ASCO 2021 Research Roundup: Focus on Immunotherapy

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Five MSK researcher headshots

Clockwise from top left: Michael Offin, Michal Sarfaty, Jonathan Peled, Jedd Wolchok, Marjorie Zauderer

Memorial Sloan Kettering researchers presented more than 100 studies at the 2021 American Society of Clinical Oncology (ASCO) annual meeting, held virtually again this year. In case you missed it, here are a few related to immunotherapy that caught our eye.

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Do Worse Side Effects Mean Better Outcomes for People with Mesothelioma?

A recurring question in immunotherapy is whether having immune-related side effects, such as inflammation of the lungs or colon, bears any relationship to how well the treatment will work — or not.

Because immunotherapies work by revving up immune cells to fight cancer, side effects that result from these immune cells harming normal tissues are not uncommon. And since they provide indirect evidence that the immune system has been activated by the immunotherapy, it’s tempting to view these side effects as a “biomarker” of potential response — a clue that the treatment is more likely to work.

But for patients, how closely do these adverse events correlate with survival? And does this relationship differ from cancer type to cancer type?

Michael Offin, an oncologist at MSK who specializes in the treatment of people with mesothelioma, wanted to know more about this relationship. Mesothelioma is a cancer of the thin layer of tissue (called the mesothelium) that lines internal organs. Pleural mesothelioma is mesothelioma that develops in the tissue lining the lungs.

I think if you have a patient in your office who is unfortunate enough to have an immune-related side effect, you can say there may be a higher chance of responding to your current treatment.
Michael D. Offin medical oncologist

In a poster presentation at ASCO, he and his colleagues — including Marjorie Zauderer, who co-directs the MSK mesothelioma program — presented data from 58 patients with pleural mesothelioma treated with immunotherapy at MSK. A total of 17 patients had an immune-related adverse event, while 41 had none. When Dr. Offin looked at how long these patients lived (their overall survival), he found that patients who had an adverse event had significantly longer survival compared to those who did not: 13.3 months versus 4.7 months. The study is small, and the data are preliminary.

Dr. Offin says he thinks it’s premature to consider adverse events to be a true biomarker of response because there were definitely patients who did not have an adverse event who benefited from treatment. Nevertheless, he thinks there is a practical takeaway for doctors and patients.

“I think if you have a patient in your office who is unfortunate enough to have an immune-related side effect, you can say there may be a higher chance of responding to your current treatment.”

This research was supported in part by the NIH/NCI (grant #P30 CA008748). Dr. Offin has received honorarium from PharmaMar, Jazz Pharmaceuticals, Novartis, Targeted Oncology, and OncLive. 

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Hints that Gut Microbes May Affect Response to Cancer Immunotherapy

Every person’s gut is home to billions of microbes, called the microbiome. Could these microbes affect how well people respond to cancer immunotherapy? Recent evidence suggests the answer is yes, although exactly how — and which microbes make the crucial difference — is not known. 

To find out, a team of researchers at MSK led by physician-scientists Michal Sarfaty and Jonathan Peled, in collaboration with scientists at the biotechnology company Seres Therapeutics, undertook a study of the gut microbiome in people with cancer. A total of 94 patients with either metastatic melanoma or metastatic lung, renal, or urothelial cancer who were treated with checkpoint blockade immunotherapy were enrolled on the study. The researchers obtained stool samples from each patient prior to treatment and identified their microbial composition. Then they compared this microbial makeup to how well each person responded to the therapy.

“We wanted to see if there is a correlation between the response to treatment and the microbiome of the patients,” explains Dr. Sarfaty, an Israeli oncologist who is currently pursuing a fellowship at MSK with Jonathan Rosenberg, Chief of the Genitourinary Medical Oncology Service. “We also wanted to know if it would be the same with different cancers or not.”

Dr. Sarfaty and her colleagues presented their results in a poster presented at ASCO. They found that there was no clear-cut difference between the microbiomes of those who responded versus those who did not — at least when they considered all the different cancers together.

“There’s not much difference, at least at a 50,000-foot view, between the fecal microbial communities of the patients who responded versus those who didn’t,” says Dr. Peled, an assistant attending in the Marcel van den Brink lab at MSK whose work is supported by the Parker Institute for Cancer Immunotherapy at MSK.  

