1. Carlson, Robert H.

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NEW ORLEANS-The PD-1 blocker nivolumab showed impressive results in two single-agent trials presented at the American Association for Cancer Research annual meeting-in head and neck squamous cell carcinoma (HNSCC) and in metastatic melanoma.

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HNSCC has not been considered a reasonable disease target for immunotherapy, but patients refractory to platinum treatment who were assigned to nivolumab in the phase-III CheckMate-141 trial had a 30 percent reduction in risk of death compared with those assigned therapy of investigator's choice. And one-year survival doubled with nivolumab, 36 percent versus 16 percent for controls.


In a phase I trial of the PD-1 blocker, five-year overall survival for nivolumab-treated metastatic melanoma patients was 34 percent. Both trials demonstrated surprisingly good durability of response with the drug, the researchers said.


Metastatic Melanoma: Survival in Years

"We are now measuring survival in terms of years," said lead author F. Stephen Hodi, MD, Director of the Melanoma Center at Dana-Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School, Boston. "The 34 percent five-year survival is much higher than historical rates for metastatic melanoma, compared with SEER data for a five-year survival rate of 16.6 percent."


Hodi said this trial had the longest survival update for any anti-PD-1 agent. Patients were treated with a minimum follow-up for 45 months, and the survival rates appeared to plateau at 48 months.


Louis M Weiner, MD, Director of the Lombardi Comprehensive Cancer Center at Georgetown University, Washington, DC, moderator of a press conference where this study was highlighted, said immunotherapy, when effective, is distinguished from other forms of cancer treatment by durability of benefit.


"Patients who have good responses [with immunotherapy] seem to be protected against disease recurrence in many cases," Wiener said. "This is in marked distinction to many of our effective chemotherapy approaches or targeted therapy approaches where you see more rapid development of resistance. The memory of the immune system and the adaptability of response to pick off resistant variants that develop, that's a really important take-home point here."


The trial comprised 107 heavily pretreated patients, including some with ocular mucosal melanomas, who had received up to five prior treatments, mainly immunotherapies but not ipilimumab. Median patient age was 61 years, and 67 percent were male. Patients could be treated for up to 96 weeks.


Retreatment with nivolumab was effective as well, Hodi reported. Five study patients were retreated with nivolumab monotherapy at the original dose after they had achieved disease control but then developed progressive disease.


"In all five patients' disease, control was obtained again and control was durable," Hodi said. "This suggests some of the important memory aspects of checkpoint blockade and its ability long-term to help patients."


Side effects of nivolumab included fatigue and rash, but Hodi said there were no adverse effects that hadn't been seen in earlier trials. There were no drug-related deaths.


"These data provide a foundation for establishing anti-PD-1 therapy as another standard for melanoma patients," Hodi said.


This study was funded by Bristol-Myers Squibb. Hodi declares no conflicts of interest.


Survival Improved in HNSCC

In the CheckMate-141 trial, nivolumab improved survival for patients with recurrent or metastatic HNSCC that progressed after platinum-based chemotherapy compared with single-agent chemotherapy of the investigator's choice.


"No cancer agent has been shown to improve overall survival in head and neck cancer, and no new treatments have been introduced in more than a decade," said lead author Maura L. Gillison, MD, PhD, Professor in the Department of Internal Medicine at The Ohio State University Comprehensive Cancer Center, Columbus.


Among 361 patients enrolled, 240 were randomly selected to receive nivolumab and 121 control patients received one of three standard single-agent chemotherapy drugs chosen by the investigator: docetaxel, methotrexate, or cetuximab. Median patient age was 60 years, and 83 percent were male.


"This was a heavily pretreated population, 90 percent had received prior radiation and 55 percent had received two or more prior systemic chemotherapy regimens before the trial," Gillison said.


She reported patients receiving nivolumab had a 30 percent reduction in risk of death compared with controls. Median overall survival was 7.5 months for nivolumab versus 5.1 months for controls. And at 12 months, 36 percent of the patients treated with nivolumab were alive compared with 17 percent of those assigned therapy of investigator's choice.


She said the survival curves overlapped for the first three months and then diverged.


"Most important in this trial is the proportion of patients who survived a year-it doubled with nivolumab, 36 percent versus 16 percent for controls-that has never been seen in this patient population before."


PD-L1 Expression & HPV Status

The improvement in overall survival with nivolumab was greater for patients whose tumors had PD-L1 expression of 1 percent or greater or who were HPV-positive, Gillison reported, although improvement was seen for both HPV-positive and HPV-negative patients.


Gillison speculated HPV-positive patients benefited because the other PD ligand, PD-L2, is expressed more frequently. HPV-positive patients are also more likely to have tumor-infiltrating lymphocytes, indicating a prior immune response to the tumor that has been suppressed, she said.


"There also may be more frequent inflammation gene signatures which might be enriching the patient population," Gillison said.


The study was funded by Bristol-Myers Squibb and the Oral Cancer Foundation. Gillison has consulted for Bristol-Myers Squibb, Eli Lilly and Company, and Merck in the past year.


The moderator of a press conference where this study was highlighted, Raymond N. DuBois, MD, PhD, Dean of the Medical University of South Carolina, Charleston, who served as AACR president 2008-2009, was impressed by the data.


"All practicing oncologists who take care of head and neck cancer patients are going to take note of this study because there hasn't been a lot of development in this area."


Robert H. Carlson is a contributing writer.