A Phase II randomized trial of neoadjuvant Carboplatin, Paclitaxel, low dose Nivolumab and metronomic therapy compared to standard chemotherapy in technically unresectable oral cavity squamous cancer

Background: Oral cavity squamous cell carcinoma (OCSCC) is the one of the most common cancers in India, with 77000 new cases per year. The primary curative treatment is surgery followed by adjuvant radiotherapy. However, only 22% of OCSCC in India are suitable for upfront curative intent surgery, and the feasibility of obtaining negative margins decreases with tumor size. A proportion of these inoperable tumours can be ‘converted’ to operable ones, with resultant improvement in survival (mOS 8.1 to 19.6 months, P<0.001). The current induction regimens use docetaxel +Cisplatin+ 5FU/capecitabine (TPF/X) or docetaxel + Cisplatin (TP) or Carboplatin + Paclitaxel, with the resultant downstaging noted to be better with three-drug rather than two-drug regimens (60% vs 40%). However, this comes at the cost of higher toxicity which has limited widespread use of three-drug regimens. Oral Metronomic therapy (OMT) has long been used as a palliative treatment strategy in the metastatic setting and has comparable efficacy with less toxicity in the second line setting. The combination of OMT with low dose nivolumab demonstrated safety and efficacy in first line metastatic disease. Their established efficacy and safety in the metastatic setting suggests that they may be viable options in the non-metastatic setting. Our retrospective analysis of 79 OCSCC cases using TP plus LD Nivolumab revealed a conversion rate of 31.6%, with low toxicity (febrile neutropenia rates of 1%). Others have shown that the combination of carboplatin, paclitaxel and OMT was associated with further improvement in the resection rate to 65%, with lower toxicity than TPF. Our ongoing single-arm study combining Carboplatin + Paclitaxel with OMT and LD Nivolumab [quadruple chemoimmunotherapy] is actively recruiting and is showing a conversion rate of 71% with low toxicity (one grade 3 anemia and immune related polyarthritis respectively).

 Hypothesis: We hypothesize that the administration of quadruple chemo-immunotherapy with carboplatin+paclitaxel+OMT+LDNivolumab, will result in increased conversion to operability, from 40% to 65%, without significantly increased toxicity. This will in-turn lead to improvement in survival compared to standard chemotherapy (TP/TPF/TPX) among patients with technically unresectable Stage III-IVA OCSCC.

 Methods: Prospective, open-label, randomized trial of adults with T3,T4a technically unresectable  OCSCC, planned for neoadjuvant chemotherapy followed by surgery reassessment. Consenting patients will be randomized into experimental (carboplatin+paclitaxel+OMT+LDNivolumab) or standard (TP/TPF/TPX) neo-adjuvant treatment. Treatments will be administered every three weeks upto a maximum of 12 weeks- with reassessment for surgery done from week 6-12. Operable patients in either arm will undergo surgery followed by adjuvant RT as per standard of care. Inoperable patients will undergo palliative RT. Patients will be evaluated every three months for the first two years and every six months thereafter. The primary outcome is rate of margin negative ( R0) resection obtained after neoadjuvant therapy in either arm. Secondary outcomes are toxicity and event-free survival (EFS) calculated from randomization to radiological progression, disease recurrence, treatment discontinuation or death.

 Impact: Inoperable OCHNSCC poses a common challenge, and this study addresses a gap in guiding treatment decisions in the immunotherapy era. If the regimen proves to enhance the conversion rate, while maintaining lower toxicity, it could translate into improved survival. This will greatly impact treatment protocols in the subcontinent.