Immunotherapy treats Ca based on genetic feature

The immunotherapy agent pembrolizumab (Keytruda) was recently approved by the FDA for treating any cancers that exhibit DNA mismatch repair deficiency, marking the first time the agency has approved a cancer treatment based on a biomarker rather than the location in the body where the tumor originated. 

Previously, the FDA granted accelerated approval of pembrolizumab to treat locally advanced or metastatic urothelial carcinoma, and one expert says it may play a role in a subset of prostate cancer patients.

Pembrolizumab was first approved for treating melanoma in 2014, and the FDA approved the agent to treat locally advanced or metastatic urothelial carcinoma in May 2017. It works by promoting the ability of the body’s immune system to fight tumors. It blocks the interaction between PD-1 and its ligands-PD-L1 and PD-L2-resulting in activation of T lymphocytes.

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Tralisa Colby, MPH, public affairs specialist for FDA’s Center for Drug Evaluation and Research, said pembrolizumab was granted accelerated approval due to the overall response rate of the therapy in clinical trials.

“The evidence of tumor shrinkage in approximately one-third of patients whose tumor was no longer responding to standard therapy, lasting for more than 6 months in the majority of those achieving a response, provides strong evidence that pembrolizumab is active against tumor and is likely to prolong survival,” Colby said.

The therapy is meant to be used as a first-line treatment in patients who have disease progression during or after platinum-containing chemotherapy or within 1 year of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Administration guidelines are for a fixed dose of 200 mg every 3 weeks by 3-minute intravenous infusion until disease progression or toxicity, or up to 24 months without disease progression, according to Merck, the drug’s manufacturer. Pembrolizumab can also be administered in combination with chemotherapy, and should be administered before chemotherapy when given on the same day.

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“T cell checkpoint therapy is being explored in combination with other immune-oncology agents within multiple genitourinary cancers,” said Akash Patnaik, MD, PhD, MMSc, assistant professor of medicine, director of the Developmental Therapeutics Laboratory, and attending physician within the genitourinary oncology program at the University of Chicago Medicine. “These strategies should result in significant advancements within the next 5 years.”

Data have previously supported use of another immunotherapy-atezolizumab (Tecentriq), which blocks the ligand for PD-1 called PD-L1-in urothelial cancers, but pembrolizumab works differently, directly inhibiting the PD-1 receptor and enhancing T-cell activation.

Speaking in regard to other genitourinary cancers, “Immunotherapy has historically not been as successful in treating prostate cancer,” Dr. Patnaik said.

In one recent study, however, Dr. Patnaik said a small subset-three of 10 patients-with very advanced prostate cancer had a significant response to pembrolizmab, so his team is investigating the genetic and molecular basis for why some patients respond to immunotherapy and what treatment or combination of treatments might be most effective.

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“Immunotherapy has clearly revolutionized the management of urothelial cancers,” Dr. Patnaik said. “There is far less toxicity than standard treatment methods, and it can be used in elderly patients with kidney function abnormalities. This is a major step forward and the efficacy is quite promising.”

Merck made the first presentation of the results of two studies evaluating the 1-year follow-up of pembrolizumab at the American Society of Clinical Oncology annual meeting in Chicago. The updated survival and biomarker analysis reveals that pembrolizumab had a 29% overall response rate as a first-line therapy in treating urothelial cancer, and reduced the risk of death by 30% as a second-line therapy when compared to chemotherapy, according to Merck.

The therapy does come with some side effects, particularly in the development of autoimmune disorders such as immune-mediated pneumonitis, autoimmune hepatitis, colitis, and hypothyroidism. Pembrolizumab seems to result in in a lower incidence of autoimmune side effects than therapies targeting CTLA-4 such as ipilimumab (Yervoy), but reactions can still occur, Dr. Patnaik said. In those cases, autoimmune reaction can be successfully managed with steroid therapy.

In clinical trials, patients with autoimmune disease were excluded, but recent observations at the ASCO annual meeting have shown that there was not a particularly higher incidence of side effects in these populations when treated with immunotherapy, Dr. Patnaik said. Pembrolizumab can also cause serious transfusion reactions, in which case the therapy should be discontinued, according to Merck.

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