We have combinations with these agents in the front-line, second-line, and third-line settings, with chemotherapy, with other immunotherapies, and with small molecules. The field is really exploding.— Anas Younes, MD
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Immunotherapy has received “a lot of attention, mainly because of the media coverage,” Anas Younes, MD, medical oncologist and Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York, said in an interview with The ASCO Post. “Many patients inquire, not about a specific drug, but about immunotherapy in general—whether it would be suitable for them.”
The number of such inquiries to the Memorial Sloan Kettering Lymphoma Service has increased, Dr. Younes said, after a recent series of articles on immunotherapy in The New York Times detailing the experiences of patients with advanced cancer in whom other therapies had failed, but immunotherapy, at least initially, produced dramatic responses. Other media reports have contributed to the surge in interest in immunotherapy as well. “There has been a general awareness within the last year or so, even before the Times articles,” Dr. Younes said.
Success With Checkpoint Inhibitors
Patients described in The New York Times series had advanced cancers that no longer responded to treatment but had dramatic initial responses to checkpoint inhibitors such as nivolumab (Opdivo) and pembrolizumab (Keytruda). These checkpoint inhibitors target interaction between the PD-1 (programmed cell death protein 1) receptor on the surface of activated T cells and its ligands PD-L1 and PD-L2, which are expressed on tumor cells.
The first article of the series noted: “When checkpoint inhibitors work, they can really work, producing long remissions that start to look like cures and that persist even after treatment stops. Twenty [percent] to 40% of patients, sometimes more, have good responses. But for many patients, the drugs do not work at all. For others, they work for a while and then stop.”
Patients with Hodgkin lymphoma have the highest response rate among all types of cancers. In non-Hodgkin lymphoma, response rates depend on the type of lymphoma, Dr. Younes noted. “We have 60 different types of lymphoma, so it is difficult to lump together the response rates across different types. Although we do not have experience with checkpoint inhibitors in all lymphoma subtypes, in a few types where checkpoint inhibitors have been tested, such as relapsed follicular lymphoma and diffuse large B-cell lymphoma, the response rate is about 35% to 40%. In Hodgkin lymphoma, it is about 66%.”
In May 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval to nivolumab for the treatment of patients with classical Hodgkin lymphoma that has relapsed or progressed after treatment with autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin (Adcetris) posttransplant. Precipitating that approval was a study published in The New England Journal of Medicine, reporting objective responses to nivolumab in 20 (87%) of 23 patients with heavily pretreated relapsed or refractory Hodgkin lymphoma1 and a larger study led by Dr. Younes that found nivolumab produced objective responses in 53 (66%) of 80 patients with classical Hodgkin lymphoma whose disease progressed after autologous HSCT and brentuximab vedotin.2 Nivolumab had previously been approved for advanced renal cell carcinoma, metastatic melanoma, and non–small cell lung cancer (NSCLC).
In August 2016, the FDA granted accelerated approval to pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma who had disease progression on or after treatment with platinum-containing chemotherapy. Pembrolizumab had previously been approved for patients with unresectable or metastatic melanoma and NSCLC whose tumors express PD-LI.
Learning How to Use Immunotherapies
Nivolumab as a first-line treatment was not successful in slowing progression of NSCLC, according to a recent report.3 Asked if this result juxtaposed with the success of trials with previously treated patients with NSCLC meant that checkpoint inhibitors were limited to use as second- or later-line therapies, Dr. Younes replied: “I wouldn’t say that. You need to put the failed trial in front-line lung cancer in context and keep in mind that the pembrolizumab trial, also in front-line cancer, was a positive trial.”
Currently, four checkpoint inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer. The general indications are listed below, although there are additional considerations and restrictions outlined by the FDA:
According to a press release issued by Merck, its drug pembrolizumab “was superior compared to chemotherapy for both the primary endpoint of progression-free survival and the secondary endpoint of overall survival” in the KEYNOTE-024 trial among patients with previously untreated NSCLC whose tumors expressed high levels of PD-L1.4
“The difference between the nivolumab trial and the pembrolizumab trial is that the nivolumab trial included patients with as little as 5% expression of PD-L1, whereas the pembrolizumab trial was more biomarker-driven, restricting entry to patients with at least 50% PD-L1 expression,” Dr. Younes commented. “So we need to learn how to use these agents. They may not be useful for all patients. In certain situations, they may work only for subsets of patients, based on the level of expression of the PD-L1 or PD-L2 proteins on tumor cells.”
