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TPS6090 Background: Evidence of efficacy and pathological response at the time of surgery was reported in two phase 2 studies (NCT02296684 and NCT02641093) of preoperative pembrolizumab in patients with high-risk, resectable, locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). The randomized, open-label, phase 3 KEYNOTE-689 trial ( NCT03765918) will evaluate efficacy and safety of pembrolizumab as neoadjuvant and adjuvant therapy in combination with SOC (radiotherapy ± cisplatin) in patients with previously untreated, resectable LA HNSCC. Methods: Patients with newly diagnosed LA HNSCC will be randomly assigned 1:1 to two treatment arms. Patients in arm A will receive neoadjuvant pembrolizumab (200 mg Q3W for two cycles) followed by surgical resection then SOC plus adjuvant pembrolizumab (15 cycles). Patients in arm B will undergo only surgical resection followed by adjuvant SOC. Eligibility criteria will include age ≥18 years; newly diagnosed, resectable, stage III/IVA HNSCC (AJCC Cancer Staging Manual, 8th edition); and ECOG performance status 0-1. Randomization will be stratified by primary tumor site (oropharynx/oral cavity vs larynx vs hypopharynx), tumor stage (III vs IVA), and HPV p16 status (oropharynx p16 positive vs oropharynx p16 negative or larynx/hypopharynx/oral cavity). Treatment will continue until disease progression, unacceptable toxicity, or decision to withdraw. Patients in arm A will undergo the first radiologic imaging assessment after two cycles of neoadjuvant pembrolizumab and before surgery. In both arms, postoperative imaging will be performed 12 weeks after SOC, then every 3 months until the end of year 3, and then every 6 months until the end of year 5. Dual primary end points are major pathological response, defined as ≤10% invasive squamous cell carcinoma within resected primary tumor and sampled regional lymph nodes per blinded central pathology, and event-free survival. Secondary end points include overall survival, pathological complete response, and safety and tolerability. Recruitment is ongoing and will continue until ~600 patients are enrolled. Clinical trial information: NCT03765918.

Background: Cabozantinib inhibits pathways involved in medullary thyroid cancer (MTC). Cabozantinib is approved as 140 mg/day in capsules for MTC and 60 mg/day in tablets for other solid tumors. This study compared the two doses in progressive metastatic MTC. Methods: In this Phase 4, randomized, double-blind noninferiority (NI) trial (NCT01896479), patients with progressive metastatic MTC were randomized 1:1 to cabozantinib 60 mg/day tablet or 140 mg/day capsules. The primary end point was progression-free survival (PFS) by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. NI would be concluded if the upper 95% confidence interval [CI] for the PFS hazard ratio (HR) was less than the NI margin, 1.58. The secondary end point was objective response rate (ORR) by BIRC per RECIST v1.1; additional end points included safety and pharmacokinetics. Results: At data cutoff (July 15, 2020), 247 patients were randomized to the 60 mg/day tablet arm ( n = 123) and the 140 mg/day capsules arm ( n = 124). NI was not met (median PFS 11.0 months vs. 13.9 months in the 60 and 140 mg/day arms [HR 1.24; CI 0.90–1.70; p = 0.19]). The ORR was 33% in both arms. Generally, adverse event (AE) incidence was lower in the 60 mg/day arm (Grade 3/4, 63% vs. 72%), as were dose reductions (69% vs. 81%) and treatment discontinuations due to AEs (23% vs. 36%). Initially, cabozantinib plasma concentrations were higher in the 140 mg/day arm but became similar between arms at later time points. Conclusions: PFS NI of the cabozantinib 60 mg/day tablet vs. 140 mg/day capsules was not met. The 60 mg/day tablet had the same ORR and lower rates of AEs. Clinical Trial Registry: NCT01896479.

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Background: In phase 2 studies (NCT02296684 and NCT02641093), neoadjuvant and adjuvant pembrolizumab demonstrated a pathological response (PR) and acceptable safety in patients with high-risk, resectable, LA HNSCC. KEYNOTE-689 (NCT03765918) is a randomized, open-label, phase 3 trial that will evaluate efficacy and safety of neoadjuvant pembrolizumab and adjuvant pembrolizumab in combination with SOC in patients with previously untreated LA HNSCC. Methods: Key eligibility criteria include histologically confirmed, newly diagnosed, resectable, nonmetastatic SCC (stage III oropharyngeal p16-positive disease [T4 (N0-N2), M0]; stage III/IVA oropharyngeal p16 negative; or stage III/IVA larynx or hypopharynx or oral cavity, independent of p16 status), evaluable tumor burden (measurable and/or nonmeasurable tumor lesions), newly obtained core or excisional biopsy, and ECOG performance status 0 or 1. Patients will be randomly assigned 1:1 to arms A and B. Randomization will be stratified by primary tumor site (oropharynx/oral cavity vs larynx vs hypopharynx), tumor stage (III vs IVA), and PD-L1 status defined by tumor proportion score 50% (TPS ≥50% vs TPS <50%). In arm A, patients will receive 200 mg Q3W neoadjuvant pembrolizumab for 2 cycles, followed by surgical resection, then 200 mg Q3W adjuvant pembrolizumab for 15 cycles in combination with SOC. In arm B, patients will undergo surgical resection followed by adjuvant SOC without pembrolizumab. SOC is radiotherapy alone (patients at low risk) or radiotherapy plus concurrent 100 mg/m2 Q3W cisplatin for 3 cycles (patients at high risk). Radiotherapy is standard fractionation at 2 Gy/fraction for 30, 33, or 35 fractions (60 Gy, 66 Gy, or 70 Gy) for patients at low risk or high risk or with gross residual disease, respectively. Treatment will continue until disease progression that is radiographically documented and verified by blinded independent central review, unacceptable toxicity, or investigator or patient decision to withdraw. Co-primary end points are major PR (≤10% invasive SCC within resected primary tumor and sampled regional lymph nodes per blinded central pathology) and event-free survival per RECIST 1.1 to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Secondary end points include overall survival, pathological complete response, health-related quality of life, and safety. All end points except safety will be evaluated in patients whose tumors express PD-L1 combined positive score ≥1 and in all patients regardless of tumor PD-L1 status. The first radiologic imaging in arm A will occur after 2 cycles of pembrolizumab and before surgery. Postoperative imaging will occur in both arms 12 weeks after SOC, then every 3 months until year 3 and every 6 months thereafter. Recruitment is ongoing; planned enrollment is ~704 patients. Citation Format: Nancy Y. Lee, Ravindra Uppaluri, William Westra, Ezra E. Cohen, Robert I. Haddad, Stephane Temam, Christophe Le Tourneau, Rebecca Chernock, Sufia Safina, Arkadiy Klochikhin, Amichay Meirovitz, Irene Brana, Joy Yang Ge, Ramona F. Swaby, Cecilia Pinheiro, Douglas Adkins. KEYNOTE-689: A phase 3 study of neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT285.