Keytruda Unlocked: How Should Merck Proceed with Trials?

Pictured: Merck sign with blue sky backdrop/courtesy of Kena Betancur/Getty Images

As a blockbuster drug raking in nearly $21 billion in 2022 alone, Keytruda (pembrolizumab) has a reputation for being omnipresent in cancer therapy discussions worldwide.

As a cancer agent, Keytruda operates by binding to the PD-1 receptor on T-cells regardless of whether these are tumor cells or healthy cells, to serve as a checkpoint inhibitor.

First approved by the FDA in 2014 for melanoma – and several other indications since - Keytruda is slated to go off-patent by 2028.

To prepare for this eventuality, Merck is evaluating still more indications for the drug. However, given this strategy's successes and failures, a better multi-pronged approach may be needed to optimize Merck's current resources.

Keytruda had a rocky start in the decades before its first approval. Merck initially deprioritized the project in 2009. When genetic biomarker testing became widespread enough to warrant another look, Keytruda began to be viewed as a serious oncology contender against competitors such as Bristol-Myers Squibb.

While Keytruda is approved for a massive variety of cancers such as breast, colorectal, stomach, NSCLC, hepatocellular carcinoma, head and neck and other solid tumors, there is evidence of cancers that do not benefit from treatment with the therapy.

These include metastatic NSCLC, metastatic castration-resistant prostate cancer, and surprisingly, head and neck cancer. Based on the evidence, there may be instances where the FDA has approved Keytruda to treat specific cancer types based on short-term trial results that have no clinical significance after long-term efficacy evaluations.

For example, results from a Phase III trial of Keytruda in locally advanced head and neck squamous cell carcinoma showed improvements in event-free survival. However, there was no statistical significance compared to the placebo.

With the financial cost and resources behind the current strategy, researchers need to learn more to extract meaningful results from current oncology studies.

One approach is to fine-tune the parameters for patient cohort segmentation based on specific criteria, such as genomic subtypes, for more granular data insights. Another would be to investigate how the gut microbiome affects the efficacy of cancer treatment with Keytruda.

An approach that may favor Merck is examining how tumor infiltration affects cancer patients since different T-cell distributions exist in different body systems. How these T-cells interact is still under investigation.

Although Keytruda is still being used in certain localized cancers with or without other chemotherapy agents, it is undoubtedly not the monolithic panache for cancer. While this allows Keytruda to be a contender in early-stage cancer treatment based on clinical guidelines, whether this success will transfer to metastatic cancers remains to be seen.

Merck shut down clinical trials such as KEYNOTE-641 in February 2023 after disappointing metastatic castration-resistant prostate cancer results. However, this does not spell the end of the company's troubles and doubts.

As 2028 approaches, stay vigilant for news from Merck and its competitors as more oncology data emerges from many trials.