“This is a big deal. This is going to change all of oncology, not just head and neck cancer,”1 Tanguy Seiwert, MD, remarked following a summary by Jeffrey Sosman, MD, on advances in immunotherapy for treating cancer.2 Dr. Sosman, Director of the Melanoma Program and Clinical Director of Cancer Immunotherapy at Robert H. Lurie Cancer Center of Northwestern University, Chicago, and Dr. Seiwert, Associate Program Director, Head and Neck Cancer Program, University of Chicago, were among the speakers at the opening Keynote Session of the 2016 Lurie Cancer Center Multidisciplinary Head & Neck Symposium.
“The fourth modality has arrived,” added Robert Ferris, MD, PhD, Associate Director for Translational Research; Co-Leader, Cancer Immunology Program; and Chief of Head and Neck Surgery, University of Pittsburgh Medical Center.3 This is a “modality that treats a different part of the patient” than surgery, radiation therapy, and chemotherapy, he declared. The promise of immunotherapy is that “the immune system can give us durability.” Not yet fully understood, he added, is “how to integrate this into the challenges that face us every day for most patients who present with locally advanced disease” and how to use clinical trial results and approval by the U.S. Food and Drug Administration (FDA) of programmed cell death protein 1 (PD-1) antibodies either “to begin targeted de-intensified therapy or enhance add-on therapy for improved survival.”
Recognizing the continuing advances in immunotherapy, ASCO recently named immunotherapy as its Advance of the Year for a second year in a row. “In less than a decade, immunotherapy has gone from being considered a promising theoretical treatment to one that has become a standard of care that is helping extend or improve the lives of thousands of patients,” said ASCO President Daniel F. Hayes, MD, FACP, FASCO, in an ASCO statement.4 The statement noted that immune checkpoint inhibitors have shown “the biggest successes so far.”
Cancer Immunity Cycle
Each of the steps in the cancer immunity cycle “is critical,” Dr. Sosman explained, from release of cancer antigens to priming and activation of T cells, infiltrating the tumor, recognizing the cancer antigens expressed, and killing the cancer. “Probably the biggest breakthrough,” he noted, “was the idea that there is a group of molecules, receptors on T lymphocytes, that actually inhibit the immune response. And there is another group of molecules that actually is activating. By manipulating these two sets of molecules, you can block inhibition and activate those centers with the correct agonistic antibodies.”
Adding chemotherapy for locally advanced therapy has not shown us a good reduction in distant metastatic disease, and that is where immunotherapy could give us the most benefit for our patients.— Robert Ferris, MD, PhD
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The first example of employing this approach came with the recognition that cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) is an inhibitory receptor that “turns off” the T cell at the site of the tumor, revealed Dr. Sosman. The use of ipilimumab (Yervoy), an anti–CTLA-4 antibody, blocks that inhibition. “It actually releases the T cell, as well as doing some other things to be able to fully attack the tumor cell,” he explained. With time, it has been shown that using ipilimumab has resulted in “clearly an improved survival that is durable,” Dr. Sosman added.
“The other major breakthrough,” he continued, “has been the recognition of a second set of receptor ligands—PD-1/programmed cell death ligand 1 (PD-L1). When they interact, usually it is at a time after the T cell has already been activated. The activated T cell migrates to the site of the tumor, and the interaction between PD-1 and PD-L1 ‘turns off’ the T cell; even more than that, it actually inhibits and can kill the T cell.” Nivolumab (Opdivo), an anti–PD-1 agent, has produced “response rates of somewhere between 30% and 45%” in melanoma, Dr. Sosman reported, “which are far greater than the 5% to 15% response we saw with anti–CTLA-4,” and the responses were durable.
Using a combination of anti–CTLA-4 and anti–PD-1 has had a “fairly amazing synergistic effect” in patients with melanoma, he revealed, producing response rates of almost 60% and “far superior” progression-free survival rates.
Search for Biomarkers Continues
“We now have a number of diseases where anti–PD-1 and anti–PD-L1 is active,” Dr. Sosman continued. In addition to head and neck cancer, they include melanoma, renal cancer, non–small cell lung cancer, bladder cancer, Merkel cell tumors, Hodgkin lymphoma, and colon cancers with mismatch repair defects, among others.
However, PD-1/PD-L1 antagonists have shown minimal to no activity in prostate cancer, myeloma, and pancreatic cancer. Until recently, mismatch repair–nondeficient colon cancers were also included in that list, but lately “we did see responses,” noted Dr. Sosman. “With the addition of a MEK inhibitor, PD-1 inhibition might very well be active.”
The search for biomarkers continues. “The hope initially was that the expression of PD-L1 itself on the cancer cell would be a sufficient marker,” Dr. Sosman said, but “that has not held up. Without question, those who express high levels of PD-L1 are more likely to respond, but tumors that don’t express PD-L1 are certainly still able to respond and be effectively killed.”
