Weekly paclitaxel, carboplatin and cetuximab (PCC) combination followed by nivolumab in platinum-sensitive recurrent and /or metastatic squamous cell carcinoma of head and neck: a retrospective analysis from two institutions in India

M V Chandrakanth; Vivek Agarwala; Pradip Mondal; Raajit Chanana; K M Parthasarathy; Sourav Dutta; Harsh Dhar; Suman Mallick; Sayan Das; Devmalya Banerjee; Md Arif Faizan; Moinak Basu; Subhabrata Kumar

doi:10.12688/f1000research.131969.3

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Research Article

Revised

Weekly paclitaxel, carboplatin and cetuximab (PCC) combination followed by nivolumab in platinum-sensitive recurrent and /or metastatic squamous cell carcinoma of head and neck: a retrospective analysis from two institutions in India

[version 3; peer review: 2 approved with reservations, 1 not approved]

M V Chandrakanth¹, Vivek Agarwala¹, Pradip Mondal¹, [...] Raajit Chanana², K M Parthasarathy², Sourav Dutta³, Harsh Dhar³, Suman Mallick⁴, Sayan Das⁴, Devmalya Banerjee⁵, Md Arif Faizan⁶, Moinak Basu⁷, Subhabrata Kumar⁷

M V Chandrakanth¹, Vivek Agarwala¹, [...] Pradip Mondal¹, Raajit Chanana², K M Parthasarathy², Sourav Dutta³, Harsh Dhar³, Suman Mallick⁴, Sayan Das⁴, Devmalya Banerjee⁵, Md Arif Faizan⁶, Moinak Basu⁷, Subhabrata Kumar⁷

PUBLISHED 07 Mar 2025

Author details Author details

¹ Department of Medical Oncology & Hemat-Oncology, Narayana Superspeciality Hospital & Cancer Institute, Howrah, West Bengal, 711103, India
² Department of Medical Oncology, Dharamshila Narayana Superspeciality Hospital, New Delhi, Delhi, 110096, India
³ Head and Neck Surgeon, Narayana Superspeciality Hospital & Cancer Institute, Howrah, West Bengal, 711103, India
⁴ Radiation oncologist, Narayana Superspeciality Hospital & Cancer Institute, Howrah, West Bengal, 711103, India
⁵ Oncopathologist, Narayana Superspeciality Hospital & Cancer Institute, Howrah, West Bengal, 711103, India
⁶ Radiologist, Narayana Superspeciality Hospital & Cancer Institute, Howrah, West Bengal, 711103, India
⁷ Senior Registrar, Medical Oncology, Narayana Superspeciality Hospital & Cancer Institute, Howrah, West Bengal, 711103, India

M V Chandrakanth
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Supervision, Validation, Writing – Original Draft Preparation

Vivek Agarwala
Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Pradip Mondal
Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation

Raajit Chanana
Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation

K M Parthasarathy
Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Supervision, Validation

Sourav Dutta
Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Supervision, Validation, Writing – Original Draft Preparation

Harsh Dhar
Roles: Conceptualization, Data Curation, Formal Analysis, Methodology, Project Administration, Supervision, Validation

Suman Mallick
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation

Sayan Das
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Supervision

Devmalya Banerjee
Roles: Conceptualization, Data Curation, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation

Md Arif Faizan
Roles: Conceptualization, Data Curation, Funding Acquisition, Investigation, Methodology, Supervision, Writing – Original Draft Preparation

Moinak Basu
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Supervision, Validation

Subhabrata Kumar
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Supervision

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REVIEWER STATUS

Abstract

Background

First line (1L) TP-Ex-like regimen followed by 2nd-line (2L) immunotherapy represents one of the standards of care in platinum-sensitive recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN). We report our experience from 2 tertiary care institutions of India.

Methods

This is a retrospective analysis of consecutive patients of platinum-sensitive R/M SCCHN treated with 1L weekly paclitaxel, carboplatin, and cetuximab (PCC) regimen followed by cetuximab maintenance (if non-progressive) or 2L nivolumab or oral metronomic chemotherapy (OMCT) on progression. Overall response rates (ORR), progression-free survival after 1L and 2L (PFS-1 & PFS-2), overall survival (OS), and safety were evaluated.

