Newer PD-1 Inhibitor Active With Dabrafenib and Trametinib in BRAF V600+ Melanoma

Georgina V. Long, BSc, PhD, MBBS

The investigational PD-1 inhibitor spartalizumab demonstrated a high rate of complete responses (CRs) in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with previously untreated advanced BRAFV600—mutant melanoma. Patients pooled from 2 parts of the 3-part COMBI-i study demonstrated a CR rate of more than 40%.

In a total of 36 patients (9 from part 1 [the run-in cohort] and 27 from part 2 [the biomarker cohort]), 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, MBBS, 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 withBRAF-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 withBRAFV600-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 metastaticBRAFV600—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 &ge;1 to <2 x ULN, and 6 (17%) had a level &ge;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 &ge;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.³All 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.

&ldquo;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,&rdquo; 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&ndash;mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-i.J Clin Oncol.2019;37(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.2019;37(suppl; abstr 9515).