Add It Up

IN THE 1940s, pediatric pathologist Sidney Farber identified a new drug called aminopterin that he thought might thwart childhood leukemia by blocking folic acid, which promotes the growth of bone marrow tissue that is the source for abnormal blood cells in the disease. In a small clinical trial of 16 children with acute leukemia that appeared in the New England Journal of Medicine in 1948, he reported a groundbreaking result: 10 children achieved a temporary remission of their cancer. The finding is regarded as one of the first demonstrations that chemotherapy could be effective against cancer. But the remissions also highlighted the limitations of single agents or monotherapy—and the work that still needed to be done—to combat a complex disease.

“A single drug works for some, and in patients where it works, it kills some fraction of the cells,” says Adam Palmer, a pharmacologist who studies combination cancer therapies at the University of North Carolina at Chapel Hill. “But single therapies don’t tend to work in all patients or to kill all the cells. With few notable exceptions, using multiple active drugs makes more patients respond and kills a larger fraction of cancer cells.”

The first application of combining multiple drugs to treat cancer more effectively occurred in the 1960s. Building on the research with aminopterin, oncologist Emil Frei and colleagues treated children who had acute lymphocytic leukemia (ALL) with four drugs—another antifolate called methotrexate, along with 6-mercaptopurine, vincristine and prednisone. While treatment choices in pediatric ALL have evolved over time, many of the drugs in this regimen, known as POMP, are still a key part of combination therapy today. And this early success with POMP gave credence to the concept of putting drugs together to target cancer in two or more different ways.

Pushing for More

Today, the number of drugs—chemotherapies, immunotherapies and molecularly targeted agents—has led to an almost unlimited number of possible drug combinations. From 2011 to 2021, the Food and Drug Administration (FDA) approved 81 new drug combinations for advanced cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma, endometrial carcinoma and gastric cancer. An online search for active clinical trials that test new combination therapies or existing combination therapies used to treat different cancers returns more than 4,400 ongoing studies.

Many of these trials are testing immunotherapy drugs, a type of treatment that spurs the person’s immune system to recognize and fight cancer. In 2015, the FDA approved the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) to treat metastatic melanoma that doesn’t express BRAF V600 mutations (called BRAF wild-type). Both drugs are checkpoint inhibitors, which block interactions between the cancer cell and immune cells that typically turn down immune response. Yervoy inhibits a protein called CTLA-4 while Opdivo blocks a different protein, PD-1, to activate an immune response.

The two drugs work independently, but the FDA approved the combination of Opdivo and Yervoy based on evidence from a study of 142 patients who had not been treated previously for metastatic melanoma or who had melanoma that couldn’t be removed with surgery. The study showed that 61% of 72 patients whose tumors didn’t have mutations in the BRAF gene responded to the combination and 22% had a complete response, meaning they had no evidence of cancer after treatment. By comparison, researchers noted tumor response in just 11% of patients who received Yervoy alone, and none had a complete response.

Jedd Wolchok, a medical oncologist and director of the Meyer Cancer Center at Weill Cornell Medicine in New York City who led the clinical trials that prompted the first FDA approvals of Yervoy and the Yervoy-Opdivo combination in melanoma, says the combination is now a standard of care for treating advanced melanoma in the U.S. Clinical trial results have shown that after 6.5 years of follow-up, median overall survival for melanoma patients treated with the combination is six years, compared with just over three years for Opdivo alone and less than two years for Yervoy alone.

“We can now safely say that the median overall survival after a person [with metastatic melanoma] received this combination therapy is just over six years, which is really a very favorable change compared to before effective [combination] immunotherapy, when it was seven months,” Wolchok says.

Toxicity Concerns

The Opdivo-Yervoy immunotherapy combination is also approved to treat renal cell carcinoma, hepatocellular carcinoma, non-small cell lung cancer and pleural mesothelioma, and clinical trials testing the combination for other cancers are ongoing.

