Senthil Kumar: First-Line Systemic Treatment for Advanced/Metastatic Head and Neck Squamous Cell Carcinoma

Senthil Kumar, Medical Oncologist at Red Hills Chennai, shared a post on X:

“First-Line Systemic Treatment for Advanced/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)

Disease Overview

Dismal Prognosis: median overall survival (OS) of 6–14 months.

Factors Impacting Survival:

Age

Performance Status (PS)

Comorbidities

Platinum-Free Interval (PFI)

PD-L1 Expression (CPS)

HPV Status

Smoking Status

Cachexia

Disease Tempo and Tumor Burden

Evidence-Based First-Line Systemic Treatment Regimens

1. KEYNOTE-048 Trial

Arms:

Pembrolizumab Monotherapy

Pembrolizumab + Platinum + 5-FU (PF)

Cetuximab + Platinum + 5-FU (EXTREME Regimen)

Median OS:

Pembro Alone: 11.5 mo (Overall) | 12.3 mo (CPS ≥1) | 14.9 mo (CPS ≥20)

Pembro + PF: 14.7 mo (Overall) | 13.6 mo (CPS ≥1) | 13.0 mo (CPS ≥20)

EXTREME Regimen: 10.7 mo

Comparison (KEYNOTE-048 vs EXTREME):

ORR: Higher in Pembro arms for CPS ≥20; numerically higher ORR in EXTREME for CPS <20.

DOR: Longer with Pembro arms.

PFS2: Longer with Pembro arms (especially when taxane was used).

PD Rates: Higher in Pembro Monotherapy arms; risk of hyperprogression present.

CPS ≥1 and ≥20: Pembro + Chemo was superior.

Overall Population: Non-inferior (95% CI crossing 1).

2. EXTREME Trial

Regimen: Cetuximab + Platinum (Cisplatin/Carboplatin) + 5-FU (PF) vs. Chemo Alone

Median OS: 10.1 mo vs. 7.4 mo

Median PFS: 5.6 mo vs. 3.3 mo

ORR: 36% vs. 20%

3. TPEx Trial

Arms:

Docetaxel + Cisplatin + Cetuximab (TPEx) vs. Cetuximab + PF (EXTREME)

Median OS:

TPEx: 14.5 mo

EXTREME: 10.1 mo

Result: Negative , but numerically higher OS in the TPEx arm.

Sequential Approach: TPEx followed by immunotherapy may theoretically improve OS to 22 months.

Toxicity: TPEx is less toxic

4. PCC Regimen (Weekly Paclitaxel + Carboplatin + Cetuximab) – An option in less fit patients

Regimen:

Paclitaxel (80 mg/m² IV weekly)

Carboplatin (AUC 2 IV weekly)

Cetuximab (400 mg/m² loading dose, then 250 mg/m² weekly)

Median OS: 14.7 mo

ORR: 40%

Negative Trials

KESTREL Trial: Durvalumab ± Tremelimumab

KEYNOTE-651:

Active Single Agents in R/M HNSCC (May be Preferred in Less Fit Patients)

Paclitaxel

Nab-Paclitaxel

Fluorouracil (5-FU)

Docetaxel

Gemcitabine

Etoposide

Pemetrexed

Afatinib (second-line)

Cetuximab

Combination Options for Less Fit Patients

PCC Regimen (Weekly Paclitaxel + Carboplatin + Cetuximab): Offers a balance of efficacy and tolerability.

OMC Regimen: Methotrexate (15 mg/m² weekly) + Celecoxib (200 mg BID) + Erlotinib

Addition of low-dose Nivolumab to OMC improves OS .

Oligometastatic Disease (OligoMets)

Curative Intent: Multimodal therapy (Surgery + SBRT + Systemic Therapy)

SBRT + Nivolumab – negative trial

Surgical Resection: an option in resectable oligometastases.

Final Insights

Treatment Strategy Based on PD-L1 CPS Expression

CPS ≥20:

Pembrolizumab Monotherapy for low burden.

Pembrolizumab + PF Chemo for high tumor burden or rapid progression.

CPS 1–19:

Pembrolizumab + Chemo is the standard of care.

CPS <1 or Immunotherapy Ineligible:

Chemotherapy (Doublet/Single Agent)

EXTREME Regimen (Cetux + PF)

TPEx Regimen (Docetaxel + Cisplatin + Cetuximab)

PCC Regimen (Weekly Paclitaxel + Carboplatin + Cetuximab)

First-Line Chemotherapy Preference:

Platinum + 5-FU (PF) — standard of care.

Taxane-based combinations may be preferred for ease of administration and lower toxicity.

Cisplatin is preferred over Carboplatin in fit patients due to superior efficacy.

Special Considerations:

For Platinum-Free Interval <6 months, platinum regimens may be less effective; immunotherapy ± chemotherapy is preferred.

In less fit patients, PCC and OMC regimens offer effective and tolerable options.

Additional Molecular Testing: Tumor NGS and DPYD testing can be considered for personalized therapy.”