Probably what has received “the most notoriety,” according to Dr. Sosman, “is the relationship between the tumor mutation burden and mutations that are not driver but rather random mutations”; some tumors “with the highest mutation rate are those that respond better. Those data hold up in melanoma, lung cancer, bladder cancer, and even mismatch repair colon cancer, where clearly the mutation burden is much higher.” Moving forward, he said, the “emphasis is on how to put data together to select patients to benefit most from treatment.”
“The power of immunotherapy” can be demonstrated by the “exceptional responder,” Dr. Seiwert said. He presented the example of a patient with advanced head and neck cancer who already had “two rounds of radiation, a powerful line of chemotherapy, and extensive surgery.” His referring physicians said they had “nothing else to offer him” but hospice. The patient still had a good performance status, however, and was entered into a trial with pembrolizumab (Keytruda), at the University of Chicago.
“Within 2 weeks, many of the lesions were gone. Within 6 weeks, this patient whose tumor was resistant to radiation, chemotherapy, and cetuximab (Erbitux), for whom surgery was not an option, had a complete response,” Dr. Seiwert reported. “After 6 months of treatment, with months of complete response, we stopped the treatment,” Dr. Seiwert revealed. “Immunotherapy has the potential to truly eradicate tumors. This patient did not have a recurrence, and we continue to follow him. So I think there is something very special about immunotherapy. It is a new entity and has some powerful features. Unfortunately, not everyone responds like this.”
‘Survival Was Stunning’
Pembrolizumab was approved by the FDA in August 2016 for patients with recurrent or metastatic head and neck squamous cell carcinoma that has continued to progress despite standard-of-care treatment with chemotherapy.”5 The approval was based on early data from the KEYNOTE-012 study6 among patients with recurrent or metastatic squamous cell carcinoma of head and neck cancer. With pembrolizumab, “50% experienced a decrease in target lesions,” Dr. Seiwert reported. “The response rate was only about 18% to 20%, but what is interesting is the durability of some of these responses”; in some cases, it exceeded 60 weeks among both human papillomavirus (HPV)-positive and HPV-negative patients. “This was a major step forward,” Dr. Seiwert announced.
Likewise, in the phase III CheckMate 141 study,7 “the response rate wasn’t that great, but survival was stunning,” according to Dr. Seiwert. The efficacy and safety of nivolumab vs investigator’s choice were evaluated in a similar patient population. “At 1 year, more than twice as many patients are alive. So while not everybody benefits, for some patients, their lives are truly changed,” he noted. Led by Dr. Ferris and Dr. Maura Gillison, the CheckMate 141 study reported 1-year survival estimates of 36% for patients receiving nivolumab vs 16.6% for patients receiving standard therapy.
Few Side Effects
Immunotherapy can offer a better alternative to salvage therapy, which can be “very morbid treatment,” according to Dr. Seiwert, and often offer only short-term survival. “We need better treatments, less toxic treatments. We have a large unmet need there.”
PD-1 blockade agents are “very well tolerated” with “few side effects,” Dr. Seiwert stated, although “most patients have a little bit of a rash. The one thing to watch for is the risk of inflammation of the lungs, which is rare (about 1% to 2%) but requires treatment. Another uncommon event, estimated to occur in 5% to 10% of patients treated with immune checkpoint inhibitors, is pseudoprogression.
“The future [of immunotherapy] is very bright,” Dr. Seiwert said. “There are almost limitless opportunities. We need to prioritize them, because it is a new modality that needs to integrated with all of our other modalities.” Combining anti–PD-1 and anti–CTLA-4 agents has been approved for melanoma, he said, and “it looks promising in lung cancer, almost doubling the response rate. Our ongoing, first-line KESTREL study, which uses a combination of CTLA-4 agent and a PD-L1 agent, is currently open to patients with recurrent/metastatic squamous cell carcinoma of the head and neck,” Dr. Seiwert added.
In the preliminary OPTIMA study, patients with HPV-positive locally advanced head and neck cancer receive induction chemotherapy followed by nivolumab. Depending on the tumor response, radiation may be reduced by 40%, and chemotherapy may be eliminated for some patients. “So far,” revealed Dr. Seiwert, “we haven’t seen any failures, although we are giving 30% to 40% less treatment. The next study, which is called OPTIMA 2, will integrate immunotherapy at the initial stage and probably feature neoadjuvant surgery in one of the arms.”
Partnering With Other Therapies
“Radiation therapy is a great partner” for PD-1 checkpoint inhibitors, according to Dr. Ferris. “Not only is PD-L1 present at baseline, but radiating the tumor upregulates PD-L1 within 24 to 48 hours.” An animal model “shows that by adding anti–PD-1 on top of radiotherapy, the mouse survives better, and the tumor is cured and rejected,” Dr. Ferris reported.
“Radiation is not the only therapy” to partner with, he noted. There is also cetuximab (Erbitux). In a study designed to look at immune effects in patients with locally advanced head and neck cancer in the preoperative setting, four rounds of cetuximab were given. Tumor-infiltrating lymphocytes were collected before and after, and computed tomography scans and positron-emission tomography correlated. “About one-third of the patients had a clinical response, and the other two-thirds were not responders,” Dr. Ferris reported. “So we began looking at locally advanced disease as the next frontier.”
