Petosemtamab-Pembrolizumab 63% ORR Shines Early But Lacks Randomized OS Proof

Genmab Reports Over Two-Year Median OS with Petosemtamab in HNSCC

Genmab A/S announced updated results from a Phase 2 trial evaluating petosemtamab in combination with pembrolizumab for first-line recurrent/metastatic PD-L1+ head and neck squamous cell carcinoma (r/m HNSCC). The combination achieved a median overall survival (OS) of 28.2 months, an overall response rate (ORR) of 63%, and a median progression-free survival (mPFS) of 9.0 months in 43 efficacy-evaluable patients, including a 19% complete response (CR) rate. Presented at ESMO Congress 2026, these findings showed responses across both HPV-positive and HPV-negative disease with a manageable safety profile, reinforcing confidence in petosemtamab's potential.

• The combination of petosemtamab and pembrolizumab demonstrated significant clinical activity in first-line r/m HNSCC, achieving a median overall survival (OS) of 28.2 months. This robust efficacy was further supported by an overall response rate (ORR) of 63% and a median progression-free survival (PFS) of 9.0 months in the 43 efficacy-evaluable patients, including a notable 19% complete response (CR) rate.
• The treatment showed durable responses, with the median duration of response (mDOR) not yet reached, and an estimated 55% of responders maintaining their response at 24 months. Importantly, clinical activity was observed across diverse patient subgroups, including both HPV-positive and HPV-negative disease, indicating broad applicability and potential to address a wider patient population.
• Petosemtamab plus pembrolizumab exhibited a manageable safety profile, with the most common treatment-emergent adverse events (TEAEs) being asthenia, acneiform dermatitis, and rash, predominantly Grade 1-2. No Grade 5 events or treatment-related deaths were reported. These positive Phase 2 results strengthen the rationale for the ongoing Phase 3 LiGeR program for petosemtamab in first-line HNSCC and other solid tumors.

Addressing the Unmet Need in Recurrent/Metastatic HNSCC

Despite the success of immunotherapy in R/M HNSCC, a proportion of patients will become immunotherapy resistant, and the optimal therapeutic strategy for patients with R/M HNSCC remains unclear. Conventional cytotoxic regimens for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) offer limited durable benefit and are associated with significant toxicity.

• Emerging immunotherapy resistance with limited subsequent options: drug resistance following immunotherapy is an emerging problem, the mechanisms of immunotherapy resistance are not yet fully understood and subsequent treatment options are limited, with an unmet need for effective and well tolerated treatments for patients who develop immunotherapy-resistant HNSCC.

• Modest and variable antitumor activity: Objective response rate (blinded independent central review) was 6.5% (15.0% for PD-L1 ≥25%, 2.6% for <25%), median progression-free survival was 1.4 months and median overall survival (OS) was 8.4 months with durvalumab; Five out of 37 (13.5%) patients achieved an objective response to ICI with Median progression-free survival and median overall survival times were 3.7 months (range 0-22.9) and 9.0 months (range 0-38.8), respectively; overall response rate was 7.7% (12 patients), clinical benefit rate was 16.1% (25 patients), Median progression-free survival was 2.3 months (95% CI, 2.0-2.9 months) and median overall survival was 8.3 months (95% CI, 7.2-11.0 months) with novel immunotherapy agents in heavily pretreated patients.

• Limited predictive value of PD-L1 and other single biomarkers: Head and neck squamous cell carcinoma (HNSCC) exhibits heterogeneous tumour-immune microenvironments that limit the utility of single biomarkers such as programmed death-ligand 1 (PD-L1) and tumour mutational burden (TMB); Given the range of antibodies and platforms for PD-L1 testing, it is essential to understand the performance of different staining and scoring methods; IC PD-L1 classification was less consistent; Overall and progression-free survival did not correlate with PD-L1 status with cetuximab and durvalumab.

• Toxicity trade-off with combination approaches: Grade 3-5 treatment-related adverse events occurred in 16.3% of monotherapy patients and 48.2% of combination therapy patients; Pembrolizumab was associated with higher OR of immune-related adverse events (IRAEs) compared to nivolumab (OR: 2.12, 95% CI: 1.49-3.03) and atezolizumab (OR: 1.63, 95% CI: 1.09-2.43); efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC).

Petosemtamab + Pembrolizumab: Promising Phase 2 HNSCC Data

Recent first-line studies in PD-L1-positive recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have evaluated novel pembrolizumab-based combinations and long-term survival with established regimens. Efficacy signals include confirmed response rates of 39.0% to 54% with combination approaches and 5-year overall survival rates of 14.4% to 16.0% in the KEYNOTE-048 total population.

Petosemtamab's Unique MoA and Expanding Clinical Program

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Petosemtamab's Place in the Evolving HNSCC Landscape

In recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), anti-PD-1 agents have demonstrated improved survival benefits compared to standard of care in both first- and second-line settings. In the second-line treatment setting compared to standard single-agent systemic therapy, the net gain in overall survival (OS) with nivolumab was 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01] and that with pembrolizumab was 1.5 mo (HR = 0.80 nominal P = 0.0161). In the first-line setting compared to standard of care (EXTREME regime), pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population, while monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME in patients with PD-L1 positive R/M HNSCC. With 5 years of follow-up in the phase III KEYNOTE-048 study (NCT02358031), median OS remained longer for pembrolizumab versus EXTREME in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20 (HR, 0.61; 95 % CI, 0.46-0.81) and CPS ≥ 1 populations (HR, 0.74; 95 % CI, 0.61-0.89), and similar in the total population (HR, 0.82; 95 % CI, 0.69-0.97), while pembrolizumab-chemotherapy prolonged median OS in the PD-L1 CPS ≥ 20 (HR, 0.63; 95 % CI, 0.47-0.84), CPS ≥ 1 (HR, 0.65; 95 % CI, 0.53-0.79), and total (HR, 0.72; 95 % CI, 0.60-0.86) populations, with 5-year OS rate in the total population of 14.4 % for pembrolizumab versus 6.5 % for EXTREME and 16.0 % for pembrolizumab-chemotherapy versus 5.2 % for EXTREME and no clinically meaningful difference in progression-free survival (PFS) among groups in any populations.