Results

The study included 54 patients; median age 56.5 years; 89% men; 11% had cardiac dysfunction; 13% had renal dysfunction. After 1L PCC, ORR was 59.3%; median PFS-1 was 7.031 months; 61% had progression; 35% were treated with nivolumab and 18% with OMCT. The ORR was 26.3% (nivolumab) and 10% (OMCT). Median PFS-2 was 6.5 months (nivolumab) and 2 months (OMCT). The median OS was 15.01 months (entire cohort), 20.6 months (nivolumab), and 7 months (OMCT). Grade III/IV adverse events on PCC included neutropenia (31.4%), anaemia (35.1%), thrombocytopenia (7.4%), febrile neutropenia (11.1%), and skin reaction (16.6%); no Grade-III/IV treatment-related toxicities on 2L.

Conclusions

 1L weekly PCC is an effective regimen for palliative therapy of platinum- sensitive R/MSCCHN with an acceptable toxicity profile. The addition of 2L nivolumab on progression further improves the outcomes.

Keywords

Palliative therapy, Cetuximab, Nivolumab, Immunotherapy, Paclitaxel, Carboplatin, Chemotherapy.

Corresponding author: Vivek Agarwala

Competing interests: No competing interests were disclosed.

Grant information: Funding for medical writing support was provided to Dr. Punit Srivastava of Mediception Science Pvt Ltd, by Merck Specialities Pvt Ltd India, an affiliate of Merck KGaA, Darmstadt, Germany.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2025 Chandrakanth MV et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Chandrakanth MV, Agarwala V, Mondal P et al. Weekly paclitaxel, carboplatin and cetuximab (PCC) combination followed by nivolumab in platinum-sensitive recurrent and /or metastatic squamous cell carcinoma of head and neck: a retrospective analysis from two institutions in India [version 3; peer review: 2 approved with reservations, 1 not approved]. F1000Research 2025, 12:802 (https://doi.org/10.12688/f1000research.131969.3) First published: 10 Jul 2023, 12:802 (https://doi.org/10.12688/f1000research.131969.1) Latest published: 07 Mar 2025, 12:802 (https://doi.org/10.12688/f1000research.131969.3)

Revised Amendments from Version 2

The authors appreciate the peer review, which has strengthened this manuscript. The study objectives have been clearly defined in the revised version. The discussion now includes results from CheckMate 141, the EXTREME arm of the KESTREL study, and the ERBITAX study to enhance understanding of sequencing with cetuximab-based regimens. These results were published after the manuscript was originally written. Figure 1 (study schema) has been updated, and the original Table 2 has been removed due to redundancy. Consequently, Table 3 has been renumbered as Table 2, and Table 4 is now Table 3. Additionally, the updated results of the TPEx regimen, which were unavailable at the time of writing, have been incorporated into Table 3. A typographical error in Figure 2 has been corrected, with the mPFS value updated from 6.4 to 6.5. The authors regret any inconvenience this may have caused.

See the authors' detailed response to the review by Ye Guo
See the authors' detailed response to the review by Lena Huber
See the authors' detailed response to the review by Santiago Cabezas-Camarero

Introduction

Squamous cell carcinomas of head and neck (SCCHN) accounts for 90% of all head and neck cancers (HNCs)¹^,² The cumulative risk of developing HNC (oral and pharynx) in India is 1 in 60, with males at higher risk than females (cumulative risk 1 in 41: 1 in 112).³ Approximately 66% of HNCs in India are diagnosed at a locally advanced (LA) stage.³ Though, a disease of sixth or seventh decade of life, HNC is increasingly being seen in younger population.¹

SCCHN is a difficult to treat cancer, especially in India, due to difference in genetic and etiological factors, in additional to logistic issues, compared to western world.² The etiology of HNC in India is primarily driven by smokeless tobacco chewing versus human papilloma virus (HPV) infection seen in western world.² In recurrent and/or metastatic (R/M) setting, treatment of SCCHN is even more difficult with poor outcomes.

