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Frontline Keytruda Effective in NSCLC Subgroup, But More Work Is Needed


In the Keynote-042 trial, researchers found a four- to eight-month overall survival benefit among patients with non-small cell lung cancer (NSCLC), which was correlated with higher levels of PD-L1 expression, however, further study is warranted.

Frontline treatment with Keytruda (pembrolizumab) appeared to be more effective than chemotherapy in a subgroup of patients with non-small cell lung cancer (NSCLC), according to results from the KEYNOTE-042 study presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.

In the phase 3 trial, which the authors noted is the largest clinical trial of Keytruda as a standalone therapy, overall survival (OS) was correlated with higher levels of PD-L1 expression — a biomarker commonly used to predict response to immune checkpoint inhibitors – among patients who did not have EGFR or ALK mutations.

“Lung cancer is a very dreadful disease. Every year, more than 230,000 patients develop it and 150,000 die from this disease. … It is a huge health care problem that we have just started to improve over the last two years,” said lead study author Gilberto Lopes, M.D., MBA, a medical oncologist at the Sylvester Comprehensive Cancer Center in the University of Miami Health System in Florida.

However, Lopes noted that much work still needs to be done in this area. “Pembrolizumab becomes an option for patients who have advanced non-small cell lung cancer and do not have EGFR or ALK mutations, and who do express PD-L1 at least the 1 percent level,” he added. “We do need to do a lot more work. Even though patients do better today, they still do not do well enough. The vast majority of patients with advanced lung cancer will have disease progression and will succumb to lung cancer. So, we need to continue doing more work.”

Chemotherapy has been the standard of care for patients with NSCLC who do not have driver mutations. However, the Food and Drug Administration (FDA) approved Keytruda — based on results from the Keynote-024 trial – for the initial treatment of patients with NSCLC with high PD-L1 expression (considered a score of at least 50 percent), which accounts for approximately one-third of NSCLC.

In this study, the researchers randomized 1,274 patients with locally advanced or metastatic NSCLC to receive chemotherapy (paclitaxel plus carboplatin or pemetrexed plus carboplatin) or Keytruda. Patients were then divided in to three groups for evaluation by PD-L1 expression score: at least 50 percent (599 patients), at least 20 percent (818 patients), and at least 1 percent (1,274 patients).

After a median follow-up of 12.8 months, patients treated with frontline Keytruda lived four to eight months longer than those who received standard of care chemotherapy, regardless of PD-L1 expression in the tumor. Median OS improved across all three groups, increasing as the level of PD-L1 expression became higher. For example, patients treated with Keytruda demonstrated superior OS in those with a score of 50 percent or more (20 vs. 12.2 months); a score of 20 percent or more (17.7 vs. 13 months) and 1 percent of more (16.7 vs. 12.1 months) compared with chemotherapy.

Compared with those who received chemotherapy, these patients experienced fewer severe side effects (17.8 percent vs. 41 percent) and treatment-related side effects (62.7 percent vs. 89.9 percent), which led to discontinuation in 9.4 percent and 9 percent of patients, respectively.

The researchers, too, added that more work needs to be done in this area. “The three broad groupings by PD- L1 expression in the current analysis do not allow researchers to predict the benefit from pembrolizumab for patients with a specific PD-L1 expression level,” they said in a press release. “Additionally, it is not yet clear whether pembrolizumab combined with chemotherapy is better than pembrolizumab alone in patients who express PD-L1, as there have not been head-to-head comparison trials of the two approaches.”

ASCO Expert John Heymach, M.D., Ph.D., commended the study findings, saying that they represent an important milestone for patients with NSCLC.

“In an era for which chemotherapy was the only option for non-small cell lung cancer patients, this is coming to a close. Virtually all non-small cell lung cancer patients can receive a nonchemotherapy regimen with immunotherapy or, if they have a driver mutation, with an appropriate targeted agent,” Heymach said. “Immunotherapy is here to stay for the vast majority of non-small cell lung cancer patients as a firstline treatment. This represents a really important advance for these patients.”

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