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Opinion articles

Tuesday, October 1, 2013

Clinical Trials Remain Essential to Evaluate Combination Immunotherapies, and Against a Broader Range of Cancers




It isn’t often that cancer patients share their thoughts and fears with their physicians in sparkling prose. So I consider myself  fortunate to have treated Mary Elizabeth Williams, who as a staff writer for Salon has been eloquently recording her experiences with metastatic melanoma for the past three years. Her more recent articles, I’m happy to report, have been celebratory: As she wrote this spring just before the ASCO Annual Meeting: “I went from a diagnosis of a metastatic, Stage 4 cancer that looked hell-bent on killing me (and expediently) to having a visible reduction in tumor size within just one week—and being completely cancer-free within three months” (


Of course, such declarations would warm any oncologist’s heart. But Williams’ case holds several lessons for all oncology researchers—and in particular, points out the need to continue to assess combination immunotherapies.


The Ipilimumab/Nivolumab Case

Williams (who has kindly given me permission to also note some of the details here) participated in a Phase I clinical trial (which I led) that evaluated a regimen of two antibody therapies for advanced melanoma—the CTLA-4 inhibitor ipilimumab, and the investigational PD-1 inhibitor nivolumab.


The results, which were presented at the ASCO meeting [OT 6/25/13 issue] and subsequently published in the New England Journal of Medicine (2013;369:122-133) were startling: Twenty-one of the 52 evaluated patients showed objective responses in measurable tumors, and in 16 of them the tumor regressions were greater than 80 percent. In five patients, including Williams, the tumors regressed completely. Responses were swift, and they appear to be durable: 90 percent of the patients have continued to respond for well over a year.


Implications for Other Cancers

The first lesson I draw from this result is that it’s time to give combination immunotherapy a chance against a broader range of cancers. Historically, such strategies have primarily been investigated for melanoma and kidney cancers. I personally suspect this is because few drugs existed for these cancers in the last century, and because spontaneous tumor regressions had been recorded with relatively greater frequency in both—which suggests a role for immune modulation for the treatment of both. Mutational load and inherent immune modulation by these two specific cancers may also be important.


But, we have every reason to believe that similar responses can be harnessed to control a wider variety of tumors with durable efficacy by combining such therapies. This is already happening to some degree: For example, also reported at ASCO were studies about experimental immunotherapies such as the PD-L1 inhibitor MPDL3280A now being applied to non-small cell lung and gastrointestinal cancers [OT 8/10/13 issue]. We need to build on this trend and test such therapies in combination with a broader variety of treatments—targeted drugs, radiation, chemotherapy—and against a wider spectrum of cancers.


More Clinical Trials Needed

This brings us to the second lesson I draw from Williams’ case. If we hope to more aggressively devise and evaluate combination immunotherapies, researchers will have to conduct more clinical trials to ensure that combining investigational and approved therapies is both safe and effective.


As more targeted and immune-modulating therapies become available, clinical oncologists are increasingly likely to use them in combination. The results may not always be optimal—they might in some instances impair the immune system and in other cases prove to be far too toxic. For example, a clinical trial I led found that the theoretically promising concurrent combination of ipilimumab and the BRAF-inhibitor vemurafenib yielded excessive toxicity in the liver. Researchers are now assessing other targeted therapies and other schedules that might be a better fit with the antibody therapy.


Researchers will need more financial resources and more dedicated time to accelerate the assessment of such strategies. This may seem a tall order. In the face of diminishing government support for science, researchers are today forced to spend a good part of their time applying for grants.


Yet it is possible to devise funding mechanisms that free researchers from some of their grant-writing so they can do more of what they do best—discover things. I am fortunate that Ludwig Cancer Research, a major source of support for my work, has deliberately established funding processes to make this possible and has the clinical trial expertise to help conduct these kinds of innovative trials. I know there are other institutions that also provide streamlined funding support for their scientists, and more institutions need to do the same.


More Collaboration Needed

My third lesson from Williams’ case is that researchers must work more collaboratively with pharmaceutical companies, whose interest in cancer drug development often dovetails with that of researchers, clinicians, nurses, and patients. Such partnerships are mutually beneficial. By bringing researchers to the table early in drug development, pharmaceutical companies gain from the insight and creativity of academic researchers.


Clinical oncologists, for their part, get to influence the selection and development of therapies that are likeliest to benefit their patients. They also gain access to novel drugs and investigational molecules being developed by companies. If researchers are empowered and equipped to test more therapeutic combinations, especially those involving immunotherapy, we’re hoping to achieve durable disease control against a broader variety of cancers.


As Mary Elizabeth Williams noted in that post in May, the arrival of effective immunotherapy has ushered in a “new era” in the battle against cancer and made her cancer-free in three months. “Mighty jazzy,” she wrote. “I’m one of the first. But I will not be the only.”


We can, and should, be doing all we can to make her prediction a reality for all cancer patients.


JEDD WOLCHOK, MD, PHD, is Director of the Ludwig Institute for Cancer Research Collaborative Laboratory at Memorial Sloan-Kettering Cancer Center. He also serves as Director of Immunotherapy Clinical Trials and Monitoring at the Ludwig Center at MSKCC and Director of the Cancer Research Institute/Ludwig CVC Trials Network. His current research focus includes investigation of the glucocorticoid-induced TNFR-related protein (GITR pathway) as it relates to regulatory and effector T cells, use of OX40 agonists alone and in combination with chemotherapy and exploration of the role of myeloid derived suppressor cells in tumor immunity.