Keytruda (pembrolizumab)

New endometrial cancer treatment can reduce recurring tumors by 70%

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A combination of immunotherapy and chemotherapy could help women with advanced endometrial cancer live longer, NBC News reported March 27.

Two studies, published in the New England Journal of Medicine, tested combinations of immunotherapy with chemotherapy. Currently, immunotherapy is approved only as a second line of treatment, after chemotherapy for endometrial cancer. The studies suggest immunotherapy has significant advantages when used as part of the first line of treatment.

“Endometrial cancer is one of the few cancers that is rising, increasing in mortality in the United States,” senior study author Carol Aghajanian, MD, a medical oncologist specializing in gynecologic cancers at Memorial Sloan Kettering Cancer Center in New York City, told NBC News. “Unfortunately, very few treatments have been developed specifically for it.”

The first study found that adding pembrolizumab, an immunotherapy drug with the brand name Keytruda, to standard chemotherapy reduced the risk of the endometrial cancer returning by up to 70 percent, depending on the type of tumor.

Some patients who received the combination treatment had an average of 13.1 months before their disease progressed, compared to 8.7 months for those who had only chemotherapy. The effect was more dramatic for women with a mismatch repair-deficient tumor.

The second study used a chemo-combination therapy that included a monoclonal antibody called dostarlimab. The risk of the cancer returning was reduced by up to 61.4 percent up to two years after treatment, depending on the type of tumor.

Starting immunotherapy before surgery improves the outlook for patients with stage III-IV melanoma

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Patients with high-risk melanoma who received the immunotherapy drug pembrolizumab both before and after surgery to remove cancerous tissue had a significantly lower risk of their cancer recurring than similar patients who received the drug only after surgery.

These results, published today in the New England Journal of Medicine, are from a research study led by the SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute (NCI). The findings originally were presented at a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2022 (Abstract LBA6).

The study, known as S1801, was led by Sapna Patel, M.D., chair of the SWOG melanoma committee and associate professor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center.

It’s not just what you give, it’s when you give it. The S1801 study demonstrates the same treatment for resectable melanoma given before surgery can generate better outcomes. In this case, we used the immune checkpoint inhibitor pembrolizumab. This treatment relies on the presence of pre-existing T cells coming in contact with cancer cells in the body to generate an immune response, and we found that starting treatment before the melanoma is removed – and with it the bulk of tumor-specific T cells – leads to a greater response than giving it after surgery.”

Sapna Patel, M.D., chair of the SWOG melanoma committee and associate professor of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center

The mechanism of action of immune checkpoint inhibitors such as pembrolizumab is often described as “taking the brakes off” the immune system’s response to tumor cells. The S1801 researchers hypothesized that there would be a larger anti-tumor immune response and longer immunologic memory if pembrolizumab was administered while the melanoma tumor was still in the body as opposed to after that tumor had been removed, when the immune system would be responding primarily to micrometastatic cancer cells.

To test this hypothesis, S1801 investigators enrolled 345 participants with stage IIIB through stage IV melanoma that was deemed operable. Participants ages 18-90 were randomized to receive either upfront surgery followed by 200 mg of pembrolizumab every three weeks (adjuvant-only) for a total of 18 doses, or to 200 mg of pembrolizumab every three weeks for three doses leading up to surgery (neoadjuvant-adjuvant), then an additional 15 doses following surgery.

The primary endpoint measured was the duration of event-free survival, defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

With a median follow-up of 14.7 months, event-free survival was significantly longer in the neoadjuvant-adjuvant therapy arm, with a hazard ratio of 0.58 when compared to the adjuvant therapy arm, which corresponds to a 42% lower event rate in the patients receiving the neoadjuvant regimen.

“Our study noted a significant improvement in event-free survival in the neoadjuvant regimen compared to the adjuvant regimen,” Patel said. “Importantly, a similar number of patients in both arms experienced events before initiating adjuvant pembrolizumab, but the rate of events after initiating adjuvant therapy was higher (worse) in the adjuvant arm.”

The researchers found that the benefit from neoadjuvant therapy was consistent across a range of factors including patient age, sex, performance status, and stage of disease. They also found that the rates of adverse events (side effects) were similar across both arms of the study and that neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery.

“Based on the findings from S1801, patients with high-risk melanoma should start immunotherapy prior to surgery to generate an immune response while the bulk of the melanoma and the anti-tumor T cells are intact,” Patel said. “Future studies can explore de-escalation strategies for both surgery and adjuvant therapy, as well as approaches for patients whose melanoma does not respond to neoadjuvant therapy.”

