PD-1 Inhibitor Spartalizumab Plus Dabrafenib/Trametinib Active in BRAF+ Melanoma

Georgina V. Long, BSc, PhD, MBBS

The triplet of the PD-1 inhibitor spartalizumab, dabrafenib (Tafinlar), and trametinib (Mekinist) led to a complete response (CR) in more than 40% of patients with previously untreated advanced BRAF V600—mutant melanoma, according to a pooled analysis of part 1 (run-in cohort) and part 2 (biomarker cohort) of the 3-part COMBI-i study.

In a total of 36 patients (9 from part 1 and 27 from part 2), first-line treatment with the triplet was associated with an overall response rate (ORR) of 78% by investigator assessment and a CR in 42% at a median follow-up of 19.9 months.¹

At the time of (April 8, 2019), the median progression-free survival (PFS) was 23.7 months and the overall survival (OS) was not evaluable. Eight (22%) of the 36 patients had died.

The updated data from COMBI-i were reported by researchers led by Georgina V. Long, BSc, PhD, chair of Melanoma Medical Oncology and Translational Research, University of Sydney, Australia, in a poster presentation at the 2019 ASCO annual meeting.

“Treatment with targeted therapy has improved outcomes in patients with BRAF-mutant, unresectable or metastatic melanoma; however, many patients experience disease progression, and new treatment strategies are needed to further improve their outcomes,” the investigators wrote. Combining anti—PD-1 antibodies with BRAF and MEK inhibitors may be able to delay progression in patients with BRAF V600-mutant melanoma, owing to potential synergistic activity between BRAF inhibition and anti—PD-1 therapy, they speculated.

Previous clinical trials have demonstrated improved response rates by adding spartalizumab to dabrafenib and trametinib compared with the doublet without spartalizumab.²

COMBI-i is investigating first-line spartalizumab, 400 mg every 4 weeks, plus the BRAF inhibitor dabrafenib, 150 mg twice daily, plus the MEK inhibitor trametinib, 2 mg daily, in patients with unresectable or metastatic BRAF V600—mutant melanoma. Treatment was continued until disease progression, death, unacceptable toxicity, loss to follow-up, or withdrawal of consent.

Of the 36 patients in this analysis, 22% had AJCC 7 stage IIIC disease, 22% had stage IVM1a, 36% had stage IV M1b, 36% had stage IV M1c with elevated levels of LDH, and 19% had stage IV M1c with normal LDH levels. Nineteen (53%) patients overall had an LDH level <1 x the upper limit of normal (ULN), 9 (25%) had an LDH level ≥1 to <2 x ULN, and 6 (17%) had a level ≥2 x ULN.

At the data cutoff, of the 15 patients with CR, the CR was ongoing in 10 (66.7%). Of the patients with a CR, 20% (n = 3) had elevated levels of LDH.

The 12-month PFS rate was 66.7%. Of the 15 patients with an elevated level of LDH at baseline, the median PFS was 10.7 months, with progression events in 10 of the 15 (66.7%). The median PFS in patients with stage IV M1c disease was 12.9 months.

The median OS was not evaluable in patients with elevated LDH at baseline, with 7 (47%) deaths in this group.

The median duration of response (DOR) was 20.7 months. The 12-month DOR rate was 80.3%. The median DOR was not evaluable in patients with elevated baseline levels of LDH nor in patients with stage IV M1c disease.

All patients experienced at least 1 adverse event (AE) of any grade, and serious AEs occurred in 64%. Pyrexia was the most common AE, occurring in 32 (89%) patients. The most common serious AEs were pyrexia (n = 8) and grade ≥3 pancreatitis, cellulitis, pneumonia, and a decrease in ejection fraction (n = 2 for each). There were no treatment-related grade 5 adverse events.

Adverse events lead to discontinuation of any study drug in 17 (47%) patients and discontinuation of all 3 study drugs in 6 (17%) patients. These AEs included increased level of gamma-glutamyltransferase, an elevated level of AST or ALT, dermatitis, hyperkalemia, paresthesia, immune-mediated hepatitis, and interstitial lung disease. Adverse events leading to dose adjustments or interruptions occurred in 100%. There were no treatment-related deaths.

Correlative data from the biomarker cohort were presented in a separate poster presented by a team led by Reinhard Dummer, MD, professor of Dermatologic Oncology, University Hospital Zurich Skin Cancer Center, Switzerland.³ All patients had a consistent increase in T-cell inflamed gene expression signature levels from baseline to biopsy at 2 to 3 weeks.

At data cutoff, 5 of 22 patients with DNA- and RNA-sequencing data available had a PFS event. Heatmap analysis showed that those with a PFS event prior to 12 months had relatively cold tumors at baseline, characterized by low tumor mutational burden values, low T-cell inflamed gene expression signature levels, or high levels of immunosuppressive tumor microenvironment (TME) signatures compared with the patients without a PFS event.

“These results suggest that treatment with spartalizumab in combination with dabrafenib and trametinib had an early impact on tumor cells and the TME, potentially promoting antitumor activity,” the investigators wrote.

The global placebo-controlled, randomized part 3 of COMBI-i is ongoing.

References

1. Long GV, Lebbe C, Atkinson V, et al. The anti—PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600—mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-i. J Clin Oncol 37, 2019 (suppl; abstr 9531).
2. Long GV, Weber JS, Infante JR, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol 2016;34:871-8.
3. Dummer R, Gusenleitner D, Campbell CD, et al. Tumor microenvironment, longitudinal biomarker changes, and clinical outcome in patients with advanced BRAF V600-mutant melanoma treated with first-line spartalizumab + dabrafenib + trametinib. J Clin Oncol 37, 2019 (suppl; abstr 9515).

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