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Neoadjuvant immunotherapy may benefit some patients with oropharynx cancer
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CHICAGO — Neoadjuvant durvalumab alone or with tremelimumab appeared well-tolerated, with a treatment effect observed in 79% of patients with oropharynx squamous cell carcinoma, according to study results presented at ASCO Annual Meeting.
However, the monotherapy and the combination showed equivalent efficacy, suggesting the addition of tremelimumab (MedImmune/AstraZeneca), a CTLA-4 inhibitor, to durvalumab (Imfinzi, AstraZeneca), a PD-L1 inhibitor, does not confer additional benefit beyond durvalumab alone.
“Locoregionally advanced oropharyngeal squamous cell carcinoma represents dual challenges to conventional treatment,” Renata Ferrarotto, MD, associate professor in the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, said during her presentation. “There are the tobacco-related cancers, which have worse outcomes. And then there are the HPV-related cancers, which have very good survival. However, 35% suffer long-term because of treatment.
“Window-of-opportunity trials in which treatment is given in the neoadjuvant setting can address both problems,” she added. “It can be used as a therapeutic-intensification strategy for poor-prognosis patients, but it can also be used as a bridge to treatment de-intensification for the good-prognosis patients.”
Ferrarotto and colleagues conducted a window-of-opportunity trial to assess the combination of durvalumab and tremelimumab in 28 patients (median age, 64 years; 96% men) with oropharynx cancer.
“The antiPD-L1 antibody durvalumab has shown activity in metastatic oropharynx squamous cell carcinoma and has an attractive toxicity profile,” Ferrarotto told HemOnc Today. “Tremelimumab targets CTLA4, another inhibitory immune checkpoint. Targeting PDL1 and CTLA4 may have additive or synergistic effects, as the mechanisms of action are nonredundant. This combination has shown higher response rates than single-agent therapy in other solid tumors such as melanoma, renal cell carcinoma, nonsmall cell lung cancer and microsatellite instability-high colorectal cancer.”
Most of the patients were newly diagnosed (68%) and had stage IVA disease (63%) per American Joint Committee on Cancer 7th edition criteria.
Thirty-two percent of patients had locoregional recurrence, 86% were p16 positive, and 79% had fewer than 10 pack-years of smoking history.
Researchers assigned the patients 1:1 to receive 1,500 mg durvalumab alone or with 75 mg IV tremelimumab every 4 weeks for two cycles.
Quantification of pre- and posttreatment differences in CD8-positive tumor-infiltrating lymphocytes in both arms served as the study’s primary endpoint.
“Our assumption was that the posttreatment-pretreatment CD8-positive tumor-infiltrating lymphocyte ratio would be 2 for durvalumab and 2.5 for durvalumab plus tremelimumab, which led to our sample size of 14 patients per arm,” Ferrarotto said during her presentation.
Secondary endpoints included safety, toxicity, overall response rate by RECIST criteria, proportion of patients who underwent surgery at 8 weeks, and percentage of viable tumor cells in the postsurgical specimen.
After median follow-up of 10.5 months (range, 2.5-21), no patients recurred, and all patients remained alive.
Researchers reported a 43% ORR, which was identical between the two arms. Fifty percent of patients demonstrated stable disease, including one patient who showed 29% tumor shrinkage.
Only two patients progressed during treatment. These two patients, along with a third who had stable disease, were switched to treatment with chemotherapy and, therefore, were excluded from the pathologic response and primary response assessments.
Of 25 patients eligible for response in their primary tumor, two patients had a pathologic compete response, and another 11 had a partial pathologic response. Of 19 patients evaluable for node response, eight had a major pathologic response in the node, defined as less than 10% viable tumor cells. Thus, 32% of patients achieved major pathologic response in the primary site or nodal metastases.
Further, 19 of 24 eligible patients (79%) showed an effect of treatment in their surgical specimen.
Researchers observed a significant association between ORR and treatment effect (P = .014). Patients who achieved a partial response had a smaller percentage of viable tumor in the primary site than patients with stable disease (37.5% vs. 82.5%; P = .003).
However, overall, researchers observed similar efficacy between the treatment arms, with equivalent infiltration of CD8-positive tumor-infiltrating lymphocytes. But, patients with major pathologic response in the primary or node had a significantly higher CD8-positive tumor-infiltrating lymphocytes ratio compared with those who did not respond (3.5 vs. 0.9; P = .04).
“We used tremelimumab 75 mg — a dose equivalent to 1 mg/kg — every 4 weeks, and at least at this dose level, efficacy was identical in both arms,” Ferrarotto told HemOnc Today. “Although toxicity was not statistically significantly higher with the twodrug regimen, durvalumab plus tremelimumab did not improve patient outcomes nor did it lead to a higher infiltration of CD8-positive cells into the tumor. Therefore, our data do not support the durvalumab-tremelimumab combination for the population studied.”
Most adverse events were grade 1 and were equally distributed between the arms, Ferrarotto said during her presentation.
The most common adverse events included fatigue (36%), leukopenia/lymphopenia (25%), transaminitis (25%) and rash (21%). Four patients (14%) experienced grade 3 adverse events — all of which were manageable — including elevated lipase, diarrhea and hepatitis.
Mean average quality-of-life scores using the MDASI-HN 28 item multi-symptom inventory were low at baseline and throughout treatment, and they were not different between the two arms, Ferrarotto said.
Researchers are conducting correlative analyses looking at potential biomarkers in pre- and posttreatment blood and tumor specimens, which Ferrarotto expects to be informative, she said. These studies and others should help to clarify the group of patients most likely to benefit from neoadjuvant immunotherapy.
“Neoadjuvant immunotherapy in oropharynx squamous cell carcinoma can be used to escalate care in the tobaccorelated, poor-prognosis patients and can also be used as a bridge to treatment deintensification in the HPVrelated, good-prognosis patients,” she told HemOnc Today. “Therefore, future studies investigating immunotherapy in the neoadjuvant setting in biomarkerselected patients are warranted.” – by Alexandra Todak
Reference:
Ferrarotto R, et al. Abstract 6008. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Ferrarotto reports consultant/advisory roles with Ayala Pharmaceuticals, Cellestia Biotech, ER Squibb & Sons and Sanofi/Regeneron; and research funding to her institution from AstraZeneca/MedImmune, EMD Serono, G1 Therapeutics, Genentech/Roche, Merck Serono and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.