyrexia management algorithm could reduce high-grade pyrexia and other pyrexia-related adverse outcomes, such as treatment cessation and hospitalization. Methods: COMBI-APlus is an open-label, Phase IIIb trial evaluating an adapted pyrexia management algorithm in pts with high-risk resected stage III BRAF V600E/K–mutant melanoma treated with 12 mo of adjuvant dab + tram. In the adapted algorithm, both dab and tram were interrupted promptly at the onset of pyrexia (temperature ≥ 38°C). In the event of suspected recurrent pyrexia, treatment may be interrupted in the presence of pyrexia syndrome (ie, chills, rigors, night sweats, or influenza-like symptoms without temperature ≥ 38°C) at investigator discretion. Treatment with dab + tram was restarted at the same dose level once pts were symptom free for ≥ 24 hours. The primary endpoint is the composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent discontinuation due to pyrexia vs a historical control from COMBI-AD (20%; 95% CI, 16.3%-24.1%). Secondary endpoints include relapse-free survival (RFS) and safety. Results: A total of 552 pts were enrolled. At the data cutoff (5 Oct 2020), all pts had completed 12 mo of treatment; median duration of follow-up was 18.4 mo. COMBI-APlus met its primary endpoint of significant improvement in composite rate of pyrexia. The composite rate was 8.0% (95% CI, 5.9%-10.6%), with rates of 3.8% for grade 3/4 pyrexia, 4.3% for hospitalization due to pyrexia, and 2.4% for discontinuation due to pyrexia. The estimated 12-mo RFS rate was 91.8% (95% CI, 89.0%-93.9%). The most common AEs (≥ 20%) were pyrexia (67.8%), headache (31.7%), blood creatine phosphokinase increase (27.9%), diarrhoea (27.0%), chills (26.4%), fatigue (25.7%), asthenia (23.6%), nausea (23.4%), rash (21.4%), and arthralgia (21.0%). AEs of any type led to permanent dab + tram discontinuation in 14.7% of pts. Conclusions: This primary analysis suggests the new adapted pyrexia management algorithm is effective in reducing grade 3/4 pyrexia, pyrexia-related hospitalization, and treatment discontinuation in pts receiving adjuvant dab + tram. The early efficacy appears consistent with that observed in COMBI-AD. The growing experience of oncologists in managing pyrexia with this simple algorithm may reduce the need for hospitalization or visits to a healthcare provider, which is highly desirable during the current COVID-19 pandemic. Thus, more pts can remain on treatment and derive benefit. Clinical trial information: NCT03551626.

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