MEDI4736, Tremelimumab Combo Active in Pretreated NSCLC


An immunotherapy combination demonstrated "high levels of clinical activity" in previously treated non-small cell lung cancer across a range of doses.

Scott J. Antonia, MD, PhD

An immunotherapy combination demonstrated “high levels of clinical activity” in previously treated non-small cell lung cancer (NSCLC) across a range of doses, results of an ongoing phase Ib study showed.

An overall response rate of 27% was observed in 63 patients with PD-L1-negative tumors treated with the immune checkpoint inhibitor MEDI4736 and tremelimumab, a monoclonal antibody against cytotoxic T lymphocyte-associated protein 4 (CTLA-4). The disease control rate (response plus stable disease for at least 16 weeks) was 48%.

Overall, grade 3/4 toxicity occurred in 41 of 102 evaluable patients, most often colitis, diarrhea, elevated lipase, and elevated liver function tests. However, in the dose combination selected for phase III evaluation (MEDI4736 20 mg and tremelimumab 1 mg/kg, each given every 4 weeks), grade 3/4 events occurred in four of 22 patients, as reported at the 2015 ASCO Annual Meeting.

The phase III dose combination “maximizes PD-1 inhibition, which is likely driving overall clinical activity, and demonstrates a manageable safety profile,” Scott Antonia, MD, PhD, a thoracic oncologist at Moffitt Cancer Center in Tampa, FL, and colleagues concluded in a poster presentation. “The combination incorporates a biologically active dose of tremelimumab associated with clinical activity, particularly in patients with PD-L1-negative tumors.

“Tremelimumab doses above 1 mg/kg did not result in greater antitumor activity but were generally associated with higher rates of adverse events.”

MEDI4736 has demonstrated single-agent activity in an ongoing phase 1/2 study involving patients with NSCLC. Treatment has been associated with durable responses.

MEDI4736 and tremelimumab have nonredundant inhibitory mechanisms and demonstrated synergy in preclinical studies. Because the agents block distinct processes involved in immunosuppression, the combination might provide greater antitumor activity as compared with monotherapy with either agent.

To evaluate the safety and tolerability of the combination, investigators enrolled patients with NSCLC who had progressed or relapsed after any line of therapy. The dose escalation/expansion trial evaluated MEDI4736 at doses of 3 to 20 mg/kg every 4 weeks or 10 mg/kg every 2 weeks, and tremelimumab at doses of 1 to 10 mg/kg every four weeks for six doses, followed by dosing at 12-week intervals for 12 doses administered for 12 months.

The primary objectives were to determine maximum tolerated dose (MTD), safety, and tolerability of the combination. Secondary objectives included antitumor activity, pharmacokinetics, and immunogenicity. Biomarker identification was an exploratory objective.

An 18-patient cohort received the phase 3 combination dose. Nine of the patients in that cohort had treatment-related adverse events, including grade 3/4 adverse events in four patients. One patient discontinued treatment because of an adverse event (sepsis), but no deaths occurred.

Across all dose cohorts, 20 of 102 patients discontinued because of treatment-related adverse events. The most common reasons for discontinuation were colitis (7%), pneumonitis (5%), diarrhea (3%), and elevated aspartate aminotransferase (2%).

The most frequent treatment-related adverse events (all grades) were diarrhea (27%), fatigue (23%), pruritus (15%), increased amylase (15%), rash (13%), and colitis (12%).

Clinical activity was observed in all of the every-4-weeks cohorts, except for the lowest dose. The 27% objective response rate included responses in 33% of patients with PD-L1-positive tumors and 27% of those with PD-L1-negative tumors. Objective responses were observed in four of eight evaluable patients treated with the phase 3 dose combination.

Patients with PD-L1-positive tumors and PD-L1-negative tumors had objective responses to treatment with MEDI4736 and tremelimumab. Multiple patients had responses that persisted off treatment. Eleven patients had ongoing responses at last evaluation, including one patient with a PD-L1-negative tumor who had an ongoing response lasting beyond 1 year.

Dose-proportional pharmacokinetics were measured for both agents. Pharmacokinetic exposure was consistent with each agent’s monotherapy studies suggesting no pharmacokinetic interaction, Antonia and colleagues reported.

The combination consistently demonstrated greater peripheral T-cell activation and proliferation as compared with MEDI4736 monotherapy.

Antonia S, Goldberg SB, Balmanoukian A, et al. Phase 1b Study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in patients with advanced non-small cell lung cancer (NSCLC). Presented at: 2015 ASCO Annual Meeting, May 29-June 2, 2015. Poster 3014.


View more from the 2015 ASCO Annual Meeting

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