Are we spoiled for choice in advanced squamous cell carcinoma of the head-and-neck?

With more than 220,000 new patients diagnosed annually, head-and-neck squamous cell carcinoma (HNSCC) contributes significantly to the overall cancer burden in India; the majority of these are diagnosed at the locally advanced stage.^[1–4] The Global Cancer Observatory (GLOBOCON) 2020 data suggested that India contributes to 1/3^rd of the world’s load of head-and-neck cancers.^[5] Despite improvement in treatment options and techniques, a significant number of patients fail and are eligible to receive palliative intent treatment.

The platinum refractory setting is a difficult scenario with poor outcomes and usually defined in the literature as patients progressing or relapsing within 6 months of a platinum-based treatment, while some studies have defined the platinum-free interval as only 3 months.^[6,7] Treatment options range from single agent immune checkpoint inhibitors^[8] to chemotherapy agents — oral (double or triple) metronomic therapy, single agent taxanes, methotrexate, cetuximab as a single agent or in combination with a taxane, among other chemotherapeutic regimens.^[7,9–11] The responses vary from single digits to nearly 42% with triple metronomic therapy, but except for the immune checkpoint inhibitors (ICIs), these responses do not last for a long time. The median overall survival is between 5 and 8 months, lower in the later lines and from the alternative regimens except for nivolumab and pembrolizumab. Hence, there is a need for better drug combinations that can not only improve oncological outcomes but also improve the quality of life indices for patients.

In India, a vast majority of these cancers are tobacco-related and affect patients from the lower socio-economic strata. These patients cannot afford costly regimens which include ICIs^[12,13] and/or cetuximab-based protocols, reminding us of the need to develop effective protocols which are accessible to all citizens of the country. In this context, the authors of the studies evaluating the role of Mycidac-C and bendamustine in advanced HNSCC need to be congratulated for their efforts to generate solutions that can make a difference to the patients with HNSCC in low- and middle-income countries (LMICs).^[14,15]

The trial of paclitaxel with Mycidac-C^[14] in the second line and beyond raises the question of whether the regimen would be superior to the previously available drugs and/or regimens. Single agent ICI (nivolumab and pembrolizumab) stand out as the best agents in terms of survival and duration of response for platinum-refractory disease in the second line.

Nivolumab and pembrolizumab are approved for use in the platinum-refractory setting based on the results of CheckMate 141 (CM-141)^[9] and KEYNOTE-040 (KN-040).^[10] CM-141 randomized 361 patients with platinum-refractory HNSCC to nivolumab versus treatment of physicians’ choice (weekly docetaxel, methotrexate, or cetuximab). Patients treated with nivolumab had better outcomes and fewer toxicities compared to physicians’ choice therapy [OS, 7.7 vs. 5.1 months; hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.55–0.9]; 1-year survival rate (34% versus 19.7%); and ORR (13.3% vs. 5.8%).^[9] Subsequently, the use of ICIs has moved to the first-line setting for patients with platinum-sensitive HNSCC.

KN-040 randomized 495 patients with HNSCC not amenable to curative intent therapy, and who had, progressed or relapsed after previous platinum-based treatment within 3-6 months in a 1:1 fashion to single agent pembrolizumab or treatment of physician choice, similar to the CM-141, except for the use of once-in-3-weeks docetaxel rather than weekly docetaxel. The median OS was 8.4 vs 6.9 months (HR, 0.80; 95% CI, 0.65-0.98; nominal P = 0.0161) in favor of the ICI, with superior responses (14.6% vs 10.1%). The pembrolizumab arm also had fewer grade 3 toxicities.^[10]

There is a problem in LMICs including India with regard to access to ICIs, making the drugs out of reach for the vast majority of patients,^[12,13] which automatically begs the need for cheaper alternatives.^[16,17] Single agent ICIs have proven their superiority when compared to single agent taxanes, methotrexate, or cetuximab in both the landmark trials, making them the standard of care (SOC) in this setting. Furthermore, there is no trial that confirms the superiority of combination therapy to single agent chemotherapy. Keeping this in mind, we need to consider whether the combination of paclitaxel with Mycidac-C is a practice-changing option.^[14]

