Two doses of nivolumab given about 1 month prior to surgery are well tolerated and reduces tumor size in about half of patients with squamous cell carcinoma of the head and neck.
Robert L. Ferris, MD, PhD
Two doses of nivolumab given about 1 month prior to surgery are well tolerated and reduces tumor size in about half of patients with squamous cell carcinoma of the head and neck (SCCHN). Reductions in tumor size occurred in the same proportion of patients with human papilloma virus (HPV)-positive and HPV-negative tumors, according to results from the first global trial of neoadjuvant anti—PD-1 therapy in patients with both HPV-positive and HPV-negative SCCHN.1 There were no surgery delays >4 weeks due to treatment-emergent adverse events.
Findings from the open-label CheckMate-358 study were reported by Robert L. Ferris, MD, PhD, at the 2017 ESMO Congress in Madrid.
“I would point out that the benefit of the neoadjuvant [nivolumab] is very different for HPV-positive patients, where we might want to de-escalate, as opposed to HPV-negative patients who’ve seen no benefit in survival for decades,” said Ferris, chief, Division of Head and Neck Surgery, Departments of Otolaryngology, Radiation Oncology, and Immunology, University of Pittsburgh Medical Center Hillman Cancer Center. The findings suggest a “new modality preoperatively [that is] less focused on reducing the surgical extent, since our current modalities have had no benefit for this group of patients,” Ferris said.
SCCHN expresses PD-L1 and infiltrating lymphocytes express the PD-1 receptor. In a phase III trial of patients with platinum-refractory recurrent or metastatic SCCHN, the PD-1 inhibitor nivolumab improved overall survival.2 In the presurgical (adjuvant) setting, immune checkpoint inhibition “may enhance systemic immunity to prevent tumor recurrence and metastasis,” said Ferris. Nivolumab has already demonstrated safety in the neoadjuvant setting in patients with non—small cell lung cancer, he said.
CheckMate-358 is an ongoing global, multicenter study investigating the safety and efficacy of nivolumab monotherapy or combination therapy in virus-associated cancers. The neoadjuvant SCCHN cohort consisted of patients with newly diagnosed cancer of the oral cavity, pharynx, or larynx with T1 or greater primary lesions and N1 or greater nodal disease. Patients were not selected for tumor PD-L1 expression. Nivolumab, 240 mg, was given intravenously on days 1 and 15, with surgery on day 29. Tumors were assessed by computed tomography at baseline, prior to surgery, and during follow-up.
Twenty-nine patients were evaluable for safety (12 who had HPV-positive tumors and 17 who had HPV-negative tumors) and 23 for efficacy (10 HPV-positive and 13 HPV-negative). All patients received both planned doses of nivolumab. Median follow-up was 21.8 weeks and 11.6 weeks for patients with HPV-positive and HPV-negative tumors, respectively.
About two thirds of patients’ tumors had PD-L1 expression ≥1%, with a nearly equal percentage in the patients with HPV-positive and HPV-negative tumors.
Treatment-related adverse events of any grade occurred in 75% of patients with HPV-positive tumors and 58.8% of those with HPV-negative tumors. Grade 3-4 treatment-related adverse events occurred in 16.7% and 11.8% of the 2 groups, respectively. No new safety signals were identified.
As of the database lock (February 2017), a presurgery reduction in tumor burden as assessed by investigator. An exploratory endpoint was observed in 11 of the 23 (48%) evaluable patients: 5 of the 10 (50%) with HPV-positive and 6 of the 13 (46.2%) with HPV-negative tumors. Three patients had tumor reductions ≥40%. The largest reduction after the 2 doses of nivolumab was 75% in a patient with an HPV-positive tumor.
One patient with an HPV-negative tumor had hyperprogression. “We occasionally see that in a 1-month preoperative period, particularly with some aggressive oral cancers,” said Ferris. “I think it’s a lesson for enrollment in neoadjuvant trials…sometimes the surgeon expects and the patient expects that every tumor will shrink and that we will be able to change the surgical plan. Sometimes the surgeon will select a borderline resectable patient, who may have not been a surgical candidate, in the hopes that the month of nivolumab or some other preoperative therapy will make them surgically resectable. It’s cautionary for neoadjuvant trials to make sure that we put clearly resectable patients in the trial and not ones who have very large tumors. This may occur in a multicenter study like this.”
Nonetheless, he said, the 1 case of hyperprogression was offset by the 40% to 50% of patients who experienced tumor shrinkage. “It’s really the long-term benefit of the potential immune priming that I think we’re relying on, not so much the expectation that we can change the surgical procedure in such an exploratory study,” Ferris said.