The prognosis of platinum-refractory head and neck squamous cell carcinoma (HNSCC) is dismal. Until the end of 2016, there were no approved therapies in this setting. Nivolumab and pembrolizumab were subsequently approved in this space based on the results of CheckMate 141 and KEYNOTE 040. In CheckMate 141, nivolumab improved the 1 year overall survival (OS) over the physician’s choice of treatment from 16.6% to 36%, In KEYNOTE 040, pembrolizumab improved the 1 year OS from 26.5% for the patients who received the physician’s choice of treatment to 37%. Both these drugs were well tolerated with grade 3 and higher adverse events occurring in approximately 13% of the patients. Hence, these drugs have been widely adopted and recommended in various international guidelines for the treatment of platinum-refractory head-and-neck cancer.
Unfortunately, the inclusion of these drugs in international treatment guidelines has failed to have a strong impact on patients in the low- and middle-income countries (LMICs). A possible reason for this is the prohibitively high cost of these drugs which are unaffordable for most of the population in LMICs. Furthermore, there is limited literature from real-world settings and community-level results with these drugs.
There is a concern about the replicability of results reported from randomized trials in routine clinical practice in various settings. Therefore, we decided to delve into our database to determine the clinical outcomes seen with these drugs in our practice as well as to shed some light on their accessibility.
MATERIALS AND METHODS
General study details
This was a retrospective study performed in the Department of Medical Oncology at the Tata Memorial Hospital, a tertiary level cancer-only hospital in Mumbai, India. The data for this study were taken from August 1, 2016 to December 31, 2018. The Institutional Ethics Committee (IEC)-3 of the Tata Memorial Hospital approved the project on September 6, 2021 (project #900835, Supplementary appendix 1). The IEC granted a waiver of the requirement to obtain written informed consent, given the retrospective nature of the study. The study was conducted according to the ethical guidelines established by the Declaration of Helsinki and other guidelines such as Good Clinical Practice Guidelines and those established by the Indian Council of Medical Research. There was no funding utilized for the study. The study was not registered in a publicly accessible clinical trials registry as it was a retrospective analysis.
The primary outcome studied was overall survival (OS). Our secondary objective was progression-free survival (PFS) . We also aimed to evaluate the accessibility of the immune checkpoint inhibitors, that is, how many patients met the criteria to receive immunotherapy and how many actually received.
We included patients who were 18 years or older, had platinum-refractory HNSCC (disease progression or recurrence within 6 months of completing the last dose of platinum-based chemotherapy), and had received nivolumab or pembrolizumab between August 1, 2016 and December 31, 2018.
We maintain a prospective database in our unit of all patients with head-and-neck cancer who have received palliative systemic therapies. This database was used for the selection of cases for the current study. The details that were extracted from the database included the demographic profile, previous treatment, nivolumab/pembrolizumab treatment details, adverse events, response rate, date of progression, date of death, date of last follow-up, and status at last follow-up. Axial imaging was used to assess the response in patients. Patients who had initial imaging using a particular modality test [e.g., initial imaging was magnetic resonance imaging (MRI)] were subsequently followed up using that same imaging modality (e.g., response assessed using MRI).
The response was defined in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, incorporating both radiologic and clinical parameters. Response was evaluated every 2 months from the start of therapy. PFS was defined as the time duration from the date of the first cycle of nivolumab or pembrolizumab to the date of progression or death, whichever occurred first. OS was defined from the date of the first cycle of nivolumab or pembrolizumab to the date of death. Lost to follow-up patients were defined as patients who had missed a follow-up appointment or treatment for over 90 days and had no contact in that period. PFS2 was defined as the time from the date of the next immediate cycle of therapy to the date of progression or death, whichever occurred first. The maximum grade of adverse events was recorded in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
The Statistical Package for the Social Sciences (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.) and RStudio version 3.6.6 were used for analysis. Descriptive analysis was performed. The sample size was not calculated a priori as this was a retrospective study; we included the entire available patient cohort that met our eligibility criteria. Continuous variables were described in terms of the median with an inter-quartile range, whereas non-continuous variables were described in terms of percentages with the 95% confidence intervals (CIs). The Kaplan–Meier method was used for the estimation of PFS and OS. COX regression analysis was performed to identify factors affecting PFS and OS. The factors selected were age, sex, primary tumor site, and European Cooperative Oncology Group Performance Status (ECOG PS). The reverse Kaplan–Meier method was used to evaluate median follow-up.
All patients were included in each analysis cohort: Efficacy and safety cohorts; they were all evaluable for efficacy and adverse events. No patients were lost to follow-up, and every patient received at least one cycle of therapy.
There were 2796 patients eligible for immunotherapy during the period of the study, but only 41 patients (1.47%) received it [Figure 1]. The baseline characteristics and previous treatment details for these 41 patients are provided in Tables 1 and 2.
Administration of checkpoint inhibitors
All patients received nivolumab. The dose administered was 240 mg flat dose in seven patients (17.1%) and 3 mg/kg in the remaining 34 (82.9%). Concurrent antibiotics and steroids were required in 19 patients (46.3%) and 5 patients (12.2%), respectively.