Collecting tumor sample before surgery “allowed us to look for biomarkers after therapy, instead of baseline tissue. I think that is key for pushing the biomarker field forward,” he added.
The study found “that regulatory T cells, immunosuppressive T cells, are upregulated in the nonresponders who received cetuximab,” Dr. Ferris said. These patients expressed CTLA-4. “But CTLA-4–positive regulatory T cells were upregulated in locally advanced patients receiving cetuximab. So if we could add an anti–CTLA-4 antibody with cetuximab, it made sense that we would suppress those regulatory T cells and then potentially convert the nonresponders to responders, who did not have an upregulation of that suppressant T-cell population.”
A phase Ib clinical trial among patients with intermediate/high-risk locally advanced head and neck cancer combined cetuximab/radiation therapy (an FDA-approved regimen) plus ipilimumab, “eliminating chemotherapy from the regimen altogether,” Dr. Ferris stated. “We had to reduce the dose of ipilimumab from the original starting dose of 3 mg/kg down to 1 mg/kg, based on some impressive autoimmune rashes.” But the results showed that these patients treated with two antibodies and radiation “can actually do quite well.”
Backbone of Chemoradiation
There are now multiple planned studies of locally advanced disease using chemoradiation as the backbone. “It turns out that chemotherapy or radiation stimulates PD-L1 expression, so it made sense to come in with an add-on, anti–PD-1, to prevent the suppressive signals to those tumor-infiltrating lymphocytes, which we know are expressing PD-1 in the microenvironment,” explained Dr. Seiwert. The add-on checkpoint inhibitors being tested are avelumab, nivolumab, pembrolizumab, and “possibly more,” Dr. Ferris added. There are also “at least three phase III trials for locally advanced head and neck, which is really exciting.”
Dr. Ferris is running the UPCI 15-132 trial with colleague Dr. Julie Bauman looking at sequential vs concomitant pembrolizumab plus chemoradiation in patients with stage III–IVb intermediate or high-risk head and neck cancer. “We built in an on-treatment biopsy, days 8 to 10 in the second week of radiotherapy, so we can get an idea of what’s happening in the microenvironment,” Dr. Ferris explained. It is a “relatively small trial, 44 patients,” he added, “and we are trying to accrue patients rapidly.”
‘Wonderful Antigen to Target’
“We shouldn’t forget that HPV gives us a wonderful antigen to target,” Dr. Ferris said. “A way to intensify therapy would be to target the virus and expand the virus-specific T cells. An investigator-sponsored trial will combine definitive chemoradiation, an HPV vaccine, and pembrolizumab. This is “a relatively complicated regimen,” he acknowledged, but with on-treatment biopsies, he hopes to understand whether they are expanding the specific T cells and whether “anti–PD-1 helps to synergize and let those cells be more active.”
The HN-003 trial is a phase I and expansion-cohort study among “surgically resected patients getting chemoradiation for positive margins or extranodal extension and asking whether adding anti–PD-1 in the adjuvant stage, in the resected setting, can improve survival for primarily an oral cavity HPV-negative group of patients who have had no increases in outcome,” Dr. Ferris explained. Patients will receive pembrolizumab every 3 weeks, for a total of 8 doses.
“We now know we can improve survival with two different anti–PD-1 antibodies that are FDA-approved: nivolumab and pembrolizumab. We don’t know exactly the sequencing, so we have to run trials that have different regimens with anti–PD-1 therapy,” he said. “Adding chemotherapy for locally advanced therapy has not shown us a good reduction in distant metastatic disease, and that is where immunotherapy could give us the most benefit for our patients.” In addition, immunotherapy has opened up a new area of investigation for radiation oncologists, who “potentially can use immunotherapy to avoid contralateral neck irradiation as well as reduce the field size, the doses, and the fractionation.” ■
Disclosure: Dr. Seiwert has served as an advisor to Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Innate, Jounce, Lilly, Merck/MSD, and Merck Serono. Dr. Ferris has served as an advisor to Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, Lilly, Pfizer, and Merck; and has received research funding from AstraZeneca/MedImmune, Bristol-Myers Squibb, and VentiRx. Dr. Sosman is on the advisory board (with honorarium) of Novartis, Array, Genentech, and Bristol-Myers Squibb. Dr. Hayes reported no potential conflicts of interest.
4. ASCO Connection: ASCO Names Immunotherapy 2.0 as Cancer Advance of the Year in Latest Clinical Cancer Advances Report. February 1, 2017. Available at https://connection.asco.org/magazine/society-member-news/asco-names-immunotherapy-20-cancer-advance-year-latest-clinical-cancer. Accessed February 22, 2017.
5. National Cancer Institute: FDA Approves Pembrolizumab for Head and Neck Cancer. August 24, 2016. Available at www.cancer.gov/news-events. Accessed February 22, 2017.
6. Seiwert TY, Burtness B, Mehra R, et al: Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial. Lancet Oncol 17:956-965, 2016.