Phase III randomized control study evaluating adjuvant metronomic chemotherapy in locally advanced head and neck cancers post-radical chemoradiation (MACE-CTRT).

Background: Locally advanced head and neck cancer treated with radical chemoradiation have unsatisfactory outcomes. Oral metronomic chemotherapy improves outcomes in comparison to maximum tolerated dose chemotherapy in the palliative setting. There is also limited evidence that it may do so in an adjuvant setting. Hence this randomised study was conducted. Methods: Patients of HN cancer with primary in oropharynx, larynx or hypopharynx, with PS 0-2 post radical chemoradiation with documented complete response were 1:1 randomised to either observation or oral metronomic adjuvant chemotherapy (MAC) for 18 months. MAC consisted of weekly oral methotrexate (15 mg/m2) and celecoxib (200 mg PO BD). The primary endpoint was OS and the overall sample size was 1038. The study had 3 planned interim analyses for efficacy and futility. Results: 137 patients were recruited and an interim analysis was done. The 3 year PFS in the observation arm was 67.1% (95% CI 53.8-77.3) and the same in the MAC arm was 62.5%(95%CI 49.4-73.1). The corresponding hazard ratio was 1.402 (95% CI 0.7393-2.66, P-value = 0.3). The 3 year OS in the observation arm was 77.3% (95% CI 64.4-86) and the same in the MAC arm was 64.1% (95%CI 51-74.5). The corresponding hazard ratio was 1.588 (95% CI 0.8734-2.886, P-value = 0.1). Any grade mucositis was seen in 30 patients (45.5%) in the MAC arm and 20 patients (28.2%) in the observation arm (P-value = 0.05). The rate of grade 3 or above mucositis was 7.6%(n = 5) in the MAC arm and 1.4%(n = 1) in the observation arm (P-value = 0.106). Conclusions: Both arms had similar OS. Hence observation post complete response post radical chemoradiation remains the standard of care. Clinical trial information: CTRI/2016/09/007315

Phase III randomized control study evaluating adjuvant metronomic chemotherapy in locally advanced head and neck cancers post-radical chemoradiation (MACE-CTRT).

Background: Locally advanced head and neck cancer treated with radical chemoradiation have unsatisfactory outcomes. Oral metronomic chemotherapy improves outcomes in comparison to maximum tolerated dose chemotherapy in the palliative setting. There is also limited evidence that it may do so in an adjuvant setting. Hence this randomised study was conducted. Methods: Patients of HN cancer with primary in oropharynx, larynx or hypopharynx, with PS 0-2 post radical chemoradiation with documented complete response were 1:1 randomised to either observation or oral metronomic adjuvant chemotherapy (MAC) for 18 months. MAC consisted of weekly oral methotrexate (15 mg/m2) and celecoxib (200 mg PO BD). The primary endpoint was OS and the overall sample size was 1038. The study had 3 planned interim analyses for efficacy and futility. Results: 137 patients were recruited and an interim analysis was done. The 3 year PFS in the observation arm was 67.1% (95% CI 53.8-77.3) and the same in the MAC arm was 62.5%(95%CI 49.4-73.1). The corresponding hazard ratio was 1.402 (95% CI 0.7393-2.66, P-value = 0.3). The 3 year OS in the observation arm was 77.3% (95% CI 64.4-86) and the same in the MAC arm was 64.1% (95%CI 51-74.5). The corresponding hazard ratio was 1.588 (95% CI 0.8734-2.886, P-value = 0.1). Any grade mucositis was seen in 30 patients (45.5%) in the MAC arm and 20 patients (28.2%) in the observation arm (P-value = 0.05). The rate of grade 3 or above mucositis was 7.6%(n = 5) in the MAC arm and 1.4%(n = 1) in the observation arm (P-value = 0.106). Conclusions: Both arms had similar OS. Hence observation post complete response post radical chemoradiation remains the standard of care. Clinical trial information: CTRI/2016/09/007315

Phase 3 randomised study evaluating the addition of low-dose nivolumab to palliative chemotherapy in head and neck cancer.