Investigational pembrolizumab-based combinations evaluated in PD-L1-selected or PD-L1-unselected first-line and second-line R/M HNSCC populations have reported encouraging antitumor activity in single-arm studies. In second-line R/M HNSCC in TACTI-002 (part C), eftilagimod alpha (efti) combined with pembrolizumab (200 mg, once every 2 weeks) in patients who were PD-L(1)-naïve who had failed first-line platinum-based therapy, unselected for PD-L1, achieved an objective response rate of 29.7%, including 13.5% complete responders, with median duration of response not reached at median follow-up of 38.8 months. In first-line treatment of R/M HNSCC overexpressing PD-L1 (combined positive score ≥1) in an expansion cohort (ClinicalTrials.gov identifier: NCT04429542), ficerafusp alfa 1,500 mg once every week in combination with pembrolizumab 200 mg once every 3 weeks achieved confirmed objective response rates (ORRs) of 54% (complete response in 21%) in efficacy-evaluable patients with HPV-negative (n = 28) tumors and 27% in those with HPV-positive (n = 11) tumors, with median duration of response (DOR) of 21.7 months (95% CI, 6.0 to not estimable [NE]), median PFS of 9.9 months (95% CI, 4.4 to 22.7), and median OS of 21.3 months (95% CI, 9.9 to NE) in the HPV-negative subgroup at median follow-up of 26.3 months. In first-line treatment for R/M HNSCC with PD-L1 CPS ≥1 in EV-202 cohort 9 (NCT04225117), enfortumab vedotin (1.25 mg/kg IV) on days 1, 8 and pembrolizumab (200 mg IV) on day 1 in 21-day cycles achieved investigator-assessed confirmed objective response rate (cORR) of 39.0% (95% CI: 24.2-55.5) with complete response rate of 9.8%, DOR not estimable and estimated 6-month DOR rate of 81.7% (95% CI: 42.0-95.4), and median PFS of 5.1 months (95% CI: 3.5-NE) at median follow-up for OS of 11.0 months, while SD-101 combined with pembrolizumab induced an objective response rate of 24% including 2 complete and 10 partial responses with median duration of response of 7.0 [95% confidence interval (CI): 2.1-11.1] months.

By contrast, PD-L1-directed strategies with or without cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade have not shown beneficial outcomes versus standard of care. The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes, and in EAGLE, a randomized, open-label phase III study (ClinicalTrials.gov: NCT02369874), no statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76), with 12-month survival rates (95% CI) of 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine), respectively. Pooled randomized evidence supports the overall class effect, with pooled hazard ratios of overall and progression-free survival for programmed cell death-1/programmed cell death-ligand 1 inhibitor monotherapy of 0.82 (95% CI: 0.73-0.91, p < 0.001) and 0.96 (95%CI: 0.84-1.07, p < 0.001), and PD-1 inhibitor plus chemotherapy significantly prolonging PFS (hazard ratio [HR] 0.66, 95% CI 0.40-0.93, p < 0.001) and OS (HR 0.73, 95% CI 0.60-0.86, p < 0.001) versus SoC in analyses including KEYNOTE-048, CAPTAIN-1st, and JUPITER-02.

A New Benchmark Emerges in First-Line r/m HNSCC

The recent Phase 2 data for petosemtamab in combination with pembrolizumab in first-line recurrent/metastatic PD-L1+ head and neck squamous cell carcinoma (r/m HNSCC) signals a potentially significant shift in the therapeutic paradigm. With a median overall survival (OS) of 28.2 months, an objective response rate (ORR) of 63%, and a complete response (CR) rate of 19%, these results substantially outperform the real-world outcomes observed with current standard-of-care pembrolizumab monotherapy or its combination with chemotherapy, which typically yield OS around 12 months and lower ORRs. This level of efficacy, particularly the durable responses and high CR rate, addresses a critical unmet need in a disease known for its aggressive nature and poor prognosis.

Petosemtamab's unique bispecific mechanism, simultaneously targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), offers a compelling rationale for its enhanced activity. EGFR is a well-established oncogenic driver in HNSCC, while LGR5 plays a role in cancer stem cell proliferation. This dual targeting, combined with PD-1 blockade, could effectively overcome multiple pathways of tumor growth and immune evasion. The demonstration of efficacy across both HPV-positive and HPV-negative disease subtypes is particularly noteworthy, given the distinct biological characteristics and varying responses to immunotherapy often seen between these groups.

However, the path forward is not without its considerations. The robust Phase 2 findings must be rigorously validated in the ongoing Phase 3 LiGeR-HN1 trial. Translating these impressive early-phase results into a definitive Phase 3 success is paramount for regulatory approval and market adoption. Furthermore, the competitive landscape in r/m HNSCC is dynamic, with several other novel combinations also showing promise. Companies must consider how petosemtamab will differentiate itself amidst this evolving environment. Finally, while PD-L1 positivity was a selection criterion, further refinement of biomarkers, potentially including EGFR/LGR5 expression, could optimize patient selection and ensure the right patients receive this potentially transformative therapy. If successful, this combination could redefine first-line treatment expectations for r/m HNSCC, offering patients a much-needed improvement in survival and quality of life.