Historically, in R/M SCCHN, combination chemotherapy regimens such as platinum plus 5-fluorouracil (5-FU)⁴^–⁷ and platinum plus taxane⁸^–¹⁴ significantly improved response rates compared with single agent chemotherapy, but they were not successful in demonstrating an improved OS and showed higher toxicity.¹⁵ Cetuximab based combinations with platinum-based doublet chemotherapy such as the EXTREME regimen (cetuximab-cisplatin/carboplatin-5-fluorouracil [5-FU])¹⁶^,¹⁷ or the TPExtreme regimen (cetuximab-docetaxel-cisplatin),¹⁸^,¹⁹ followed by maintenance cetuximab until disease progression, showed increased OS compared with doublet chemotherapy and became the best 1L approach in R/M SCCHN.²⁰^,²¹

Also the EXTREME regimen is associated with hematological toxicities that raised the need for safer regimens.²² The CEMET trial showed that paclitaxel, carboplatin and cetuximab (PCC) regimen is a feasible 1L treatment option and is associated with significantly lesser toxicities than the EXTREME regimen (40% vs. 60%; p = 0.034).²³

Many patients with R/M HNSCC show disease progression after first line platinum-based therapies.²⁴ In these patients, the U.S. Food and Drug Administration (FDA) has approved PD-1 inhibitors like nivolumab and pembrolizumab for 2^nd line treatment.²⁵^,²⁶

After the success of the Keynote-048 study,²⁷ first line immuno-chemotherapy (IC) with pembrolizumab-platinum-5FU combination (irrespective of programmed death-ligand 1 [PD-L1] status) or immunotherapy alone with pembrolizumab (for PD-L1 ≥ 1%) became the preferred option of systemic therapy for platinum sensitive R/M SCCHN.¹⁵ However, the EXTEME and TP-Extreme regimens, still remain one of the standard first-line options in R/M SCCHN, especially if immunotherapy is not feasible, in PD-L1 negative patient population, in oral primary, and in rapidly progressive bulky disease which requires faster responses.¹⁸^,¹⁹^,²²^,²⁴^,²⁶^,²⁸^,²⁹

With increasing treatment options in R/M SCCHN, sequencing becomes important. However, sequencing has not been addressed well in the clinical trials. In KN -048 study, only 16.7% patients in cetuximab arm received subsequent immunotherapy, while in IC or immunotherapy arm only 16.4% patients received subsequent EGFR inhibitor.³⁰ So, the right sequencing of therapies in RM SCCHN is still elusive.

Here we report our experience with first-line weekly PCC combination followed by second-line immunotherapy (nivolumab) in platinum-sensitive R/M SCCHN from two tertiary care centers of India.

Methods

This study involved a retrospective analysis of consecutive patients with platinum-sensitive R/M SCCHN treated between August 2017 and May 2020 at the two tertiary care centres in India with first-line weekly combination paclitaxel 80 mg/m², carboplatin AUC2 and cetuximab 400 mg/m² loading followed by 250 mg/m² (PCC) for a maximum duration of 12 weeks. Non-progressive patients were then started on cetuximab maintenance. Patients were further treated with second-line nivolumab or oral metronomic chemotherapy (OMCT) on progression as per feasibility. Nivolumab was given as 3 mg/kg two weekly and OMCT was administered as celecoxib 200mg twice daily + erlotinib 100 mg once daily + methotrexate 12 mg/m² once weekly.

Eligible patients 18–70 years old with ECOG-PS 0-2 and had at least one measurable lesion as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) were included. Exclusion criteria included any previous systemic chemotherapy for HNSCC surgery or radiotherapy within the previous 6 weeks; a previous dose of cisplatin more than 300 mg/m²; treatment with EGFR-targeting therapy within the previous 12 months; clinically significant cardiovascular disease; other malignancies within 5 years before randomization.

