Immunotherapies Changing the Treatment Landscape of Advanced Cancer Care
San Francisco, CA—Recent approvals of several checkpoint inhibitors across multiple cancer types have brought more than only new and improved treatments. According to David R. Spigel, MD, Chief Scientific Officer, Sarah Cannon Research Institute, Nashville, immunotherapy’s rapid ascent has created unexpected problems as well. 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.
Those looking for a sign of the times can start with the recent results of the KEYNOTE-024 trial, in which pembrolizumab (Keytruda) demonstrated superior progression-free survival and overall survival compared with chemotherapy as first-line treatment for newly diagnosed advanced lung cancer in patients with PD ligand 1 (PD-L1) tumor expression of ≥50%.
These outcomes signal a major shift in how patients with lung cancer are cared for, said Dr Spigel, but it is just the tip of the iceberg in terms of drug development. Several checkpoint or PD-1 inhibitors are available for the treatment of patients with lung cancer or renal-cell carcinoma, Hodgkin’s lymphoma, head and neck cancer, bladder cancer, and melanoma. More FDA approvals are expected before the end of 2016. Several new checkpoint inhibitors are in the pipeline, including durvalumab, avelumab, and tremelimumab.
At last count, said Dr Spigel, these immunotherapies are being tested in more than 17 tumors or settings, and many are likely to become available for patients in the coming years.
Role in Patient Selection
Despite the obvious clinical benefits, many oncologists are still struggling to figure out which patients should be using immunotherapies, Dr Spigel reported.
One diagnostic biomarker, the PD-L1 test, which measures PD-L1 expression on tumor cells, can be problematic, he said. There are 4 diagnostic assays available, each with a differing definition of a positive score. Pembrolizumab is the only drug currently on the market that requires upfront selection in the form of PD-L1 testing.
“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,” said Dr Spigel.
But there are other biomarkers that may be available to predict benefit, including the number of mutations in a patient’s tumor samples (ie, mutation burden index).
“Patients with high-burden [mutation] 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.”
Similarly, 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 a history of smoking and a history of autoimmunity (eg, rheumatoid arthritis or lupus), may predict benefit from these therapies, too, Dr Spigel said.
Surveillance and Stratification with Immunotherapies
The greatest challenge facing patients and providers with immunotherapy, however, may be the unpredictable patient response once treatment has begun.
“We don’t know what’s going to happen when we start these therapies,” Dr Spigel said. “It could get better from the start, it could get worse, or nothing could change.”
Scans at 6 weeks, 8 weeks, or even at 3 months may show new lesions in the liver or lung of a patient with cancer, he said, but the patient may feel fine; however, if you continue to treat such a patient, the tumor may begin to regress, a phenomenon called pseudoprogression. In other patients, their scans are neither completely negative nor positive, but they will survive for months and even years.
In other words, the classic way to treat cancer, which is to assess whether drugs are working with scans, doesn’t apply to immunotherapy, said Dr Spigel. Slow disease progression may 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. We need to find a better way to know what to do when we’re giving these drugs,” he said.
Less Incentive for Clinical Trial Enrollment
Finally, said Dr Spigel, although certainly a positive development, the rapid adoption of immunotherapies could hinder the development of future treatments.
Patient enrollment in clinical trials is critical for testing the wealth of drugs currently in development that may hold even greater promise, including LAG3 and TIM3 inhibitors, costimulatory agents, and other immune modulators, CAR T-cell, and vaccines. These must be tested alone and in combinations and sequences, which certainly strains resources, he observed.
“It’s hard to convince patients to go on clinical trials or doctors to have their patients go on trials when it’s easier just to give nivolumab or pembrolizumab for whatever tumor they may have,” Dr Spigel said.