Wolchok also notes that the combination’s “formidable toxicity”—the data show almost 60% of patients with melanoma have a serious adverse event—continues to challenge doctors and patients. That’s one reason oncologists are especially hopeful about the March 2022 approval of a new immunotherapy combination for advanced melanoma—Opdivo combined with a new checkpoint inhibitor called relatlimab that targets the protein LAG-3. The combination is being marketed as Opdualag.

The Opdualag approval is based on evidence from more than 700 patients with stage III or IV melanoma. Patients who got the new combination lived more than twice as long without the cancer getting worse as patients who got Opdivo alone. The median progression-free survival was 10.2 months for those taking Opdualag and 4.6 months with Opdivo. Importantly, the most common adverse reactions—muscle pain, fatigue, rash and diarrhea—were each seen in fewer than 25% of those who took the new combination. For comparison, the clinical trial evaluating Opdivo‑Yervoy found that nearly half of people taking that combination experienced diarrhea, while more than a third experienced fatigue or rash.

“Not everyone gets the [Opdivo-Yervoy combination] because the side effect profile has been quite high,” says Rodabe Amaria, a medical oncologist at the University of Texas MD Anderson Cancer Center in Houston. “The new regimen with nivolumab and relatlimab gives the opportunity for a combination that’s shown to be better than single agents with a toxicity that is not as high as the one we’ve used for many years.”

Opdualag is approved for anyone with advanced melanoma, but Amaria cautions that the “really favorable data exists only for people that are treatment-naive,” meaning patients who have not been treated before with immunotherapy. Still, the approval of a new and less toxic checkpoint inhibitor combination is generating enthusiasm among doctors specializing in melanoma and other cancer types as well.

“There is excitement now that LAG-3 might also be a target of interest in kidney and other tumor types,” says James Brugarolas, a kidney cancer oncologist and director of the Kidney Cancer Program at UT Southwestern Medical Center in Dallas.

More Cancer Types

In kidney cancer, five treatment combinations—either combining different immunotherapies or linking immunotherapy with anti-angiogenic treatments targeting blood vessel growth—have replaced the standard of care. One reason the new combination treatments are so plentiful is that the former standard of care, a drug called Sutent (sunitinib), didn’t treat metastatic kidney cancers as effectively as the new therapies.

“Sutent was effective, but is now being replaced by combination therapies, which are superior,” Brugarolas says. The challenge now, he says, is deciding whether patients will fare best with an immunotherapy-only combination or a combination of immunotherapy and targeted therapy.

“It’s a very nuanced discussion,” he says. For metastatic kidney cancer patients treated with Opdivo and Yervoy, survival at five years is approaching 50%, which Brugarolas considers remarkable. The five-year relative survival for metastatic kidney cancer based on data from 2012 to 2018 was 16%. “Many patients treated with the immunotherapy combination have come off therapy and remain progression-free, and a subset may be cured of metastatic kidney cancer. It’s a game changer for the field.”

The combinations of immunotherapy plus the anti-angiogenic targeted medicines don’t yet have a track record long enough to know how they will perform over time. On its own, anti-angiogenic targeted therapy isn’t seen as curative, Brugarolas says, because it targets blood vessels and not the cancer. However, 40% of kidney cancer patients respond to the immunotherapy combination compared with up to 70% for immunotherapy plus anti-angiogenic targeted therapy. Immunotherapy combinations, when they work, may offer the best treatment long-term, but immunotherapy plus targeted therapy, he says, “may be best to control the disease quickly.”

Patients with metastatic or unresectable hepatocellular carcinoma (HCC), which is the most common form of liver cancer, also have a new front-line combination standard treatment. In 2020, the Food and Drug Administration approved the immunotherapy and anti-angiogenetic combination of Tecentriq (atezolizumab) plus Avastin (bevacizumab).

“This is the go-to therapy,” says Won Jin Ho, an oncologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. “The combination was a huge difference-maker because before, sorafenib [Nexavar] would shrink tumors in 5% to 10% of patients at best. Here we’re talking a third of patients see their tumors shrink and more than half remain stable.”

