Recent approvals of several checkpoint inhibitors across multiple cancer settings have brought more than just new and improved treatments to the clinic. According to David R. Spigel, MD, Chief Scientific Officer at the Sarah Cannon Research Institute, the rapid ascent of immunotherapy has created unexpected problems, too. At the 2016 Palliative Care in Oncology Symposium, Dr Spigel outlined the challenges facing patients and providers alike, including diagnostic uncertainty, treatment-related toxicity, new expectations, and a changing approach to care.
Checkpoint Inhibitors
Those looking for a sign of the times can start with the recent results of the KEYNOTE-024 trial, in which pembrolizumab demonstrated superior progression-free and overall survival compared with chemotherapy as first-line treatment for newly diagnosed advanced lung cancer (in patients who have PD-L1 tumor expression of 50% or more).
These outcomes signal a major shift in how we care for patients, said Dr Spigel, but it’s just the tip of the iceberg in terms of drug development. Several checkpoint or PD-1 inhibitors are already in the clinic, approved to treat not only lung cancer but renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, bladder cancer, and melanoma, and more approvals are expected before the end of the year. There are also new drugs coming, including durvalumab, avelumab, and tremelimumab.
At last count, said Dr Spigel, these immunotherapies are being tested in over 17 different cancer settings, and many are likely to find their way into the clinic in the next year or two.
Patient Selection
Despite the obvious clinical benefits, there is still confusion regarding patient selection. Many clinicians are still struggling to figure out which patients should be using these therapies, Dr Spigel reported.
Testing of one diagnostic biomarker, PD-L1, which measures the expression of the PD-L1 protein on tumor cells, is problematic to say the least. There are 4 diagnostic assays available, each with differing definitions of a positive score. Pembrolizumab is the only drug currently on the market that requires up-front selection in the form of PD-L1 testing.
“Data are mixed,” said Dr Spigel. “There is increasing evidence that pembrolizumab may be the only drug where PD-L1 testing is necessary. With nivolumab, the other big immunotherapeutic, for example, PD-L1 testing has not proved to be an effective way to select patients for benefit. Whether you have that expression or not, patients seem to benefit.”
But there are other biomarkers that may be available to predict benefit, including the number of mutations in a patient’s tumor samples, the so-called mutation burden index.
“Patients with high-burden indices seem to benefit from immunotherapy compared to patients who have low indices,” he said. “There are no prospective data yet, but this is very intriguing.”
Likewise, data for colorectal cancer have shown that patients with mismatch repair deficiency, the inability to repair defects in DNA damage, have a greater chance of benefiting from immunotherapy than patients with intact mismatch repair.
Clinical factors such as smoking history and history of autoimmunities like rheumatoid arthritis and lupus may predict benefit from these therapies, too, Dr Spigel noted.
Surveillance and Stratification
The greatest challenge facing patients and providers, however, may be unpredictable response once treatment has begun.
“We don’t know what’s going to happen when we start these therapies,” he said. “It could get better from the start, it could get worse, or nothing could change.”
Scans at 6 weeks, 8 weeks, or even 3 months may show new lesions in the liver or lung, he explains, but the patient feels fine. Continue to treat these patients, though, and the tumor may begin to regress, a phenomenon called pseudoprogression. Then there are those patients whose scans are neither completely negative nor positive, but who will survive for months and even years in a sort of stalemate with their tumor.
In other words, said Dr Spigel, the classic way to treat cancer, which is to assess whether drugs are working with scans, doesn’t apply to immunotherapy. Slow progression might be a worthwhile end point—in addition to disease response.
“Patients can do very well for long periods of time, so doctors have to be quick not to stop therapy,” he said. “We need to find a better way to know what to do when we’re giving these drugs.”
Less Incentive for Clinical Trial Enrollment
Finally, said Dr Spigel, while certainly a blessing, the rapid adoption of immunotherapeutic agents could hinder the development of future treatments.
Clinical trial enrollment is critical for testing the wealth of drugs now in development that may hold even greater promise, including LAG3 and TIM3 inhibitors, costimulatory agents and other immune modulators, CAR-T cells, and vaccines. These must be tested alone and in combinations and sequences, he observed, which certainly strains resources.
“It’s hard to convince patients to go on clinical trials or doctors to have their patients go on trials,” he said, “when it’s easier just to give nivolumab or pembrolizumab for whatever tumor they may have.”
