CHICAGO – At the American Society of Clinical Oncology (ASCO) annual meeting last week, there were plenty of individual trial results vying for attention. But there were also presentations that focused on the science of the trials: how one might make those trials better at observing the true effects of drugs on tumors and, ultimately, on patients.

In randomized controlled trials RECIST – the Response Evaluation Criteria in Solid Tumors – is the gold standard of these studies. First published in 2000 by an international collaboration including the European Organization for Research and Treatment of Cancer, the National Cancer Institute and the National Cancer Institute of Canada Clinical Trials Group, and updated in 2009, the RECIST criteria are used in the majority of clinical trials. (See BioWorld Today, Jan. 27, 2009.)

Bringing Progress

RECIST clearly brought progress to cancer trials, not least by just introducing standardized criteria at all. But the specific criteria have always had their shortcomings. And they do not appear to be the optimal way to measure the effects of the therapeutic class that generated the greatest excitement at this year's ASCO meeting, namely, immunotherapies.

So many new trial results on immunotherapy drugs targeting the T cell activator PD1 or its ligand, PDL1, were presented at ASCO 2013 that one reporter joked on Twitter he would get a tattoo of such drugs' mechanism of action. Certainly, anyone going to immunotherapy sessions had that mechanism more or less tattooed on their brain by the end of the meeting. (See BioWorld Today, June 4, 2013, June 3, 2013, and May 16, 2013.)

One reason for the excitement about immunotherapies is that they can lead to extremely durable responses.

As first shown by very long-term responses to Yervoy (ipilimumab, Bristol-Myers Squibb Co.), immunotherapy offers metastatic cancer patients the best shot at what they really want: not a three-month or six-month increase in survival, but a chance to bore their grandchildren with war stories about their illnesses and how they survived.

More than a decade later, some of the patients treated with what would become Yervoy in the very first trials are still alive.

But although the way such therapies work is the opposite of economist John Maynard Keynes' famous quote – so often all-too-applicable to cancer drugs – that "in the long run, we are all dead," using RECIST criteria, in the short run such drugs can look like they are not working at all.

To be sure, many patients do show the tumor shrinkage that is key to demonstrating a benefit by RECIST criteria. But others do not.

Overall, "response patterns anatomically are much different than what we see with cytotoxic therapy," the University of Pennsylvania's David Mankoff told the audience at an ASCO session on "Rethinking How We Look At Response and Progression: When to Resist RECIST."

Tumors may appear to grow during successful immunotherapy because as immune cells come to fight cancer cells, there is a net increase in cells in the tumor. Essentially, during immunotherapy treatment, an inflammatory response can show up as progressive disease.

Response Patterns

Those response patterns were first described by Yervoy study lead Jedd Wolchok and his colleagues in 2009, when they published data showing that there are at least four different ways that tumors could respond to immunotherapy that were associated with favorable survival. Increased survival could be seen in patients whose tumors shrank, but also in some whose tumors initially remained stable or even grew, and in some who developed new metastases even though their primary tumors were responding.

At this year's ASCO meeting, some patients were described who had long-term stable disease after treatment with nivolumab – even though they stopped receiving the drug after progressing according to RECIST criteria.

Not surprisingly, researchers are now trying to find ways to distinguish tumors that are being attacked by the immune system from those that are truly progressing.

In their original article, Wolchok and his team suggested a set of criteria, the so-called immune-related response criteria or irRCs. Those criteria do not necessarily see new metastases that appear during treatment as evidence of progressive disease, so long as the total tumor burden is decreasing. And for a patient to be defined as having progressive disease, their tumor burden must not only increase by 25 percent, but stay at the higher level for at least four weeks.

T cells are metabolically active and dividing themselves. This means there is no simple way to use some other sets of criteria that researchers are studying as alternatives or adjuncts to RECIST, to distinguish necrotic tissue from tumors, such as metabolic measurements or methods looking at the rate of cell division within a tissue.

Mankoff told BioWorld Insight that a combination of metabolic measurements and those looking at DNA synthesis have shown some success in telling immune responses from tumor progression tumor progression. But definitive criteria remain to be identified, let alone adopted widely in trials or by regulatory agencies.

In the meantime, he told the audience, "do not assume that enlarging tumors, especially those that are painful or warm, are necessarily a sign of progressive disease . . . we're still very much on a learning curve."