WASHINGTON—The advocacy group Friends of Cancer Research (FOCR) announced at a conference here the activation of an ambitious “master” clinical trial protocol for squamous cell lung cancer, an innovative, collaborative public/private partnership, which aims to start enrolling patients by next spring. The trial protocol is believed to be unique.
The protocol consists of a broad, multi-biomarker screening platform for mutations and will be open to hundreds of academic and community North American sites. Speakers at the conference, also sponsored by the Brookings Institution, said the multi-drug, multi-arm Phase II/III registration trial of second-line therapy has the potential to revamp the way cancer clinical trials are currently conducted.
The number of patients expected to be included is approximately 35,800.
“Squamous cell lung cancer is really an orphan disease,” said Vali Papadimitrakopoulou, MD, Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center, who is on the master protocol trial's multi-sector oversight committee and co-chair of its executive operations group. She said the primary endpoint of the Phase II trial will be progression-free survival, and the primary endpoint of the Phase III trial will be overall survival.
The lung cancer master protocol trial's project management office will be run collaboratively by the Foundation for the National Institutes of Health, the Southwest Oncology Group, and FOCR, with a multi-sector oversight committee composed of scientists from the Food and Drug Administration, the National Cancer Institute, FOCR, and academia. The ultimate goal, according to FOCR, is to “revolutionize and accelerate the cumbersome, costly, lengthy, bureaucratic process inherent in the current clinical trial process and help speed effective new drugs to cancer patients.”
FOCR Chair and Founder Ellen Sigal, PhD, said the extraordinary success of the FDA's new Breakthrough designation gives her hope that new models for drug development such as the master trial protocol can speed up the process of bringing promising investigational drugs from bench to bedside, and do so safely. “Nobody is interested in pushing things that don't work on patients,” said Sigal, who is on the new trial's oversight committee.
In lung cancer, the need for a master trial protocol with multiple drug arms is clear, said Roy Herbst, MD, PhD, Chief of Medical Oncology at Yale Cancer Center, a member of the new trial's oversight committee and co-chair of its executive operations group. “While we're making some progress, it's still quite slow,” he said. “We have to do better.
“We have a team that's working together to make this happen. We hope to improve the standard of care for lung cancer in general in clinical practice,” he said, noting that a high number of lung cancer patients referred to him have not been genetically profiled.
5 Drugs, 5 Companies
Five investigational drugs from five different companies directed at specific mutations will be studied, including an immunotherapy drug, anti-PD-L1, an antibody that inhibits a protein that suppresses cancer-fighting immune cells.
“There is a need for a completely new way of thinking about the development of targeted drug/biomarker combinations” for squamous cell lung cancer, agreed David R. Gandara, MD, Director of the Thoracic Oncology Program at the University of California at Davis and a member of the trial's oversight committee. He noted that many new molecular targets have been found in lung squamous cell cancer.
The master trial protocol, he said, “represents an unmet need” because it offers a new way of studying uncommon genotypes. He added, “To my knowledge there is nothing like this that has been tried before.”
Janet Woodcock, MD, Director of the FDA's Center for Drug Evaluation and Research (CDER) and a member of the master protocol trial's oversight committee, said, “As conducted today, clinical trials are too expensive, and they limit the number of drug candidates that can be evaluated. We need to turn the clinical trial paradigm on its head.”
Studying different candidate drugs at the same time is a way of using biomedical resources wisely, she continued. “However, it takes pioneers. It's going to be rough at first because we haven't done this before; however, this is the best hope for patients.”
She said it is going to be important to reach out to community oncologists and involve them in the lung cancer master protocol trial, adding, “If there are winners, it will be great for patients.”
The decision to include an immunotherapy drug in the master trial protocol lung cancer study marks increasing recognition of its importance in the treatment of cancer patients, according to speakers at a session on immunotherapy at the FOCR conference. The FOCR gave conference participants an issue brief, “Facilitating the Development of Immunotherapies: Intermediate Endpoints for Immune Checkpoint Modulators,” which explores the intermediate clinical endpoints that will be needed in immunotherapy trials.
“This [immunotherapy] is a whole paradigm shift,” said session moderator James Allison, PhD, Immunology Chair at the University of Texas MD Anderson Cancer Center and a coauthor of the issue brief.
Allison pointed out that immunotherapy has a number of advantages in cancer treatment, including the fact that T cells have memory and adaptability; thus the immune system can change as the cancerous tumor changes. “We've gone from a situation where metastatic melanoma was uniformly fatal” to a situation where half the patients respond to immunotherapies, he pointed out. “Our job now is to more effectively evaluate these therapies.”
The key difference with immunotherapy is that, in contrast to cytotoxic therapies, “we're not treating the cancer directly,” said Axel Hoos, MD, PhD, Vice President of Oncology R & D at GlaxoSmithKline and a coauthor of the immunotherapy issue brief.
He emphasized that there are different patterns of immunotherapy response. With immunotherapies, the actual clinical response may take some time (in months), and the patient may experience delayed treatment effects. “As clinicians, we certainly don't want to miss that [delay] and deny the patient further therapy,” he said.
In addition, he noted, there may be tumor volume increase initially (thought to be due to lymphocyte infiltration), which could be mistaken for tumor progression before a response is shown. Also, Hoos said, “You may never detect a response, but you may actually slow down tumor growth.”
All of these issues matter for setting up the analysis for a successful immunotherapy clinical trial, he explained.
Also a coauthor of the immunotherapy brief, Steven Rosenberg, MD, PhD, Head of NCI's Tumor Immunology Section, said, “There's no question that you can see progression and then regression with immune modulators. Each kind of immunotherapy might have very different kinetics of response.”
So, he noted, as intermediate endpoints for immunotherapies are considered, each has to be specific for the type of immunotherapy under study. “We have to be very careful abut using soft endpoints that haven't been validated,” he said. Also, he added, unanswered questions remain about the sequencing of immunotherapy drugs.
Overall survival remains the gold standard as a clinical trial endpoint, emphasized Amy McKee, MD, Lead Medical Officer at the FDA's CDER. “There's a lot of work to be done” before the FDA can accept new clinical trial endpoints for immunotherapies, she said, adding, “We have to evaluate each individual trial as we make decisions about these issues.”
Richard L. Schilsky, MD, Chief Medical Officer of the American Society of Clinical Oncology, told the FOCR panel, “There's a lot of excitement” about immunotherapy. But, he said, clinicians need specific guidance on how to use immunotherapy in clinical practice.
“What I'm excited about is that it seems to work in a whole variety of tumor types,” Schilsky told OT. But he noted that for clinicians, specific, unanswered issues remain, including the fact that a patient's response to a given immunotherapy cannot now be predicted in advance.
Also, he said, these questions need answering:
* How long should the physician wait for a response to a given immunotherapy?
* How should the physician sequence immunotherapeutic agents?
* If there is prolonged durable survival, how does that impact subsequent therapy?
In addition to the issue brief on immunotherapy, Friends of Cancer Research also distributed an issue brief on cancer drug dosing, “Optimizing Dosing of Oncology Drugs,” and held a panel session on the topic. Schilsky, who moderated that panel, is a coauthor of the issue brief, which describes different potential approaches to the dosing of drugs used in oncology.