Parker Institute for Cancer Immunotherapy
A unique collaboration of immunologists at MSK and five other academic medical centers that is devoted to pursuing research in cancer immunotherapy.

However, when they looked at the data more closely, they observed two noteworthy trends. First, a small number of the patients whose tumors didn’t respond tended to have a more-similar microbiome composition to each other than to those of responders. Second, when the researchers organized the data by cancer type, there did appear to be an association between microbiome composition and response. The association was of modest statistical significance and a correlation only.

To address causation — that is, to find out if the association was more than just coincidence — the MSK team provided Seres with a fecal sample from one of the non-responding patients to use in a mouse study. The Seres scientists gave mice with cancer either a sample of the non-responding patient’s stool or a stool sample from a healthy donor with no cancer. Then they treated the mice with checkpoint blockade therapy. The results? The mice with stool from a healthy donor saw their cancers controlled while the mice with stool from the non-responding patient did not. The researchers concluded that the microbiome of the non-responding patient influenced the response to immunotherapy in the mice, but more research is needed to confirm and expand upon these results obtained from the small study.  

“We would love one day to find a microbiome composition that helps patients respond better to immunotherapy,” Dr. Peled says. “What we have so far is a clue about the composition of a microbiome that drives nonresponse.”

This research was supported by Seres Therapeutics and the National Institutes of Health. Dr. Peled reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics, and consulting fees from Da Volterra, CSL Behring, and from MaaT Pharma. He has filed intellectual property applications related to the microbiome (reference numbers #62/843,849, #62/977,908, and #15/756,845).

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Immunotherapy Grows Up: 6.5 Year Follow-Up Data from Pivotal Melanoma Trial

When the combination of ipilimumab (Yervoy®) plus nivolumab (Opdivo®), two checkpoint immunotherapy drugs, was approved by the US Food and Drug Administration in 2015 for the treatment of advanced melanoma, it marked a landmark in cancer care. Just five years had passed between the start of clinical testing and FDA approval, an indication of how well the drugs worked and how eager regulators were to get them to patients.

MSK physician-scientist Jedd Wolchok led the phase III trial, which enrolled 945 people with previously untreated, inoperable stage III or IV melanoma. Patients were randomly assigned to receive one of three possible treatments: ipilimumab alone, nivolumab alone, or both drugs given together.

On June 6, 2021, at ASCO, Dr. Wolchok presented the latest data on patient outcomes. After 6.5 years of follow-up care, 23% of patients who received ipilimumab, 42% of patients who received nivolumab, and 49% of patients who were treated with the drug combination were still alive.

When Dr. Wolchok last reported on the trial results after five years of follow-up, the median overall survival had not yet been reached for the drug combination; now, it has.

(Median overall survival is the point at which half of the patients treated are still alive; the longer it takes to reach this point, the better the therapy is working.) 

This is a moment to reflect on how far melanoma therapy has come based on science, driving more effective treatments.
Jedd D. Wolchok immunologist

For patients treated with the ipilimumab and nivolumab combination, the median survival was 72 months (six years). For those treated with nivolumab alone, it was 36.9 months (just over three years), and for those treated with ipilimumab alone, it was 19.9 months (just over one and a half years).

“This is a moment to reflect on how far melanoma therapy has come based on science, driving more effective treatments,” Dr. Wolchok said in his presentation, noting that in 2011, the median overall survival of patients receiving the standard-of-care chemotherapy was nine months. “Within 10 years, median overall survival estimates have improved from that nine to now 72 months,” he said.

There are potential side effects associated with immunotherapies, and these were more than twice as common with the combination of drugs than with either drug given alone. Nevertheless, Dr. Wolchok noted that these side effects can be managed effectively.

Dr. Wolchok has played a pivotal role in the clinical development of immunotherapies for people with cancer and continues to research new combinations in his lab at MSK. He is Chief of the Immuno-Oncology Service in the Human Oncology and Pathogenesis Program, Director of the Parker Institute for Cancer Immunotherapy at MSK, and Associate Director of the Ludwig Center for Cancer Immunotherapy. He holds the Lloyd J. Old/Virginia and Daniel K. Ludwig Chair in Clinical Investigation at MSK.

Funding for CheckMate 067 was provided by the drug manufacturer, Bristol Myers Squibb.

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