Merck, Others Look to Immunotherapy Combos as Next Frontier in Oncology

Pictured: Cancer cells and IV bags over an abstract background/Taylor Tieden for BioSpace

As the oncology space moves away from single oncogene-targeted treatments, immunotherapies that aim to prevent immune fatigue and enhance immune cell engagement are emerging as promising therapeutic trends, experts told BioSpace. But these therapies are not always intended to be deployed on their own. Increasingly, scientists and clinicians are mixing and matching therapeutic strategies based on patient needs.

“We are moving toward a future where we have enough medications that each work individually and have minimal side effects so that we can create even larger combinations, which offer the most benefit to people,” said David Weinstock, vice president of discovery oncology at Merck, whose blockbuster immunotherapy Keytruda is a go-to for such combos.

Combining ADCs and STRIs with Immune Checkpoint Inhibitors

One popular therapy now being explored in combination with immunotherapies is a class known as antibody-drug conjugates (ADCs). ADCs marry monoclonal antibodies to potent cytotoxic drugs to precisely deliver those drugs to tumor cells while reducing off-site toxicities. According to a new report from market intelligence firm Evaluate, the market value of ADCs was about $10 billion in 2023 and will reach almost $30 billion over the next few years.

“We are just starting to understand what’s the single-agent activity of an ADC, and there is a population of patients treated with the standards of care who will respond to ADC treatments,” Weinstock said.

But for those who don’t respond to ADCs on their own, a combo option may perform better. A recent Merck-sponsored Phase III EV302 study combined Keytruda, a type of immunotherapy called an immune checkpoint inhibitor (ICI), with Padcev, an ADC used in the treatment of renal cancer. Compared with patients in the chemotherapy arm of the trial, those who received the combination had better outcomes in terms of both progression-free survival, overall survival and overall response rate, according to findings published in October 2023. Weinstock said this combination has since been established as the frontline treatment for bladder cancer.

“The synergy between ADCs and ICIs overcomes resistance mechanisms and augments the immune response,” Daina Graybosch, a senior research analyst covering immuno-oncology at Leerink Partners, told BioSpace. While most immunotherapies prevent or reverse immune fatigue, studies have shown that ADCs recruit T cells to the tumor microenvironment to further improve antitumor immune response.

To a similar end, eFFECTOR Therapeutics is developing selective translation regulation inhibitors (STRIs) such as tomivosertib to lower the abundance of immune checkpoint proteins and slow down T cell exhaustion. “One of the key ways that tumors fight against the immune system is to drive T cell exhaustion by upregulating PD-L1 and other proteins that activate exhaustion pathways,” Steve Worland, the company’s president and CEO, told BioSpace. Tomivosertib inhibits the protein synthesis pathways of immune checkpoint proteins and other factors responsible for T cell exhaustion and improves T cell function, he explained.

Tomivosertib can improve T cell function and therapy response in patients who stop responding to ICI therapies, Worland said, and it’s also being investigated in combination with Keytruda in a Phase II clinical trial for non-small cell lung cancer. While official results of the trial are expected in the first quarter of 2024, Worland said durable treatment benefits are evident in the trial’s combination arm versus the arm receiving Keytruda and placebo. The addition of tomivosertib to Keytruda slows down immune exhaustion and reverses resistance to checkpoint inhibitors, he added.

Supercharging Targeted Therapies 

In the past, most targeted therapies involved blocking single oncogenes. However, tumors develop resistance mechanisms that render them insensitive to the drugs. Combining targeted therapies with Keytruda and other immunotherapies could improve outcomes, Weinstock noted. 

KRAS G12C inhibitors, including Merck’s MK1084, can be combined with Keytruda and other anti-PD1 drugs, he added. Merck has also partnered with Eisai to test the combination of Lenvima, a small molecule tyrosine kinase inhibitor, and Keytruda. In 2021, this combo won FDA approval for advanced endometrial cancer after reducing the risk of death by 32% and reducing the risk of disease progression or death by 40% versus chemotherapy in a pivotal Phase III trial.

“Universally, combination therapies offer patients additional benefits beyond just a single therapy in almost all of our curative therapies,” Weinstock said. “Having multiple different drugs that work through different mechanisms has benefits because they address different mechanisms of resistance and have different side effects.”

Of course, there are limitations to the success of such combos. For example, EGFR mutations cannot be combined with immunotherapies because tumors that respond to EGFR inhibition do not engage the immune system. Single oncogene-targeted therapies do work for some patients and will continue to be developed, Graybosch and Weinstock agreed. But on the whole, they both said that having a robust immune response as part of the cancer treatment strategy and multi-pronged approaches seems to be a promising future direction in the cancer treatment space.

Sunitha Chari is a freelance science writer and academic editor based in Toronto. See more of her work at sunithachari.contently.com and reach her at sunithachari.02@gmail.com.