Inquiries About CAR T Cells
“Patients ask not just for checkpoint inhibitors, ” Dr. Younes stated. “They also inquire about CAR T cells.” This form of therapy is based on genetically reprogramming the patient’s own immune T cells to express a chimeric antigen receptor (CAR). By doing so, we artificially redirect the immune cells to the sites of cancer cells and attack them. An expanded population of the reprogrammed CAR T cells is infused into the patient and then multiplies in vivo; these cells recognize and kill cancer cells that harbor the antigen on their surfaces.
CAR T-cell therapy is not yet approved, but patients want to know if they qualify for clinical trials. “There are multiple clinical trials including CAR T cells as a single modality and in combination with other treatments,” Dr. Younes noted.
CAR T-cell therapies have produced high response rates for patients with leukemia—up to 90% for acute lymphoblastic leukemia. On average, for relapsed diffuse large B-cell lymphoma, “CAR T cells produce about a 40% to 60% response rate,” according to Dr. Younes.
A criticism of CAR T-cell therapy is that it is not being used for more common malignancies such as breast, colon, lung, and prostate cancers. “It is an emerging field,” Dr. Younes commented. “Trials are looking at different types of solid tumors, building on the success of immunotherapy and checkpoint inhibitors in typically immune-unresponsive diseases, like lung cancer. Nobody expected that lung cancer would respond to immunotherapy.”
Patients with classical Hodgkin lymphoma represented “an obvious patient population” in which to test nivolumab, Dr. Younes said. The disease is characterized by Reed-Sternberg cells with genetic alterations resulting in overexpression of PD-1 ligands. “More than 90% of the patients would have high levels of PD-L1 on Reed-Sternberg cells. So you don’t need a selection biomarker for Hodgkin lymphoma,” Dr. Younes explained.
Classical Hodgkin lymphoma also has a “unique pathology,” Dr. Younes remarked. “Only about 5% of the tumor mass contains cancer cells, and 95% are immune-reactive cells—T cells and other immune cells—that are waiting to be activated. Together, the unusual pathology and high level of PD-L1 creates a “perfect storm” for immunotherapy, such as PD-1 inhibitors, to work.
The multinational phase II study led by Dr. Younes addressed an unmet medical need. No other current treatment existed for patients with classical Hodgkin lymphoma who have disease progression after both autologous stem cell transplantation and treatment with brentuximab vedotin, “which, up until recently, was the only FDA-approved drug for relapsed Hodgkin lymphoma,” Dr. Younes noted. Identifying a treatment that would produce deep and long-lasting responses is important for these patients, who are often young and otherwise healthy.
The 80 patients in the study received nivolumab intravenously over 60 minutes at 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxicity, or withdrawal from the study. “Some trials capped it at up to 2 years,” Dr. Younes said. “Our trial was not capped, so patients may stay on treatment for more than 2 years.”
At a median follow-up of 8.9 months, 53 of 80 patients had achieved an objective response and 33 of those were ongoing, including 16 of the 22 patients with a complete response. The median duration of response was 9.1 months. “Updated results that will be presented at the American Society of Hematology meeting in December will show that these remissions are of longer duration,” Dr. Younes told The ASCO Post.
Safety and Selection Criteria
Adverse events with nivolumab were as expected, with the two most common being fatigue and infusion-related reactions. “The Hodgkin trial came late in the game,” Dr. Younes said. “Thousands of patients have been treated with nivolumab for different cancers, and the toxicity in Hodgkin lymphoma is no different from anything that has been reported for lung cancer and melanoma. So there is collective experience about how safe this agent is.”
Dr. Younes noted that in rare cases, immunotherapy agents “can overactivate the immune response, inducing autoimmune reactions that might occur in the lungs, kidneys, or gastrointestinal tract. Most of the time, discontinuation is related to this rare effect.” In the Hodgkin lymphoma trial, four patients discontinued treatment due to toxicity. Three patients died while on the study, but none of the deaths were considered treatment-related.
