Triplet Therapy With Novel PD-1 Inhibitor Holds Promise in Melanoma

The addition of a novel PD-1 inhibitor to a combination of BRAF inhibitor dabrafenib (Tafinlar) and MEK inhibitor trametinib (Mekinist) is being tested to determine whether the triplet is safe and effective for patients with metastatic or unresectable melanoma. Although the combination of BRAF and MEK inhibitors is already a preferred treatment option for patients with BRAF V600 mutation—positive melanoma, investigators are hopeful that adding the PD-1 inhibitor spartalizumab (PDR001) will improve responses to therapy.¹

Checkpoint inhibitors and other targeted therapies have improved outcomes for patients with advanced melanoma, but patients still have progression and die from the disease.

Spartalizumab is an investigational humanized monoclonal antibody that binds to PD-1 expressed on activated T cells and blocks the interactions with its ligands, PD-L1 and PD-L2. This inhibits PD-1 signaling, activates T cells, and induces an immune response to tumor cells,² causing a reduction of tumor growth.³

Combinations with BRAF and MEK inhibitors have the potential to reverse immunosuppressive phenotypes induced by an oncogenic BRAF mutation. These combinations can also improve sensitivity to checkpoint inhibitors by enhancing the expression of human leukocyte antigen and melanocytic antigen as well as the recognition of tumor antigen— specific T lymphocytes.

The phase III, multicenter COMBI-i clinical trial, which is currently enrolling, is testing the spartalizumab, dabrafenib, and trametinib triplet against a placebo plus dabrafenib and trametinib in patients with unresectable or metastatic melanoma with a BRAF V600 mutation (NCT02967692). Investigators are hopeful the addition of PD-1 inhibition will lead to improved and more durable responses over therapy with MEK and BRAF inhibition alone.⁴

Figure. Spartalizumab in Patients With Unresectable or Metastatic Melanoma

The trial is being conducted in 3 parts (Figure). A safety run-in will evaluate dosing to establish a safe regimen of spartalizumab in combination with dabrafenib and trametinib. The second part will describe changes in PD-L1 levels and CD8-positive cells in patients with BRAF V600—mutated melanoma treated with the combination, and the third part is a randomized, double-blind, placebo-controlled study of the combination in roughly 500 patients with untreated unresectable and metastatic BRAF V600—mutated melanoma.

Patients who are eligible for the dose-setting portion of the COMBI-i trial must have an ECOG performance status of 0 or 1. The biomarker cohort and randomized portion of the trial are accepting patients with an ECOG performance status of 0 to 2.

The primary endpoint for the dose-setting portion of the trial is the incidence of dose-limiting toxicities. The primary endpoint for the biomarker cohort is immune microenvironment and biomarker modulation. In the randomized portion, the primary endpoint is progression-free survival. Secondary endpoints include overall survival, overall response rate (ORR), and duration of response.

Preliminary results of an interim study of the safety run-in portion of the trial showed that spartalizumab can be combined with dabrafenib and trametinib with a manageable safety profile. Of the 9 patients treated, treatment was ongoing in 8, and 1 patient discontinued treatment due to an adverse event (AE). All patients had at least 1 dose reduction or interruption, primarily due to AEs. The most common AEs observed were pyrexia (100%), chills (78%), and headache (67%). Notably, the study protocol was amended to implement a new management strategy for patients who experience pyrexia.²

Grade 3/4 AEs were observed in all patients, regardless of the relationship to the study drug, and grade 3/4 treatmentrelated AEs were observed in 8 patients. These were primarily laboratory abnormalities and liver toxicity, including hepatitis, increase in alanine aminotransferase, and increase in gamma-glutamyltransferase.

Confirmed responses were observed in all 9 patients, with 3 achieving a complete response and 6 achieving a partial response. The confirmed ORR was therefore 100%, suggesting that there is potential for improved response rates with the addition of spartalizumab.

References

1. NCCN Clinical Practice Guidelines in Oncology. Melanoma, version 3.2018. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Published July 12, 2018. Accessed October 3, 2018.
2. NCI [National Cancer Institute] drug dictionary: spartalizumab. NCI website. cancer.gov/publications/dictionaries/cancer-drug/def/spartalizumab. Accessed October 3, 2018.
3. PDR001. Immuno-oncology news website. immuno-oncologynews.com/pdr001/. Accessed October 3, 2018.
4. Dummer R, Arance Fernández AM, Hanson J, et al. Preliminary findings from part 1 of COMBI-i: a phase III study of anti—PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma. Presented at: 2018 American Society of Clinical Oncology–Society for Immunotherapy of Cancer Clinical Immuno-Oncology Symposium; January 25-27, 2018; San Francisco, CA. meetinglibrary.asco.org/record/156504/abstract.