Source:

The University of Texas MD Anderson Cancer Center

Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma

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Abstract

Background

Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.

Methods

In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant–adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.

Results

At a median follow-up of 14.7 months, the neoadjuvant–adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P=0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant–adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant–adjuvant group and 14% in the adjuvant-only group.

Conclusions

Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified.

Melanoma Drug Boosting Survival for Many, Study Shows

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A new drug for advancedmelanoma is dramatically shifting the odds in favor of patients, extending survival for many and even curing some.

Keytruda (pembrolizumab) helped keep four in 10 patients with advanced melanoma alive three years after starting treatment, according to the results of a new clinical trial.

The drug also caused complete remission in 15 percent of patients, and many remained cancer-free even after they quit taking Keytruda, said Dr. Caroline Robert, head of the dermatology unit at the Institut Gustave-Roussy in Paris, France.

Keytruda already has scored one very high-profile success — it’s one of the drugs taken by former President Jimmy Carter, 91, in his successful battle last year against melanoma that had spread to his brain.

However, the drug comes with a hefty price tag — an estimated $12,500 a month.

Prior to the advent of targeted therapies like Keytruda, advanced melanoma patients had an average survival prognosis of less than one year, Robert said.

“Pembrolizumab provides long-term survival benefit in patients with advanced melanoma, with 41 percent of patients alive at three years, which is so different from what we’ve come from,” Robert said. “We have durable responses in one-third of the patients, and we have complete responses that are durable even after stopping the treatment.”

The latest clinical trial findings, which are the first long-term follow-up results for Keytruda, are to be presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago next month. Research presented at meetings is typically considered preliminary until published in a peer-reviewed journal.

Cancer expert Dr. Don Dizon called the results “incredibly exciting.”

“I think it’s incredibly encouraging that we could see a potential cure in melanoma as evidenced by the very prolonged response rate and the durability of this response,” said Dizon. He is an ASCO spokesman and clinical co-director of gynecologic oncology at Massachusetts General Hospital in Boston.

Keytruda helps the body’s immune system locate and destroy tumor cells by thwarting a genetic cloaking mechanism that cancer has developed to avoid immune detection.

“It teaches the body’s own immune system how to fight and control melanoma,” said Dr. Michael Postow, an oncologist specializing in immunotherapy with Memorial Sloan Kettering Cancer Center in New York City.

Robert’s clinical trial involved 655 patients diagnosed with advanced melanoma. Three-fourths of the patients had received other treatments for their cancer prior to the study.

Participants received Keytruda either every two or three weeks. The drug is administered via IV.

Long-term follow-up showed that four out of 10 patients were alive three years after starting Keytruda, whether or not they had been previously treated.

Further, 95 patients went into complete remission after taking Keytruda, Robert said.

Of those patients, 61 stopped taking Keytruda after they were judged cancer-free, Robert said. Only two wound up relapsing.

About 8 percent of the patients dropped out of the study due to drug side effects, Robert said. The most common were fatigue (40 percent), itchiness (28 percent) and rash (23 percent).

But, Postow said, “Most patients get through the drug without any serious side effects.”

The main downside is the cost of the drug. The drug’s maker, Merck, has set the price at about $12,500 a month, or about $150,000 a year, according to The New York Times.

“It is pretty expensive, unfortunately,” Postow said.

Keytruda OK’d for Non-Small Cell Lung Cancer

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The U.S. Food and Drug Administration on Friday granted accelerated approval for Merck & Co’s immunotherapy Keytruda (pembrolizumab) to treat patients with advanced non-small cell lung cancer whose disease has progressed after other treatments and with tumors that express programmed death-ligand 1 (PD-L1).

“Keytruda is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 expression in non-small cell lung tumors,” the FDA said.

Keytruda and another similar treatment from Bristol-Myers Squibb Co called Opdivo (nivolumab) are designed to block the PD-1 protein, whose natural function is to put checks on the immune system.

Wall Street analysts expect cancer immunotherapies to earn combined annual sales of over $20 billion by 2020.

Keytruda was approved last year to treat patients with advanced melanoma.

Opdivo is approved by the FDA to treat melanoma as well as squamous non-small cell lung cancer, a smaller subset of the disease.

Lung cancer is the leading cause of cancer deaths in the United States with an estimated 221,000 new cases diagnosed and 158,000 deaths this year, according to the National Cancer Institute.