Demographic, clinical and treatment characteristics data were collected from patients’ charts until July 7, 2020. Response evaluation was performed as per RECIST 1.1 (for solid tumors) after every 8–12 weeks.³¹ Toxicities during treatment were documented in accordance with CTCAE version 4.03.³² The institutional ethics committees of the Narayana Superspecialist Hospital, Howrah and Dharamshala Narayana Superspecialist Hospital, New Delhi approved the study.

Study objectives

To evaluate the overall response rates (ORR-1), progression-free survival (PFS-1), and overall survival (OS-1) from the start of 1L PCC to the end of 1L PCC (progression on 1L PCC or intolerable adverse effects) and ORR-2, PFS2, and mOS2 from the start of second line therapies (nivolumab or OMCT) to the end of the study. The PFS and mOS of the entire study cohort was assessed from the start of first line PCC to the end of the study. The study also evaluated the safety of first-line PCC and second-line therapies.

Statistical analysis

Statistical measures were calculated using software SPSS Version 20. PFS and OS were estimated by Kaplan-Meier method and compared by log rank test. Median follow-up was calculated using the reverse Kaplan Meier method. Mean ± S.D. and Median were used to summarize the quantitative variables.

Results

Baseline characteristics

Fifty-four patients with R/M SCCHN were treated at the two centers between August 2017 and May 2020. Median age of the study population was 56.5 years; 89% were males. Oral cancer was the primary cancer site in 30 (55%) patients and 24 (45%) had non-oral primary cancer sites. Of the 54 patients, 16 (30%) were treatment naïve; 38 (70%) had received prior treatments (chemotherapy or surgery or radiation or a combination of these) and had a median treatment free interval (TFI) of 10 months; 28 (51%) had not received any previous systemic therapy. A history of tobacco abuse was present in 41 (75%) of patients. All patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 or 2 at the start of PCC; 6 (11%) had cardiac dysfunction and 7 (13%) had renal dysfunction. Demographic details of the study population are provided in Table 1.

Table 1. Baseline characteristics of the study population.

Baseline characteristics	No. of patients N = 54 (100%)	Baseline characteristics	No. of patients N = 54 (100%)	Baseline characteristics	No. of patients N = 54 (100%)
Sex		Site of primary		ECOG performance
Male	48 (88.9%)	Oral Cavity	30 (55.6%)	1	32 (59.3%)
Female	06 (11.1%)	Oropharynx	06 (11.1%)	2	22 (40.7%)
Comorbidities	27 (50%)	Hypopharynx	03 (5.6%)	Site of current disease
Hypertension	19 (35.2%)	Larynx	13 (24.1%)	Only Locoregional	20 (37%)
Diabetes	14 (25.9%)	Unknown Primary	02 (3.7%)	Only Distant Metastasis	04 (7.4 %)
Cardiac Dysfunction	0.6 (11.1%)	Sub-site of Primary		Locoregional + Distant	30 (55.6%)
Renal Dysfunction	07 (13%)	Buccal Mucosa	14 (25.9%)	Site of Distant metastasis
History of Tobacco		Tongue	10 (18.5%)	Nodal	21 (38.9%)
Yes	41 (75.9%)	Alveolus	06 (11.1%)	Lung	14 (25.9%)
No	12 (22.2%)	Tonsil	01 (1.9%)	Bone	10 (18.5%)
Not Known	01 (1.9%)	Soft Palate	01 (1.9%)	Skin	05 (9.3%)
Prior Treatment		Base of Tongue	04 (7.4%)	Muscle	05 (9.3%)
Surgery + RT	08 (14.8%)	Pyriform Sinus	03 (5.6%)	Liver	01 (1.9%)
Surgery + CT + RT	05 (9.3%)	Supraglottis	08 (14.8%)	Brain	02 (3.7%)
CT + RT	23 (42.6%)	Glottis	05 (9.3%)	Bone Marrow	02 (3.7%)
Only RT	02 (3.7%)	Unknown Primary	02 (3.7%)
Treatment Naive	16 (29.6%)	Unknown Primary	02 (3.7%)

Treatment outcomes

The study schema is outlined in Figure 1. All patients received the study specified first-line weekly PCC for maximum 12 weeks, followed by weekly cetuximab maintenance 250 mg/m² until disease progression or intolerable adverse effects. Non-progressive patients were continued on single-agent cetuximab in maintenance dose. Median number of cetuximab cycles were 23. The ORR-1 (59.3%), PFS-1 (7.031 months), OS-1 (15.014 months) and other efficacy outcomes after first-line PCC are provided in Table 2.

