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Anti-PD-1/IFN Combo Active in Advanced Melanoma

Patients with advanced melanoma had a high response rate with the dual immune system-targeted combination of pembrolizumab (Keytruda) and pegylated interferon alfa-2b (PEG-intron), a small phase Ib/II clinical trial showed.

The combination resulted in an objective response rate (ORR) of 60.5% in 43 patients with stage IV melanoma and no prior exposure to pembrolizumab or other anti-PD1/PD-L1 drugs. After a median follow-up of 25 months, responses persisted in almost half of the patients, reported Diwakar Davar, MD, of the University of Pittsburgh Medical Center, and colleagues.

Median overall survival (OS) had yet to be reached, they wrote in the Journal of Clinical Oncology.

“The results are promising, but we need to keep the overall response rate in context,” Davar said. “We have shown that the response rate is very high and that the responses are also very durable, so we may actually be doing something with the combination. However, in the absence of a control group, we have to be very careful about overinterpreting the results.”

Despite the favorable results, the future of the combination remains unclear, as it joins a crowded field of potential multidrug strategies for melanoma, he added. Multiple clinical trials are underway to evaluate anti-PD-1/PD-L1 agents with other immune checkpoint inhibitors, immunomodulatory drugs, and small-molecule inhibitors.

Multiple studies with different drugs demonstrated that immunotherapy targeting programmed death-1 (PD-1) produces durable responses in advanced melanoma with a favorable safety profile. However, single-agent anti-PD-1/PD-L1 therapy has a response ceiling of 30-40%, the authors noted. Combining a PD-1 inhibitor with the CTLA-4 inhibitor ipilimumab (Yervoy) led to ORRs approaching 60% but with a substantial incidence of grade 3/4 adverse events.

Correlative studies have identified several potential biomarkers of response to anti-PD-1 therapy, including CD8+ T-cell infiltrate, PD-L1 expression, tumor mutation burden, and interferon (IFN) gamma gene expression profile. The biomarker data suggested that patients with melanoma and pre-existing T-cell immune responses have an increased likelihood of responding to PD-1/PD-L1 inhibitors, the authors noted.

Several lines of evidence suggested that type 1 IFN directly and indirectly modulates immune response to melanoma: direct antitumor activity; facilitation of cytotoxic T-lymphocyte-mediated killing; direct activation of innate and adaptive immune cells; melanoma progression in association with suppression of type I IFN signaling; and increased PD-L1 expression in human melanoma after exposure to IFN-α.

The accumulation of evidence provided a rationale to evaluate a type I IFN in combination with a PD-1-targeted agent. Davar and colleagues enrolled patients with stage IV mucosal or cutaneous melanoma, untreated or a maximum of three prior regimens. During the first phase of the trial, investigators evaluated escalating doses of PEG-IFN in combination with a standard dose of pembrolizumab. During the second part of the trial, additional patients were treated with the recommended phase II dose of PEG-IFN (3 µg/kg) plus pembrolizumab (2 mg/kg).

The primary endpoints were safety, recommended phase II dose, and ORR. Secondary endpoints included progression-free survival (PFS) at 6 months, OS, and correlative analyses.

The study population included 13 patients who had received at least one prior therapy for metastatic disease, and 22 patients had received IFN or ipilimumab in the adjuvant setting. Involved sites included distant skin, subcutaneous, or nodal metastases in 13 patients; pulmonary metastases in 12; and visceral metastases in 18. Nine patients had treated or stable brain metastases.

By investigator assessment, 26 of 43 patients achieved objective responses to the combination, including two complete responses. An additional eight patients had stable disease. The median time to response was 12 weeks, and median response duration was not reached.

Median PFS for all patients was 11 months, 6 months in patients who did not achieve an objective response, and not reached in responding patients. PFS at 6, 12, and 24 months was 64%, 46%, and 46%, respectively. PFS did not differ significantly in patients with prior exposure to IFN or ipilimumab. OS at 1 and 2 years was 73% and 57%, respectively, and median OS had yet to be reached.

Treatment-related adverse events (TRAEs) occurring in ≥10% of patients consisted of grade 1 hyponatremia (11.1%), grade 2 lymphopenia (10.8%), grade 3 hyponatremia (10.3%), grade 3 lymphopenia (12.0%), and grade 3 fatigue (16.2). Additionally, 15 patients developed immune-related adverse events: vitiligo (16.3%); hypothyroidism (16.3%); and one case each of grade 3 adrenal insufficiency, grade 4 pneumonitis, and grade 4 uveitis.

In a subgroup of 22 patients, T-cell analyses showed that responding patients had greater pretreatment CD8+ T-cell infiltrates at the invasive margin (P=0.0342). Analysis of PD-L1 expression in 15 patients showed that responding patients had numerically higher levels of PD-L1 expression.

The study was supported by an Academy-Industry Award from the Melanoma Research Alliance and Merck, the National Cancer Institute, Cancer Center Foundation Genentech BioOncology Young Investigator Award, and the Harry J. Lloyd Trust.

Davar disclosed relevant relationships with Merck, Incyte, Bristol-Myers Squibb, and Checkmate Pharmaceuticals.

2018-12-20T11:30:00-0500

Source: MedicalNewsToday.com