The response rate was 19.5% (n = 8). The response was complete in 1 (2.4%) patient and partial in 7 (17.1%). Data censoring was performed in May 2022, and at that time, 34 events of progression were noted. The median PFS was 2.27 months (95% CI, 1.51–4.14). Post-progression therapy was received by 15 of the 34 (44.1%) patients. Details of post-progression therapy are provided in Table 3. The median PFS2 was 2.96 months (95% CI, 1.97–3.95). The median follow-up was 5.29 months (95% CI, 3.78–11.67) with 32 events of death. The median OS was 5.29 months (95% CI, 3.78–11.67) [Figure 1]. The 1 year OS was 33.6% (95% CI, 19.5–48.4). The impact of pre-treatment factors on PFS and OS is shown in Table 4. The median OS among responders (complete response or partial response) was 16.93 months [95% CI, 3.85 not available (NA)], and that among non-responders (stable disease and progressive disease) was 4.37 months (95% CI, 2.66–10.82). The impact of the primary tumor site on the OS is shown in Figure 2.
Any grade immune-related adverse events (irAEs) were noted in 8 patients (19.5%). A detailed description with the grading of adverse events is provided in Table 5.
To the best of our knowledge, this is the first report from an LMIC on the use of checkpoint inhibitors in patients with HNSCC. The outcomes noted in our patient cohort were roughly comparable to those reported in CheckMate 141; the median PFS in our study was 2.3 months versus 2.0 months in CheckMate 141, and the corresponding 1 year OS were 33.6% and 36%, respectively. The patients included in our study were distinctly different from those in CheckMate 141. Our study included a large proportion of patients with oral cancers (58.5% versus 48.5%) and a higher proportion of patients who had received epidermal growth factor receptor (EGFR)-targeted therapies (>85% versus 61.5%). Thus, it is reassuring that nivolumab has efficacy even in heavily pretreated patients.
In a resource-limited setting, a possible strategy could be to initiate therapy with nivolumab, followed by response assessment. The primary reason for the low proportion of patients receiving immunotherapy was financial. The limited uptake of checkpoint inhibitors because of financial constraints reflects the similar limited utility of cetuximab in LMICs. LMICs are the hub of head-and-neck cancers, and it is sad that in these countries, the use of checkpoint inhibitors is limited. This is a challenge for treating physicians and investigators in this part of the world. This needs to be overcome by developing or innovating novel drugs or formulating protocols for the wider use of these checkpoint inhibitor drugs. A recent study suggested that the addition of low-dose nivolumab led to improved OS and may represent a promising alternative standard of care for those who cannot access full dose nivolumab.
The outcomes for oral cancer have traditionally been poor with systemic therapy, as was evident in the EXTREME study [cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil (5-FU) in the first line treatment of subjects with recurrent and/or metastatic squamous cell carcinoma of the head and neck], where the median OS with cisplatin- 5FU in patients with oral cancers was only 4.4 months as opposed to approximately 8 months for those with primaries originating from any other sub-site. The results of our study suggest that this is the case with nivolumab too. It is important that in future studies, the primary site of the cancer should be a stratification factor. Additionally, ethnic differences are known to occur in the responses and outcomes from systemic therapies. The east Asian subset of CheckMate 141 had a median OS of 12 months compared to 7 months for the overall study cohort. The results of our study suggest that the outcomes in Indian patients are similar to those reported globally.
The timeframe for our study was from 2016 to 2018, and hence, the results are a reflection of the clinical practice at that time. The use of checkpoint inhibitors was restricted to the second line and beyond setting. Furthermore, the initial results of KEYNOTE-040 with pembrolizumab suggested that OS was not superior to the physician’s choice of treatment. Hence, there was a higher utilization of nivolumab in this setting than pembrolizumab. In 2019, based on the results of KEYNOTE-048, pembrolizumab as monotherapy or in combination with cisplatin-5FU was established as the first line agent of choice, along with the EXTREME regimen, and would subsequently change the pattern of care.
The adverse events profile in our study was in line with the known side effects of nivolumab. No new safety signals were observed. The two most common side effects that developed in our patients were fatigue and anorexia, similar to what was reported in CheckMate 141.
The strength of our study was that we included a homogeneous population of patients with platinum-refractory disease and squamous cell carcinoma. Our study provides real-world data which are applicable to the group of patients encountered in the clinic on a daily basis. However, our study was retrospective and from a single center. We did not document the reasons why patients who were eligible for immunotherapy did not receive it. We did not have the data about programmed-death ligand 1 (PD-L1) expression on the tumors of these patients, and hence, an analysis related to PD-L1 expression was not performed.
Nivolumab had a good impact on both OS and PFS even in a real-world setting of patients with extensively pretreated platinum-refractory HNSCC as seen in key, pivotal studies. Patients with oral cancers have relatively lower survival outcomes compared to those with other primary sites; this finding is hypothesis-generating and needs further study.
Study concept: KP, VP, HM, JC, DP, GA, VN, NM, SD; design: KP, VP; data collection: KP, VP, HM, JC, DP, GA, VN, NM, SD; analysis and interpretation: KP, VP; manuscript writing: KP, VP, HM, JC, DP, GA, VN, NM, SD; approval of final article: all authors; accountability for all aspects of the work: KP.
Data sharing statement
Individual de-identified participant data will be made available on reasonable request to the corresponding author, starting from the date of publication until 10 years after publication. Requests beyond this timeframe will be considered on a case-by-case basis. In addition, the study protocol, including the statistical data, is already available as part of this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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