Biomarker-Led Claim Is Small Step For Merck's Keytruda, Giant Leap For Cancer Indications

Accelerated approval for patients with microsatellite instability-high or mismatch repair deficient solid tumors is the first time the US FDA has granted an indication that does not specify the location of the tumor – a change precision medicine researchers have been eager to make.

FDA's approval of Merck & Co. Inc.'s Keytruda for use in any patient with a solid tumor with a particular genetic mutation is the first of its kind and could herald a new approach to treating cancer.

The agency announced the accelerated approval of Merck's PD-1 inhibitor Keytruda (pembrolizumab) May 23, noting "this is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated."

The new indication, Keytruda's ninth, is for adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and specifically in colorectal cancer patients with the biomarkers that have completed earlier lines of treatment (see box). Labeling cautions that pediatric patients with MSI-H central nervous system (CNS) tumors have not been adequately studied.

New Indication

Microsatellite Instability-High Cancer: for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient

• solid tumors that have progressed following prior treatment in patients who have no satisfactory alternative treatment
• colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

• Limitation of Use: The safety and effectiveness of Keytruda in pediatric patients with MSI-H central nervous system cancers have not been established.

“This is an important first for the cancer community,” Richard Pazdur, director of FDA’s Oncology Center of Excellence, said in FDA's statement on the approval. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started – for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”

More To Come?

Multi-histology or tissue-agnostic approaches have mostly been viewed as a mechanism for low-incidence tumors, but in this case it also means finding the subpopulation more likely to respond to immunotherapy in a tumor type that generally hasn't been receptive.

"Basket" trials that assign patients to therapy based on molecular signatures are an increasingly popular clinical trial design, with high-profile efforts like the National Cancer Institute's MATCH study, the American Society of Clinical Oncology's TAPUR trial and Novartis AG's SIGNATURE protocol. (Also see "Genomics-Driven Trials Built To Be Fast And Flexible" - Pink Sheet, 21 Sep, 2015.)

But while their ability to speed research and improve targeting is clear, the regulatory path has been less certain. The closest example was the approval of Novartis' Gleevec based on a histology-independent trial that included more than 40 uncommon cancers with high unmet need; the FDA issued four indications for specific tumor types from that pivotal trial. (Also see "Gleevec: A Groundbreaking Example" - In Vivo, 27 May, 2014.)

The Keytruda approval clearly demonstrates FDA's openness to this approach. With a recent spate of breakthrough designations (BTDs), including for Keytruda's new indication, the agency has guided a few drugs through late-stage development for treatment of cancer patients based on molecular signatures, as opposed to the traditional paradigm focused on tissue of origin.

Keytruda first received a BTD for MSI-H colorectal cancer, then added another for MSI-H non-colorectal cancers.

Loxo Oncology Inc.'s larotrectinib and Ignyta Inc.'s entrectinib both hold BTDs for tissue-agnostic indications. Loxo's larotrectinib, a selective inhibitor of the Trk family of receptor tyrosine kinases, is currently in the Phase II NAVIGATE basket trial, potentially supporting a late 2017 or early 2018 NDA filing for NTRK fusion-positive solid tumors. Ignyta's entrectinib, which also targets the Trk family, has the Phase II STARTRK-2 basket trial under way with a possible 2018 NDA filing for NTRK fusion-positive solid tumors.

Loxo's larotrectinib is also in Phase I studies for sarcoma, while Ignyta's entrectinib is in Phase II trials for NSCLC and colorectal cancer as well.

Datamonitor Healthcare analyst Jared Wolff told the Pink Sheet that the approval for Keytruda "certainly sets a precedent that it can be done."

How Merck Got It Done

Merck's approval was based on a collection of patients with MSI-H or dMMR solid tumors from across five uncontrolled, single-arm clinical trials. (See chart below.)

Some of the trials were solely in biomarker-selected populations, but in other trials a subgroup was built of patients who tested for MSI-H or dMMR after treatment began. In total there were 15 cancer types among 149 biomarker-positive patients across the five trials; the most common cancers were colorectal, endometrial and other gastrointestinal cancers, FDA noted.

Of the 149 patients who received Keytruda in the five trials, 39.6% had a complete or partial response and the response lasted six months or more in 78% of those patients.

Merck is conducting additional studies in patients with MSI-H or dMMR tumors to meet the accelerated approval requirements for confirmatory trials.

Both MSI-H and dMMR mutations affect the natural processes of DNA damage repair inside the cell. According to FDA, the biomarkers are most commonly found in colorectal, endometrial and gastrointestinal cancers and less commonly in other cancers, including breast, prostate, bladder and thyroid gland. "Approximately 5% of patients with metastatic colorectal cancer have MSI-H or dMMR tumors," the agency reported.

Bristol-Myers Squibb Co.'s PD-1 inhibitor Opdivo (nivolumab) is under review at FDA for MSI-H colorectal cancer only with an Aug. 2 user fee goal. (Also see "Keeping Track: Teva's Austedo Clears US FDA, Merck Sitagliptin CV Outcomes Labeling Draws Complete Response" - Pink Sheet, 7 Apr, 2017.)

Additional reporting by Lucie Ellis ([email protected]) and Bridget Silverman ([email protected])

Keytruda MSI-H Trials
Study	Design & Patient Population	Number of patients	MSI-H/dMMR testing	Dose	Prior therapy
KEYNOTE-016 NCT01876511	prospective, investigator-initiated 6 sites patients with CRC and other tumors	28 CRC 30 non-CRC	local PCR or IHC	10 mg/kg every 2 weeks	CRC: ≥ 2 prior regimens Non-CRC: ≥1 prior regimen
KEYNOTE-164 NCT02460198	prospective international multicenter CRC	61	local PCR or IHC	200 mg every 3 weeks	Prior fluoropyrimidine, oxaliplatin, and irinotecan +/- antiVEGF/EGFR mAb
KEYNOTE-012 NCT01848834	retrospectively identified patients with PD-L1-positive gastric, bladder, or triple-negative breast cancer	6	central PCR	10 mg/kg every 2 weeks	≥1 prior regimen
KEYNOTE-028 NCT02054806	retrospectively identified patients with PD-L1-positive esophageal, biliary, breast, endometrial, or CRC	5	central PCR	10 mg/kg every 2 weeks	≥1 prior regimen
KEYNOTE-158 NCT02628067	prospective international multicenter enrollment of patients with MSI-H/dMMR non-CRC retrospectively identified patients who were enrolled in specific rare tumor non-CRC cohorts	19 l	local PCR or IHC (central PCR for patients in rare tumor non-CRC cohorts)	200 mg every 3 weeks	≥1 prior regimen
Total		149

Source: Keytruda labeling