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#AACR16 Update: New Hope for Patients with Rare Skin Cancer, Head & Neck Cancer

April 20, 2016

Epithelium

New hope now exists for patients with a rare and aggressive form of skin cancer know as Merkel cell carcinoma (MCC). While melanoma is more common, MCC is more deadly, and patients currently have no approved drugs to help them.

Today, Paul Nghiem, M.D., Ph.D. presented the results of a phase II clinical trial in which the checkpoint inhibitor pembrolizumab led to durable responses in MCC patients when used as a first-line therapy, with 56% of MCC patients responding. More importantly, those responses have held up: 86% of responders still have their disease under control more than six months later. These results are being simultaneously published in the New England Journal of Medicine.

MCC is associated with viral infection, so the doctors also looked at how patients with the virus responded to immunotherapy compared to those with UV-induced MCC. While 44% of UV-induced MCC tumors responded, 63% of the virus-induced MCC tumors shrunk after pembrolizumab treatment. This may be because the viral infection makes those MCC cells appear foreign and thus makes them more ‘visible’ to the immune system than the UV-induced MCC cells, which don’t stand out as much. Future work will be needed to determine exactly why this difference exists.

Pembrolizumab, a checkpoint inhibitor that blocks the activity of the PD-1 pathway, is already helping patients with melanoma and lung cancer, and hopefully soon will be able to benefit MCC patients too.

Next came a presentation from Aaron Hansen, M.D., Ph.D., on a small safety and dose escalation trial testing an OX40 agonist called MOXR0916 in patients with cancers that have recurred, including soft tissue sarcoma, non-small cell lung cancer, clear cell renal cancer, pancreatic cancer, colorectal cancer, and others. When engaged, OX40 activates antigen-dependent (or cancer specific) effector T cells while also inhibiting regulatory T cells that can dampen an immune response.

Among the heavily pre-treated “all-comer” patient participants, 23 provided investigators with pre-treatment biopsies, allowing for comparison with on-treatment biopsies. Evaluable pairings revealed that treatment with MOXR0916 generated significant effector T cell costimulation characterized by the presence of greater number of infiltrating CD8+ T cells, IFN-gamma, granzymes A and B, and perforin, all of which aid in the killing of cancer cells. MOXR0916 was also shown to decrease PD-L1 expression on immunosuppressive, regulatory T cells and increase PD-L1 expression on tumors.

Additional patient cohorts who will soon receive the OX40 agonist include melanoma, renal cell carcinoma, non-small cell lung cancer, bladder, and triple-negative breast cancer patients. Results from a phase Ib trial of MOXR combined with the anti-PD-L1 immunotherapy atezolizumab will be released in June at the annual meeting of the American Society of Clinical Oncology.

Moving from the stimulatory to the inhibitory side of the cancer immunotherapy equation, Jeffrey Infante, M.D., reported on a small safety study testing a pegylated recombinant human IL-10 (AM0010) cytokine therapy in 51 patients with melanoma, renal cell carcinoma, non-small cell lung cancer, castration-resistant prostate cancer, colorectal cancer, and pancreatic cancer.

IL-10 normally controls inflammation, such as inflammatory responses to bacterial infection. IL-10 works on different cells of the immune system differently. For example, it reduces secretion of IFN-gamma, an important immune system activating cytokine, in monocytes and neutrophils, but increases IFN-gamma in CD8+ T cells. The study showed that AM0010 is safe, primes tumors with activated PD-1+ CD8+ effector T cells, and shifts a patient’s immune response away from immune suppression toward greater anti-cancer effector function by altering the ratio of effector cells to regulatory cells within the tumor. One patient experienced a complete response, two a partial responses, and others stable disease. Numerous questions remain about the precise mechanisms of action of AM0010. Meanwhile, a phase 2/3 registrational study is planned for later this year.

Wrapping up the session was a highly anticipated talk from Maura Gillison, M.D., Ph.D., on a safety and efficacy study of the anti-PD-1 immunotherapy nivolumab in patients with recurrent metastatic head and neck cancer, compared to treatment with methotrexate, docetaxel, or cetuximab.

The study, called Checkmate 141, was stopped early after reaching its primary endpoint of overall survival, which demonstrated a more than doubling in survival for these patients over chemotherapy, from 17% of patients treated with chemotherapy to 36% of those receiving nivolumab. The improved survival held across various patient segments, including former smokers, older people, and those who had received multiple prior lines of systemic therapy. And while PD-L1 expression was not correlated with overall survival, higher expression did correlate with a reduction in the risk of death.

Nivolumab now offers a new standard of care for patients with refractory head and neck cancer who have failed treatment with platinum-based chemotherapy.


Arthur N. Brodsky, Ph.D., contributed to this article.

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