In October 2022, the FDA approved another immunotherapy combination option for HCC —Imjudo (tremelimumab), which targets CTLA-4, and Imfinzi (durvalumab), which targets PD-L1. Trial results showed that the immunotherapy combination led to a significant and clinically meaningful improvement in overall survival when compared with the single-agent Nexavar, with a response rate of 20%. Similar progress is being made in other forms of advanced solid tumors.

More Progress to Come

Based on the success of combinations in treating advanced HCC cases, Ho says researchers are also looking into using these therapies to shrink liver tumors enough to allow surgery in patients otherwise deemed ineligible for surgery and therefore incurable. In the July 2021 issue of Nature Cancer, Ho and colleagues reported findings on Opdivo with the kinase inhibitor drug Cabometyx (cabozantinib), a combination that is approved by the FDA for advanced kidney cancer but not liver cancer. The trial enrolled 15 participants, all of whom had HCC but were ineligible for surgery. By the end of the study, 12 were able to have their cancer removed. Five of those whose tumors shrank significantly and who had surgery remained disease-free for at least 230 days.

“We’re learning a ton,” Ho says. “Liver cancer is also unique in that we have a variety of options—not just systemic [drugs] but also liver-directed therapies,” including targeted radiation and catheter-guided approaches to delivering chemotherapy straight to the liver. “There is a lot of opportunity and a whole new group of drugs to work with. The window of opportunity is here to convert a lot of patients long considered incurable [to curable]. If we can change that calculus, that’s what I’m really optimistic about.”

In kidney cancer, Brugarolas is excited about the potential of a new drug he helped to develop called Welireg (belzutifan), which hits a new target that is an important driver of kidney cancer called the HIF2α protein. The FDA approved the drug in August 2021 to treat people with a form of kidney cancer that runs in families. What makes Welireg especially promising, Brugarolas says, is that it is highly specific, meaning that it hits its intended target and not other targets, compared with other targeted drugs used in kidney cancer. As a result, it comes with fewer side effects. This advantage could increase the likelihood of combining Welireg with immunotherapies or other medicines.

“When you combine drugs with [lots of] side effects, it makes it harder for patients,” Brugarolas says. “This has potential to be more easily combined.”

Hedging Bets

Recent research suggests there’s still room for improvement in finding treatment combinations that work optimally together. Some studies have indicated that existing drug combinations produce better outcomes not because the paired drugs are more effective together, but because they give patients “two opportunities to benefit from one drug or the other,” says Peter Sorger, a systems biologist and pharmacologist at Harvard Medical School in Boston. A study published in Clinical Cancer Research in January 2022 by Sorger and Palmer, from the University of North Carolina, suggests the benefit of immunotherapy combinations can generally be explained by easily predicted, individual effects from one drug or the other. In the study, the researchers explain this effect colloquially as “bet hedging,” which means the use of more drugs increases the chances that patients will have a response. (Clinical Cancer Research is published by the American Association for Cancer Research, which also publishes Cancer Today.)

As it turns out, Frei and colleagues, who are credited with the early success using combination chemotherapy in children with leukemia in the 1960s, first considered independent drug action when they observed similar overall survival rates in patients who received two chemotherapy drugs one after another versus receiving both drugs simultaneously. Sorger and Palmer remain optimistic that a better understanding of the underlying biology in cancer might lead to even greater success and precision in advanced cancer therapies.

While the benefits of approved combinations may come from different mechanisms that are related to one drug or the other in the combination, Sorger stresses that these treatments showed superiority to existing treatments, which is why they were approved.

“We’ve come a long way, but there’s more work to do,” Wolchok says. “We still have open questions about who needs combination therapy in context and who might receive a single agent with less toxicity and a modestly lower survival rate. The more we learn scientifically about important pathways that affect tumors and the immune system, the more options we’re going to have. We hope to bring only the most effective and mechanistically rational combinations forward.”

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