Table 2. End points of the study result.

End points	First-line PCC 54 (100%)
Best Objective Response	-
Complete Response (CR)	7 (13%)
Partial Response (PR)	25 (46.3%)
Stable disease (SD)	15 (27.8%)
Progressive disease (PD)	7 (13%)
Overall Response Rate (CR + PR)	32 (59.3%)
Clinical Benefit Rate (CR + PR + SD)	47 (87%)
Median PFS-1 (in months)	7.031
Median OS (in months)	15.014

Thirty-three (61%) patients progressed on first-line PCC and 21 (39%) did not. The patients who progressed on first-line PCC, were further treated with second line nivolumab (n = 19) or OMCT (n = 10) as per feasibility. Four patients who progressed on first-line PCC were managed on best supportive care (BSC) alone.

Figure 1. Study schema.

The median number of Cetuximab cycles used as 23.

The best response after second line therapies is summarized in Table 3. The ORR was 26.3% with nivolumab and 10% with OMCT. Median PFS and OS after second line therapy were 6.5 months and 20.6 months with nivolumab, whereas 2 months and 7 months with OMCT, respectively ( Figure 2).

Table 3. Outcomes Post Progression – on 2^nd-line therapy.

End points	Nivolumab 19 (100%)	OMCT 10 (100%)
Best Objective Response
Complete Response (CR)	0 (0%)	0 (0%)
Partial Response (PR)	05 (26.3%)	01 (10%)
Stable disease (SD)	11 (57.8%)	05 (50%)
Progressive disease (PD)	3 (15.7%)	04 (40%)
Overall Response Rate (CR + PR)	05 (26.3%)	01 (10%)
Clinical Benefit Rate (CR + PR + SD)	16 (84.2%)	06 (60%)
Median PFS-2 (in months)	6.5	2.0
Median OS (in months)	20.6	7.0

Figure 2. Outcomes Post Progression – on 2^nd-line therapy – PFS-2 & OS.

After a median follow-up of 21 months, 30 patients were alive; 21 on first-line PCC who were on cetuximab maintenance and nine on second-line nivolumab; 24 succumbed to the disease. The mOS of the entire cohort was 15.01 months and mPFS was 5.25 months.

Safety

First line PCC was generally well tolerated. Grade III/IV adverse events on 1st-line PCC included neutropenia (31.4%), anemia (35.1%), thrombocytopenia (7.4%), febrile neutropenia (11.1%) and skin reaction (16.6%). There were no grade III/IV treatment related toxicities in second line therapies.

Discussion

Current study shows that weekly paclitaxel-carboplatin appears as an equally effective backbone for cetuximab with acceptable safety profile as compared to EXTREME regimen (cisplatin-5FU)¹⁶^,¹⁷ or TPExtreme regimen (docetaxel-platinum)¹⁸^,¹⁹ in first-line platinum sensitive R/M HNSCC ( Table 3). Further, second-line immunotherapy after first-line PCC is shown to significantly improve outcomes in comparison with OMCT.

