Novel Therapies Prompt Push for New Paradigms to Evaluate Treatments

Thomas F. Gajewski, MD, PhD

As immunotherapy options grow, oncologists will need new frameworks of reference for evaluating whether patients are benefiting from the treatments, experts say.

The FDA’s approval last month of ipilimumab (Yervoy) as a treatment for latestage metastatic melanoma marks another breakthrough for the concept of immunotherapy that comes less than a year after the agency endorsed the first anticancer therapeutic vaccine, sipuleucel-T (Provenge), for prostate cancer.

Yet although ipilimumab has demonstrated the capacity to improve survival for patients, the response patterns among those treated with the drug in clinical trials indicate standard methods of evaluating a treatment regimen may not be adequate for immunotherapy.

Thomas F. Gajewski, MD, PhD, president of the Society for Immunotherapy of Cancer, said using immunotherapies “could require a new kind of patience by treating physicians to give it a little bit of time to work.” Gajewski is a professor in the departments of Pathology and Medicine, Section of Hematology/Oncology, at the University of Chicago Medical Center, Illinois.

Some patients may experience tumor growth after starting ipilimumab, an occurrence that typically would prompt a clinician to reconsider the therapy, before the benefits become evident, Gajewski noted in an interview. The drug is administered intravenously, with a complete course of treatment consisting of 4 infusions of 3mg/kg doses during a 3-month period.

Axel Hoos, MD, PhD

Established and Proposed Response Criteria

WHO, World Health Organization; irRC, immune-related response criteria; PD, progressive disease; BOR, best overall response; CR, complete remission; PR, partial response; SD, stable disease; SPD, sum of the product of perpendicular diameters.

Adapted from Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412-7420.

“You can imagine if your tumor starts to grow on the first CAT scan that you get to check progress of the therapy, normally we, as treating oncologists, want to switch to a new therapy,” he said. “Similar things have been seen with a couple of other immunotherapies, and so I think there will be some sort of, some level of, education required to alert treating oncologists to that pattern.”

Indeed, researchers supported by Bristol-Myers Squibb, which is bringing ipilimumab to market, argue that clinical practice guidelines are based on chemotherapies and that new criteria are needed for emerging immunotherapies.

“Adjusting the clinical development paradigm from chemotherapy to immunotherapy requires addressing the unique characteristics of immunotherapeutic agents in clinical trials to provide more adequate tools for evaluation, including the adjustment of clinical trial endpoints,” researchers wrote in a review article last year in the Journal of the National Cancer Institute (2010;102(18):1388-1397).

Axel Hoos, MD, PhD, the lead author of the paper, is medical lead for Yervoy at Bristol-Myers, co-chair of the executive committee of the Cancer Immunotherapy Consortium, and a board member at the Sabin Vaccine Institute in Washington, DC.

He explained in an interview with OncLive how response patterns among patients treated with ipilimumab can vary.

“We see conventional patterns of response, which means the tumor may shrink right after treatment, so there is no growth in between, or we see tumors enlarge and later shrink,” he said. “And there is a third pattern where some new lesions may occur, and those new lesions may go away over time together with previously existing lesions.

“So it’s a new pattern, and we attribute those to the role of the immune system, which is activated through the use of the drug, and may lead to infiltration of lymphocytes into the tumor, which can then increase the tumor volume, and may then be followed by shrinkage when the lymphocytes begin to attack cancer cells,” Hoos said.

Initiatives to develop systems for evaluating immunotherapies have been in the works since at least 2004. Two years ago, Hoos co-authored a paper arguing that the Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) standards do not adequately address biologic therapies. (Clin Cancer Res. 2009;15[23];7412-7420).

In fact, the researchers argued, 9.7% of 227 patients in one single-arm study of ipilimumab were characterized with progressive disease (PD) under WHO standards when they actually showed a response to the drug.

The investigators proposed new criteria, which they called the immune-related response criteria (irRC). “The core novelty of the irRC is the incorporation of measurable new lesions into ‘total tumor burden’ and comparison of this variable to baseline measurements,” they wrote.

Although the research team developed its new guidelines using ipilimumab data, they anticipate the irRC could be applied to other immunotherapy treatments. And, they said, the irRC “may still not capture or fully characterize all relevant patterns of clinical activity” and likely will need further refinement, even as immunotherapy itself evolves.