As HNSCC incidence rates continue to escalate, the need for effective treatment options becomes increasingly urgent. Despite breakthrough medications like pembrolizumab, which demonstrates efficacy in only around 20% of patients, proving the effectiveness of PD-1 inhibitors remains a significant challenge in HNC management. According to the DelveInsight analysis, the incident cases of Head and Neck Cancers were ~67,000 in 2023.

EGFR and LGR5 play pivotal roles as oncogenic drivers in HNSCC, further emphasizing the demand for targeted therapeutic interventions. Petosemtamab (MCLA-158), a cutting-edge bispecific antibody targeting both EGFR and LGR5, emerges as a promising solution in this domain. When paired with pembrolizumab, it showcases potential as a groundbreaking first-line therapy for HNSCC.

The recent breakthrough therapy designation bestowed upon petosemtamab by the US FDA underscores its significance in combating recurrent or metastatic HNSCC. Supported by encouraging data from ongoing trials, including Phase II investigations, this designation signifies a substantial leap forward in the realm of HNSCC treatment.

Interim findings from petosemtamab monotherapy trials at the recommended Phase II dose (RP2D) in 2L/3L HNSCC patients reveal a notable 37.2% overall response rate, with a median duration of response spanning 6.0 months. Furthermore, the ongoing Phase II study expansion cohort exploring petosemtamab in conjunction with pembrolizumab in first-line HNSCC offers promising prospects for enhanced patient outcomes. The results presented at ASCO 2024 were as follows:

Efficacy outcomes 

• 67% response rate overall (13/24 confirmed and 3/24 unconfirmed responses)

• Responses observed across HPV-related and unrelated cancer; and across PD-L1 CPS subgroups

Safety result: 

• Favorable safety profile including manageable IRRS (38% all Grades, 7% Grade 3; no Grade 4 or 5). IRRs were managed with premedication and prolonged infusion

• Treatment-emergent adverse events (TEAEs) were reported in 45 patients; most were Grade 1 or 2

• Treatment-related TEAEs led to study discontinuation in 2 patients, both were Grade 1-2

• No significant overlapping toxicities

In summary, the collaborative efforts of petosemtamab and pembrolizumab represent a beacon of hope for patients grappling with HNSCC, signaling a potential paradigm shift in the landscape of first-line treatment options.

KOL insights

“Petosemtamab combined with pembrolizumab in the first line demonstrated a 67% response rate, regardless of HPV status and regardless of PD-L1 expression. It had a favorable safety profile, including manageable infusion-related reactions (IRRs).”–MD, Department of Medical Oncology at Leon Berard Center of University, France.

“In the first-line setting, the combination of petosemtamab (MCLA-158) plus KEYTRUDA (pembrolizumab) was effective and well-tolerated in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).”–Associate Editorial Director.

Conclusion- 

 

Despite existing standard therapies, HNSCC poses a significant threat with a poor prognosis. Petosemtamab, a human IgG1 bispecific antibody targeting EGFR and LGR5, exhibits ADCC-enhanced activity. Its combination with pembrolizumab is currently under investigation in a Phase II study expansion cohort for 1L HNSCC. Initial findings presented at ASCO reveal clinically meaningful activity and favorable safety, with an impressive overall response rate of 67%. Despite recent strides, HNSCC remains a deadly disease with limited treatment options. However, the synergistic approach of petosemtamab and pembrolizumab shows promise as a potential game-changer, poised to redefine treatment standards for untreated head and neck cancer patients.