In our study, first-line PCC had a good efficacy profile in R/M SCCHN with ORR of 59.3%, and PFS and OS of 7.03 months and 15.01 months. In the EXTREME regimen first-line cetuximab plus chemotherapy significantly prolonged median OS compared to chemotherapy alone (10.1 versus 7.4 months; hazard ratio [HR] for death 0.80, 95% CI 0.64-0.99). Median PFS (5.6 months versus 3.3 months) and ORR also improved significantly (36% versus 20%).¹⁷ A phase III trial compared EXTREME regimen with cetuximab plus cisplatin and docetaxel (TPExtreme regimen).¹⁸^,¹⁹ After a median follow-up of 30 months, the median OS of the EXTREME and docetaxel based TPExtreme regimen was comparable (14.5 months versus 13.4 months). However, in the phase II GORTEC study, cetuximab plus cisplatin and docetaxel resulted in an ORR of 51.9% and PFS and OS of 6.2 and 14 months, respectively ( Table 3).²¹ The TPExtreme regimen was more tolerable than EXTREME with lower grade ≥3 adverse events (34% versus 50%) and had more patients initiating maintenance cetuximab than EXTREME regimen (73% versus 53%). In our study also, the PCC regimen had an acceptable safety profile that was safer than EXTREME and comparable to TPExtreme.

Our results of efficacy and safety of first- line PCC are in tandem with other data on first-line PCC like CSPOR-HN02³³ and CACTUX³⁴ study ( Table 4). The CSPOR-HN02 study which used split dose paclitaxel (100 mg/m² on days 1 and 8 every three weeks) showed that the PCC regimen can be given on an outpatient basis, thereby reducing cost of treatment.²² In our study also, PCC was given on outpatient basis. This is an important aspect to consider in a country like India as it significantly reduces cost of treatment and need for admission beds. However, the CSPOR-HN02study did not look at treatment after progression on first-line PCC. On the other hand, only 22% of patients in the CACTUX trial received PD-1 inhibitor immunotherapy after progression and demonstrated a: median PFS of 2.2 months.³⁴ Comparatively, in our study, 19 of 33 patients who progressed (57.5%) received immunotherapy (nivolumab) and showed good response with an ORR of 26.3% and median PFS and OS of 6.5 months and 20.6 months, respectively.

Table 4. Efficacy and safety of 1^st line PCC in our study compared with other cetuximab based regimens.

Parameters	1^st line PCC in our study	EXTREME¹⁶^,¹⁷	TPExtreme¹⁸^,¹⁹	GORTEC trial (initial results)²¹	CACTUX²²^,³⁴	CSPOR-HN02³³	CEMET compared EXTREME and PCC regimens²³	ERBITAX³⁵
Regimen	Weekly paclitaxel (80 mg/m²) and cetuximab (400/250 mg/m²) and carboplatin AUC 2							Weekly paclitaxel (80 mg/m²) and cetuximab (400/250 mg/m²)
ORR (%)	59.3	36	57 (vs 59 with EXTREMME)	51.9	63	40	51.2	54
PFS (months)	7.03	5.6	6.0 (vs 6.2 with EXTREME)	6.2	6.3	5.2	6.5	4.2
OS (months)	15.01	10.1	14.5 (vs 13.4 with EXTREME)	14	18.8	14.7	10.2	8.1
Grade ≥3 adverse events	Neutropenia (31.4%), anemia (35.1%), thrombocytopenia (7.4%), febrile neutropenia (11.1%), skin reaction (16.6%)	Neutropenia (22%), anemia (13%), thrombocytopenia (11%), severe skin reactions (9%), severe hypomagnesemia (5%), sepsis (4%), and severe infusion-related reactions (3%)	Lower than EXTREME regimen (81% versus 93%) Serious adverse events: 45% vs 54%	Skin rash (16.6%) and non-febrile neutropenia (20.4%); no febrile neutropenia; 3 non-cancer related deaths (1 pulmonary embolism and 2 infectious events	Grade 4 AEs occurred in 6 patients (19%)	Neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%); 1 treatment related death (intestinal pneumonia)	Toxicity higher in EXTREME regimen arm than PCC arm (60% vs. 40%; p = 0.034)	Grade 3/4 adverse events: acne-like rash: 24% asthenia: 17% Neutropenia: 13%

Though EXTREME regimen continues to be the first-line standard of care in R/M SCCHN, many patients are ineligible for cisplatin-based regimen primarily due to renal and cardiac dysfunction.³⁶^,³⁷ We found that PCC was safe and well tolerated even in patients with cardiac and renal dysfunction. Patients in our study could receive median of 23 cycles of Cetuximab based therapy.