At the time of analysis, 36% of the patients had discontinued treatment with nivolumab, mostly due to disease progression. These patients had PD-L1 expression levels in the first quartile vs in the third or fourth quartile for patients who achieved a complete remission.
Asked if the PD-L1 expression could be used to predict who might benefit most from nivolumab, Dr. Younes responded, “No, not yet. This is a retrospective analysis. It is observational. I don’t know if this is going to be a selection criterion, especially given that PD-L1 is expressed in almost all patients. Future studies should not aim at who to exclude, but rather, at identifying patients who may benefit from combination regimens.”
The FDA’s accelerated approval of nivolumab for patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous HSCT carried a warning about complications of allogeneic HSCT after nivolumab. “Transplant-related deaths have occurred, and health-care professionals should follow patients closely for early evidence of transplant-related complications, such as severe graft-vs-host disease (GVHD), and other immune-mediated adverse reactions. The FDA has required the manufacturer to further study the safety of allogeneic HSCT after nivolumab.”5
Dr. Younes explained that “early on in the phase I trials, the trend was that if you had patients in whom autologous transplant and brentuximab vedotin failed—many of them were actually refractory to brentuximab vedotin—and they have treatment that induced remission, the knee-jerk reaction was then to offer them allogeneic transplant. We didn’t know how durable these remissions would be, and the only potentially curative modality was allogeneic transplant, although this strategy is also associated with a lot of side effects and toxicity.”
He continued: “At least in the initial experience with the few patients who were offered allogeneic transplant immediately after checkpoint inhibitors, an exaggeration of GVHD was seen, which is not surprising. That is how the drug works. The antibody stays in the blood for a while before it is completely washed out. So the infused donor T lymphocytes get hyperactivated and may induce a severe GVHD reaction, which was fatal in some cases.”
Urging caution, he noted, “What most clinicians do now is delay the allogeneic transplant until most of the drug is cleared. You don’t do it right away. You can space it out for a couple of months before you proceed to allogeneic transplant, as a precaution.”
“There are emerging lines of new biospecific antibodies that also have potential. Combination trials of one or more of these immunotherapy modalities (checkpoint inhibitors, CAR T cells, and bispecific antibodies) are also exciting,” Dr. Younes reported. “We have combinations with these agents in the front-line, second-line, and third-line settings, with chemotherapy, with other immunotherapies, and with small molecules. The field is really exploding.”
Many of these trials are being conducted at Memorial Sloan Kettering, including one combining nivolumab and brentuximab vedotin for either Hodgkin or non-Hodgkin lymphomas. “It is logical to combine these highly active drugs in patients with relapsed Hodgkin lymphoma. Brentuximab gives about a 75% response rate; nivolumab, 66%. So it is a no-brainer to combine them and see what happens,” Dr. Younes said. “In another trial, we are combining checkpoint inhibitors in the front-line setting with traditional chemotherapy for both follicular lymphoma and diffuse large B-cell lymphoma,” he added.
“We are also seeing preclinical development of oral agents aimed at interrupting the interaction between PD-1 and PD-L1. If those small-molecule inhibitors produce responses similar to those achieved by antibodies targeting PD-1 or PD-L1, they could simplify the chronic administration of these agents, as they can be given by oral administration.” ■
Disclosure: Dr. Younes has received honoraria from Takeda, Bristol-Myers Squibb, Merck, and Roche.
2. Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. July 20, 2016 (early release online).
4. Merck’s Keytruda (pembrolizumab) demonstrates superior progression-free and overall survival compared to chemotherapy as first-line treatment in patients with advanced non-small cell lung cancer. Merck press release, June 16, 2016.
5. U.S. Food and Drug Administration: Nivolumab (Opdivo) for Hodgkin lymphoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.htm. Accessed May 26, 2016.
When patients who are likely to be cured with chemotherapy request immunotherapy, it is part of the educational responsibility of physicians to advise these patients that immunotherapy is not the most suitable treatment for them.— Anas Younes, MD
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