Data presented during the 2012 ASCO Annual Meeting demonstrated the potential of anti–PD-1 and anti–PD-L1 therapy for multiple cancers and introduced groundbreaking change in oncology research and treatment. Two researchers who presented key data about this promising therapy, and whose results were concurrently published in the New England Journal of Medicine,1,2 recently discussed the impact on oncology 6 years later.
In 2012, Suzanne Topalian, MD, of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, John Hopkins Medicine, presented the results from a phase I study (Abstract CRA2509) that enrolled patients with five cancer types who were then treated with anti–PD-1 therapy. These data opened a “new age in oncology, a new way that we were thinking about attacking cancer,” Dr. Topalian said.
Dr. Suzanne Topalian
Scott S. Tykodi, MD, PhD, with the Seattle Cancer Care Alliance, presented data in 2012 from a phase I trial (Abstract 2510) demonstrating the safety and efficacy of anti–PD-1/PD-L1 therapy in patients with advanced cancers. “These datasets were the kickoff to remarkable change that spans most of oncology,” Dr. Tykodi said. “It was a pivotal moment, and the changes since that time have been exponential. Not only did those drugs come forward and become standard therapy very quickly, but clinical research is dominated by those drugs and other immunotherapy approaches.”
Blocking a Pathway
In the study presented by Dr. Topalian, 296 patients with advanced melanoma, non–small cell lung cancer (NSCLC), prostate cancer, renal cell carcinoma (RCC), or colorectal cancer were treated with the novel anti–PD-1 antibody.1 Objective responses were found in approximately one in four to one in five patients with NSCLC, melanoma, or RCC. Most patients had been heavily pretreated, and 47% had been treated with at least three prior regimens. The durability of the responses was notable, according to the report, and contrasted with the relatively modest durability of objective responses that were observed in patients with NSCLC, melanoma, or RCC who were treated with conventional chemotherapy, tyrosine-kinase inhibitors, or both.
Dr. Scott Tykodi
The two studies, according to Dr. Topalian, can be considered “bookends” that demonstrated the results of using drugs to block either one of the partners of a pathway that restrains the immune response against cancer. “Whether you block PD-1, the receptor on immune cells, or you block PD-L1, the ligand on tumor cells, you are interrupting the interaction of those two molecules. Simply doing that can cause the regression of advanced cancers that have not responded to other therapies. That was the main message looking at those two studies combined,” she said.
“We have been pleasantly surprised that, since those reports in 2012, not only have the three cancer types that we reported on with anti–PD-1 responded—melanoma, RCC, NSCLC—but there are other types of cancer that have also responded to this therapy,” she said.
In the years following, the U.S. Food and Drug Administration (FDA) has approved immunotherapy drugs that block PD-1 or PD–L1 for nine individual cancer types, as well as for the overall category of microsatellite instability high (MSI-H) or mismatch repair deficient solid tumors. In 2017, the FDA granted accelerated approval to pembrolizumab for the tissue/site-agnostic MSI-H indication.3 This is the first time the FDA has granted approval based on a biomarker rather than a single tumor indication, Dr. Topalian said.
The activity in multiple cancer types with immunotherapy has been encouraging, but certain cancer types such as pancreatic and prostate cancers do not generally respond to these drugs—creating a dilemma that is at the cornerstone of ongoing research. “The few responses we have seen [in prostate and pancreatic cancers] are probably in the MSI-H tumors that we find at low frequency in those cancers. We have a lot of work to do there,” Dr. Topalian said.
In 2012 there was a promising lead on a biomarker that could help identify patients who would be more likely to respond to anti–PD-1, based on tumor biopsies conducted on 42 patients from Dr. Topalian and colleagues’ research. Those biopsies showed a clear correlation of response to anti–PD-1 if the pretreatment tumor was PD-L1 positive. Subsequent research with thousands of patients from many trials led to FDA approval of four different commercial tests for PD-L1 immunohistochemistry in certain cancer indications, such as NSCLC.
That is now an area of very active research—to find biomarkers that will be more highly predictive and that will be useful for many different cancer types,” Dr. Topalian said.
Another research question introduced by this therapy is the recognition that response is heterogeneous, and that there is clearly a subset of patients where the onset of meaningful antitumor effects is delayed in time. Biomarkers are needed that could help guide specific treatment decisions, such as how long therapy should be given if response is delayed.
Research is ongoing to develop a clinically available assay or molecular test to identify whether the patient is hardwired to even mount an antitumor response, Dr. Tykodi said. “There are very few complete responders with immunotherapy. Current understanding of either intrinsic or acquired resistance remains imperfect, driving the search for a biomarker that could help guide decisions about which patients can be expected to respond to immunotherapy and which ones will not benefit,” he said.
“Hopefully, as time goes on, there will be better insight and better clues about who is the optimal patient to treat. Without a viable biomarker, however, it remains unclear how to choose whether a patient should or should not be exposed to these drugs,” he said.
Controlling Adverse Events
Patients receiving PD-1 or PD-L1 antibodies often experience immune-related adverse events (irAEs), effects that are familiar to those associated with anti–CTLA-4 therapy. Although most of these adverse events are mild, some can be severe. The focus of intense research now is discovering how to separate irAEs from the antitumor responses with these drugs, Dr. Topalian said.
“Is there a way we can prevent or treat the side effects without dampening antitumor immunity? Right now we rely on steroids, the first line for treating these irAEs, but the question is whether we can do that in a more refined way,” Dr. Topalian said. “We need to know whether there are certain cytokines or other molecules that are driving the irAEs but that are not so important for antitumor immunity. We might be able to be more selective by blocking just those molecules without using blanket therapy such as steroids.”
Early diagnosis and management are key, as most irAEs can be managed if physicians remain alert and recognize them early, she said.
Biomarker research is being conducted in this area as well, with researchers trying to identify which patients may be at high risk for developing adverse events. “If we thought that a patient was particularly susceptible to a certain side effect, such as lung inflammation, would there be a marker we could use to monitor in that patient for that specific type of inflammation? That is all part of the vision now, and it’s a work in progress,” Dr. Topalian said.
Early-Stage Cancer Therapy
Although the initial work with anti–PD-1 and anti–PD-L1 therapy was successful for advanced disease, research is now testing these drugs for their impact on early-stage cancers. According to Dr. Topalian, results have been encouraging for patients with resectable NSCLC treated with anti–PD-1 prior to surgery (neoadjuvant therapy), and other studies have shown encouraging results in head and neck cancer.
Nivolumab was granted FDA approval4 for adjuvant treatment of melanoma in December 2017 based on results of a positive, randomized phase III study published in the New England Journal of Medicine,5 Dr. Tykodi said. “The PD-1 story has now thrown open the door for immunotherapy being front and center. Promising CAR T-cell data in leukemia and lymphoma are generating much enthusiasm that there will be new tools and techniques [available],” he said.
–Kathy Holliman, MEd