We do note that first-line immunotherapy has shown OS advantage in KN48 study (mOS: 11.6 months).²⁷ However, the OS advantage for immunotherapy over EXTREME in the Keynote -048 study were mainly driven by the PD-L1 combined positive score (CPS) > 20 subgroup (14.7 months versus 10.7 months) as the mOS for immunotherapy was non-inferior to the cetuximab-based EXTREME regimen in the total population (11.6 months vs 10.7 months).²⁷^,³⁸ Further, long-term data of the CheckMate 651 trial showed no OS difference with first-line immunotherapy (nivolumab plus ipilimumab) versus EXTREME in the whole patient population (mOS: 13.9 v 13.5 months) and in patients with CPS ≥ 20 (mOS: 17.6 v 14.6 months).³⁹

Moreover, front line immunotherapy in R/M SCCHN in India is limited by the accessibility to immunotherapy, PDL-1 CPS testing and the relatively higher cost.⁴⁰

Another matter of concern is that, pembrolizumab alone nor pembrolizumab with chemotherapy failed to improve PFS in KN48.²⁷^,³⁸ This is more worrisome in Indian patients because they have a far higher disease burden than that of the western population.⁴¹^–⁴⁵ Hence, clinicians may lose this narrow window of opportunity and the patients may not remain eligible for subsequent anticancer therapy in view of rapid disease progression and deteriorating performance status. Therefore response rate has become a more important endpoint in Indian patients and may act as a surrogate to better quality of life and survival. The results of the KESTREL study also showed that first-line cetuximab-based EXTREME regimen produced a better ORR of 49.0% for all the patients than first-line immunotherapy (durvalumab alone [17.2%] or durvalumab plus tremelimumab [21.8%]).⁴⁶

R/M SCCHN treatment sequencing with first-line cetuximab-based regimen followed second-line immunotherapy-based regimen has demonstrated improved outcomes.⁴⁷^,⁴⁸ The mOS after second-line nivolumab in our study was 20.6 months which was far superior to mOS of 7.7 months after first-line nivolumab in CheckMate 141 trial.⁴⁹ The posthoc analysis of the EXTREME arm of the KESTREL study showed that patients who received immunotherapy after EXTREME regimen (24.3% of patients) had better survival than those who did not.⁴⁶ The sequencing results of nivolumab after PCC of our were mirrored by an Japanese study. In this study, first-line weekly PCC followed by nivolumab demonstrated favourable survival (19.5 months since starting PCE) compared to patients who did not receive second-line nivolumab (HR: 0.47).⁵⁰ Another retrospective study from Spain too demonstrated that immunotherapy after ERBITAX (cetuximab+paclitaxel) achieved better mOS than no immunotherapy after ERBITAX (29.8 months vs 13.8 months).⁵¹

The study is limited by its retrospective design and small patient population. Additionally, PD-L1 expression was not performed, so we cannot access which patient population actually benefited from immunotherapy. Despite this our study has contributed to the growing body of knowledge that cetuximab based PCC regimens can be used effectively and safely in first-line palliative care of R/M SCCHN. To the best of our knowledge, this is the first real-world data of first-line PCC followed by immunotherapy from India and one of the few studies from Asia.

Conclusions

First-line weekly PCC is an effective regimen for palliative therapy of platinum-sensitive R/M SCCHN with acceptable toxicity profile. Addition of second-line nivolumab on progression, further improves the outcomes.

Ethics compliance

Its retrospective data were collected and analyzed at the Narayana Super Specialty Hospital, Howrah, and Dharamshila Narayana Super Specialty Hospital, New Delhi; hence, EC approval was not required. Written consent was obtained from each patient.

Data availability

Underlying data

Figshare: TP Ex for analysis- Weekly paclitaxel baseline data- Revised.xlsx, https://doi.org/10.6084/m9.figshare.22657699.v1.⁵²

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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