Merck & Co. Inc.'s first regulatory win in breast cancer for the immunotherapy Keytruda is one part of the company's overall strategy to gain a foothold in the disease market led by Swiss rival Roche Holding AG.
The latest green light for Keytruda, also called pembrolizumab, brings the number of cancer uses to 32 different approvals with 28 indications in 17 major cancer types, more than any other immuno-oncology competitor.
Merck Head of Global Clinical Development and Chief Medical Officer of Merck Research Laboratories Roy Baynes
Source: Merck & Co.
"We're still quite early in the process," Roy Baynes, Merck head of Global Clinical Development and chief medical officer of Merck Research Laboratories, told S&P Global Market Intelligence in an interview. "There's an enormous amount of work still to be done in different lines of treatment, different combinations and different tumor types, so we're very convinced pembrolizumab is foundational in the treatment of many cancers."
Keytruda was granted an accelerated approval for use in triple-negative breast cancer patients whose disease has spread to other parts of the body and whose tumors express the protein PD-L1 on Nov. 13. This is a pathway that Keytruda blocks to stop cancer cells, putting it in a class of drugs called checkpoint inhibitors. The approval is based on results from a late-stage clinical trial called Keynote-355, which showed that Keytruda prolonged patients' lives without disease progression.
Roche's Tecentriq along with Bristol-Myers Squibb Co.'s Abraxane chemotherapy collected the same approval in March 2019, cementing a lead the Swiss company established in breast cancer with Herceptin in 1998.
The U.S. Food and Drug Administration's nod for Merck is contingent upon confirmatory trials, which Baynes said could include final analysis of Keynote-355 to determine patient survival, as well as additional paths to full approval from other trials in breast cancer, showcasing the number of studies Merck has undertaken at once.
One of these is Keynote-522, a late-stage trial investigating Keytruda and chemotherapy in triple-negative breast cancer patients before surgery or after another treatment. The FDA has set a target date for potential approval of the indication for March 29, 2021. Preliminary results have been positive with a 35% reduction in disease recurrence among survivors, Baynes said.
The additional trials give Merck "a number of opportunities to confirm the accelerated approval," Baynes said.
The Keytruda breast cancer trials have included disappointments, as well, such as a failure to improve survival in triple-negative breast cancer in May 2019. In that study, patients received either Keytruda or chemotherapy as opposed to a combination, and Baynes said the lessons helped establish which patients were best suited for treatment.
Including the breast cancer trials, Keytruda alone and in combination with other cancer drugs is part of more than 1,200 clinical studies to expand the therapy's use in cancer patients, Baynes said. The cancer drug has stayed ahead of the competition in terms of regulatory approvals as a result of the wide-sweeping approach. Merck spent $9.87 billion in total on research and development in 2019, with Keytruda leading the way. The drug brought in $3.7 billion for the third quarter, a 21% increase over the same period in 2019.
Keytruda has received seven FDA approvals in 2020 so far, including dosage and biomarker indications, out of 16 total in the checkpoint inhibitor class, Mizuho analysts Mara Goldstein and Gabriel Fung said in a note. Roche's Tecentriq received three approvals while Bristol-Myers' combination of Opdivo and Yervoy received three. Opdivo alone, Imfinzi from AstraZeneca PLC and Bavencio from Pfizer Inc. and Germany's MERCK KGaA each had one.
"The dominant checkpoint inhibitor is Merck's Keytruda, and we see this unlikely to change, particularly as new indications continue to be approved," Goldstein and Fung said in the Nov. 17 note.
'The concept of synergy'
The combination of Keytruda with other drugs such as tyrosine kinase inhibitors like Pfizer's Inlyta or Eisai Co. Ltd.'s Lenvima is a calculated effort to slow cancer by blocking as many pathways for the disease to spread to healthy cells as possible, Baynes explained.
"In clinical oncology, it's quite hard mathematically to prove synergy," Baynes said. "The concept of synergy tends to come more from the microbiology world where you put two antibiotics together and you get more bacterial killing than you would with just one plus one — that's much harder to show in clinical trials."
Merck has shown that there does seem to be a benefit in combining other therapies with Keytruda, Baynes said. Whether they are synergistic or additive does not matter as much.
"This hasn't been blunderbuss therapy; we have used informative biology to try and determine which combinations make sense," Baynes said. The types of tumors and their levels of inflammation and mutation all provide insight into which therapies will work best with Keytruda or if the drug is better on its own.
For example, Keytruda and Inlyta improved survival in first-line renal cell carcinoma in a trial called Keynote-426 and another trial with Lenvima called Keynote-581 has shown similar efficacy, with full results expected in 2021.
"Our strategy was actually always pretty straight forward — we knew early on that this was going to be an important drug," Baynes said, as melanoma patients responded frequently in early-stage studies at the beginning of Keytruda's journey, then called by its scientific name pembrolizumab.
The company used precision medicine tools to identify patients who would respond most readily to Keytruda and which combinations would serve best alongside the therapy.