A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma

Abstract

Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH <=2x upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m2 orally days 1–4 every three weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every four weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24·5 months. There were 10 (15·6%) confirmed partial responses and 10 (15·6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.

Evolving synergistic combinations of targeted immunotherapies to combat cancer

“…Although the exact mechanism has not been clearly elucidated, this synergistic dose-limiting toxicity is a cautionary note for immuno-oncology combinations. Interestingly, data presented at the 2014 American Society of Clinical Oncology (ASCO) annual meeting showed that a combination of ipilimumab with temozolomide (a drug similar in structure to dacarbazine) did not have such a high rate of dose-limiting liver toxicity, as unlike dacarbazine, temozolomide is not metabolized by the liver 118 .…”

Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma

“…Accordingly, a combination strategy has been tried to improve the outcome, such as using chemotherapy and targeted therapies to increase tumor-specific antigen release and presentation [56]. So far, the combination of checkpoint blockade and TMZ therapy has yielded a promising anti-tumor efficacy in experimental models and clinical trials [57,58]. However, unlike vemurafenib, which reduces tumor-associated inflammation [50], TMZ not only enhances inflammatory response as observed in our current study but also promotes immune escape by upregulating PD-L1/L2 expression and reducing lymphocyte infiltration [57,59], thus potentially favoring a therapeutic response to immunotherapy [60].…”

Unusual metastases of melanoma

“…Therefore, the immune checkpoint inhibitor was continued up to 14 months, obtaining durable stable disease and good quality of life. A final severe encephalic progression, uselessly treated with temozolomide and re‐challenging ipilimumab, caused patient's death after 3 years from the first‐line therapy. In our experience, selected patients with BRAF‐mutated melanoma and without imminent risk of death can be suitably treated with up‐front immunotherapy followed by targeted therapy.…”