Background: The regimens approved for the treatment of advanced head and neck squamous cell carcinoma (HNSCC) are accessible to only 1-3% of patients in low and middle-income countries due to cost. In our previous study, metronomic chemotherapy (MC) improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low dose nivolumab to MC improved the overall survival.Methods: This was a randomised phase 3 superiority open-label study. Adult patients with relapsed -recurrent or newly diagnosed advanced HNSCC being treated with palliative intent with ECOG PS 0-1 were eligible. Patients were randomised 1:1 to MC consisting of methotrexate 15 mg/m2 PO weekly, celecoxib 200 mg PO daily and erlotinib 150 mg PO daily, or MC with intravenous nivolumab 20 mg flat dose once-every-3-weeks. Therapy was continued until disease progression or intolerable adverse events. Response assessment (RECIST version 1.1) was performed every 2 months. The primary endpoint was 1-year overall survival (OS) and this was a pre-specified interim analysis with the nominal p-value for efficacy being 0.006.Results: 151 patients were randomised, 75 in MC and 76 in the MC-I arm respectively. The addition of low dose nivolumab led to an improvement in the 1-year overall survival from 16.3% (95%CI 7.95-27.4) to 43.4% (95% CI 30.8-52.3) [Hazard ratio-0.545; 95%CI 0.362-0.82; P=0.00358]. The median overall survival in MC and MC-I arms was 6.7 months (95%CI 5.83 -8.07) and 10.1 months (95%CI 7.37-12.63) respectively (P=0.0052). The median progression-free survival in MC and MC-I arms was 4.57 months (95%CI 4.2 -5.3) and 6.57 months (95%CI 4.43-8.9) respectively (P=0.0021). Response rate in MC and MC-I arm were 49.3% (95% CI 37.8-60.8) and 65.2% (95%CI 53.4-75.4) respectively (P=0.085). The rate of grade 3 and above adverse events was 50% and 46.1% in MC and MC-I arm respectively (P=0.744).Conclusions: In this first-ever randomised study, the addition of low dose nivolumab led to improved overall survival and is an alternative standard of care for those who cannot access full dose nivolumab. Clinical trial information: CTRI/2020/11/028953

Phase 3 randomised study evaluating the addition of low-dose nivolumab to palliative chemotherapy in head and neck cancer.

Background: The regimens approved for the treatment of advanced head and neck squamous cell carcinoma (HNSCC) are accessible to only 1-3% of patients in low and middle-income countries due to cost. In our previous study, metronomic chemotherapy (MC) improved survival in this setting. Retrospective data suggest that a low dose of nivolumab may be efficacious. Hence, we aimed to assess whether the addition of low dose nivolumab to MC improved the overall survival.Methods: This was a randomised phase 3 superiority open-label study. Adult patients with relapsed -recurrent or newly diagnosed advanced HNSCC being treated with palliative intent with ECOG PS 0-1 were eligible. Patients were randomised 1:1 to MC consisting of methotrexate 15 mg/m2 PO weekly, celecoxib 200 mg PO daily and erlotinib 150 mg PO daily, or MC with intravenous nivolumab 20 mg flat dose once-every-3-weeks. Therapy was continued until disease progression or intolerable adverse events. Response assessment (RECIST version 1.1) was performed every 2 months. The primary endpoint was 1-year overall survival (OS) and this was a pre-specified interim analysis with the nominal p-value for efficacy being 0.006.Results: 151 patients were randomised, 75 in MC and 76 in the MC-I arm respectively. The addition of low dose nivolumab led to an improvement in the 1-year overall survival from 16.3% (95%CI 7.95-27.4) to 43.4% (95% CI 30.8-52.3) [Hazard ratio-0.545; 95%CI 0.362-0.82; P=0.00358]. The median overall survival in MC and MC-I arms was 6.7 months (95%CI 5.83 -8.07) and 10.1 months (95%CI 7.37-12.63) respectively (P=0.0052). The median progression-free survival in MC and MC-I arms was 4.57 months (95%CI 4.2 -5.3) and 6.57 months (95%CI 4.43-8.9) respectively (P=0.0021). Response rate in MC and MC-I arm were 49.3% (95% CI 37.8-60.8) and 65.2% (95%CI 53.4-75.4) respectively (P=0.085). The rate of grade 3 and above adverse events was 50% and 46.1% in MC and MC-I arm respectively (P=0.744).Conclusions: In this first-ever randomised study, the addition of low dose nivolumab led to improved overall survival and is an alternative standard of care for those who cannot access full dose nivolumab. Clinical trial information: CTRI/2020/11/028953