The progression-free survival (PFS) and overall survival (OS) of 2.9 and 5.9 months, respectively, are at best comparable to those reported in the standard treatment arms (single agent therapies) of KN-040 and CM-141.^[9,10] In addition, there are additional intradermal injections — at least two doses per cycle and the likelihood of developing an abscess at the injection site.^[14] The triple metronomic chemotherapy regimen of methotrexate, celecoxib, and erlotinib (received by 17% in this study) appears to be a superior alternative for those who have not received this regimen in the first-line. The study by the same group on triple metronomic chemotherapy published in the Journal of Clinical Oncology in a similar setting achieved an excellent response rate of 42.9%, PFS of 4.6 months, and a median OS of 7.17 months with an improved patient-reported outcomes scale.^[11]

The trial for single agent bendamustine^[15] in advanced HNSCC makes one wonder when to discuss the option of best supportive care alone, which might be the best option as the survival achieved with bendamustine in this study was not numerically superior to that reported in few of the published studies that had a best supportive care arm, along with the added toxicity resulting from the administration of bendamustine. Does a median OS of 3.2 months in a heavily pre-treated cohort of patients with advanced HNSCC instill confidence to offer this regimen to such patients? Fushimi et al. in their study of 56 patients who had failed at least two lines, including nivolumab, demonstrated that treatment with the EXTREME regimen (cisplatin, 5-fluorouracil, cetuximab) or cetuximab with paclitaxel was superior to best supportive care alone. The OS in the best supportive care group was 3.5 months compared to 5.8 months in the salvage chemotherapy arm,^[18] which was superior to the survival achieved with bendamustine in the current study.^[15] At best, the study confirms that the regimen is safe and feasible, but to consider it as an option in the third line and beyond is stretching things a little too far.

Considering the argument of accessibility to costlier regimens, especially the ICI in India, one would prefer an outpatient-based regimen (not requiring admissions – as was not the case in both the studies), tilting the scale towards the oral triple metronomic regimen which is 1/6^th the cost of single agent docetaxel, 1/80^th of the cost of cetuximab, and 1/120^th of the cost of ICI.^[11]

Assuming a change in practice as per the data published by Patil et al. with regards to the first line regimen; combining triple metronomic chemotherapy with ultra-low dose nivolumab,^[19] single agent taxane, or the combination with a platinum could be the go-to second line regimen, especially with the evidence of superior outcomes of taxanes after exposure to ICI.^[20]

As these are incurable settings with patients having limited survivals, quality of life data assume paramount importance. This is an important drawback as both the studies lacked patient-reported outcomes, which is understandable as these were retrospective data, but these data would have given valuable insights into the degree of improvement of the quality of life scales of these patients compared to the baseline.

The other drawbacks of these studies, apart from being retrospective series, were the small sample sizes of both studies. At best, these studies highlight two novel regimens which should be tested against cheaper and more effective regimens, especially oral triple metronomic chemotherapy in platinum-refractory settings. Any guesses as to which regimen my vote would go to?

In conclusion, as in most cancers, there needs to be a continuum of care in advanced and recurrent HNSCC. My proposed regimens are:

(A) In financially challenged settings:

Post failure of triple oral metronomic chemotherapy with ultra-low dose immunotherapy, the option of a platinum doublet with a taxane would be my preferred choice if the performance status is acceptable. If the performance status is poor, single agent platinum or taxane would be the preferred option. Best supportive care alone could be reserved for the third or even the fourth line.

(B) In the optimal setting:

The combination of pembrolizumab with platinum and taxane or 5-fluorouracil and platinum would be the go-to choices, followed by single agent cetuximab (or in combination with weekly paclitaxel), followed by triple oral metronomic chemotherapy, and then best supportive care alone.