Immunotherapy Meets Targeted Therapy in Advanced Melanoma

Antoni Ribas, MD, PhD

Antoni Ribas, MD, PhD

The past decade has witnessed remarkable advances in the treatment of advanced melanoma. Those advances include the development of antibody-based immune checkpoint inhibitors that target cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand, PD-L1, as well as therapies targeting specific mutations such asBRAF^V600. Results presented at the 2015 ASCO Annual Meeting by Antoni Ribas, MD, PhD, examined the feasibility of combining these two therapies in a phase I study.¹

According to Ribas, professor, Department of Medicine, Hematology/Oncology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), the principal options for patients withBRAF^V600-mutant melanoma include immunotherapies and targeted therapy with BRAF inhibitors, either as a monotherapy or in combination with MEK inhibitors.

Ribas noted that therapy with immune checkpoint inhibitors is associated with durable and clinically significant responses, although immediate, measurable responses in tumor shrinkage are less frequently observed. Conversely, therapies that targetBRAFor other components in this signaling pathway (ie,MEK) have been associated with immediate, measurable overall responses in the short term, while the durability of these responses is usually limited. Consequently, Ribas explained, there is a rational basis for combining these two types of therapies in an effort to improve both short-term responses and durability of response over the longer term.¹

Ribas also outlined data from biopsy studies and preclinical data suggesting that BRAF inhibitors have been associated with creating a permissive environment for immune responses. In experimental studies, BRAF inhibition has been associated with increased tumor infiltration with CD8+ tumor infiltrating lymphocytes (TIL).^2,3In addition, the expression of melanoma antigens such as melanoma-associatedantigen(MART) and gp100 appears to be increased in the early period of BRAF inhibitor therapy, which may be helpful in augmenting T-cell recognition by the immune system.²Moreover, in mouse models, the addition of an anti-PD-1 antibody to combined BRAF (dabrafenib) and MEK (trametinib) inhibitors was associated with the best outcomes compared with all of the relevant controls.⁴These favorable outcomes in triple therapy were mediated by an increase in antigen-presentation activity, resulting in an associated increase in the intratumoral inflammatory activity, as assessed by interferon gamma response.⁴These data served as a background for the design of the current phase I study, which examined the feasibility of adding an anti—PD-L1 immunotherapy (MEDI4736) to combined BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) therapy.¹

The study consisted of three cohorts. In Cohort A, patients hadBRAF^V600E-mutation-positive orK-mutation—positive disease, and had received therapy with MEDI4736 over a 12-month treatment period, initiated simultaneously with dabrafenib and trametinib at approved doses, until progressive disease (PD). In Cohorts B and C, patients had wild-type BRAF status, and received treatment with MEDI4736 initiated simultaneously with trametinib until PD (Cohort B), or with trametinib given for 4 weeks, followed by the addition of MEDI4736, with continuation of trametinib for 2 weeks, followed by MEDI4736 alone (Cohort C).¹

Patients in the trial had advanced stage IIIC and IV melanoma withBRAF^V600E/K-mutation—positive disease (Cohort A only) or confirmedBRAF^V600E/K-negative disease (Cohorts B and C) and, notably, the trial permitted progression on prior immunotherapy (anti-CTLA-4, anti-PD-1, or anti-PD-L1). The main exclusion criteria were patients with active or prior autoimmune disease, prior BRAF inhibitor or MEK inhibitor therapy, or prior severe or persistent immune-related adverse events (irAEs). The number of enrolled patients in Cohorts A, B, and C was 26, 20, and 19, respectively, with a median follow-up duration of 7.1, 6.8, and 3.7 months; thus, follow-up was more limited in Cohort C. Demographics were broadly representative of patients with phase I advanced melanoma, with roughly 80% of patients having stage IV disease. Cohorts B and C patients were more likely (>60%) to have received prior therapy, with approximately half having received anti-CTLA-4, and 30% and 26% of patients in Cohorts B and C, respectively, receiving anti-PD-1.¹

In terms of overall drug-related AEs, those of grade 3 or higher, serious AEs, and AEs leading to discontinuation, there were no major differences between the cohorts, with either triple (Cohort A) or the double therapy used concomitantly (Cohort B) or in sequence (Cohort C). There were no toxicities leading to death, and the full doses of all agents were tolerable and used for expansion, with MEDI4736 at 10 mg/kg every 2 weeks, dabrafenib at 150 mg twice a day, and trametinib at 2 mg/day. There were no single drug-related AEs occurring in 25% or more of patients in any cohort that were not expected with the single agents alone. Dabrafenib/trametinib-associated toxicities (eg, pyrexia, chills, arthralgia) did not appear to be increased by MEDI4736, nor were the trametinib-related toxicities of peripheral edema or folliculitis. Similarly, selected drug-related AEs of special interest (eg, pneumonitis, colitis, hypothyroidism) were not increased with the combination.¹

The study also reported on some pharmacodynamic parameters, including the impact of treatment on immune activation in the different cohorts. A subset of patients had baseline and day 15 biopsies that were stained for CD8+ cell infiltration into the tumor. Patients in all cohorts, but most notably in Cohort A, had evidence of increased CD8+ infiltration post-treatment. There was also evidence of increased levels of interferon gamma in peripheral blood, which was again most pronounced and rapid in Cohort A, but also showed smaller and more protracted increases in Cohorts B and C.¹

Ribas also reported on the clinical activity observed to date in the study, which was evaluated in patients who were dosed for 16 or more weeks prior to the cutoff date, who had measurable disease at baseline and 1, or more follow-up scan(s), or death or discontinuation for PD prior to the first scan. Overall response rate for Cohorts A, B, and C was 69%, 21%, and 13%, respectively, and the corresponding disease control rate, including complete response, partial response, and stable disease (SD), was 100%, 79% and 80%, respectively. Moreover, some patients experienced SD for 12 weeks or more (15%, 53%, and 40%, respectively). In all, 16 of 18 patients (89%) in Cohort A continued to respond to therapy, with up to 50 weeks of follow-up. In presenting the response rate data, Ribas reminded the audience that Cohorts B and C included patients who had previously progressed on anti-PD-1 therapies, and that the duration of follow-up was shorter in Cohort C.

Taken together, the results of this phase I trial demonstrated the feasibility and tolerability of this combination therapy; there was no maximum tolerated dose identified, and toxicities were consistent with the expected AE profiles for the individual components of the combination. Post-treatment, markers of immune activation, as well as early clinical activity, were observable in all cohorts, with most patients experiencing ongoing responses. Patients with a BRAF mutation who were treated with BRAF/MEK inhibitor had the greatest detectable immune activation and the greatest clinical activity. With regard to concomitant versus sequential dosing for the MEDI4736/trametinib combination, Ribas noted that results were too preliminary and longer follow-up would be needed to detect relevant differences between these cohorts.

Commenting on these findings, Michael Postow, MD, a co-investigator on the study and assistant attending physician in the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, noted, “This study is the first demonstration of the successful combination of a PD-1/PD-L1 antibody with targeted therapy, and provides a foundation for future exploration of combination therapy.”

References

1. Ribas A, Butler M, Lutzky J, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma.J Clin Oncol.2015;33(suppl): Abstract 3003.
2. Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma.Clin Cancer Res.2013;19(5):1225-1231.
3. Wilmott JS, Long GV, Howle JR, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma.Clin Cancer Res.2012;18(5):1386-1394.
4. Hu-Lieskovan S, Mok S, Homet Moreno B, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.Sci Transl Med.2015;7(279):279ra41.