Petosemtamab Generates Early Clinical Activity and Tolerability in HNSCC

Ezra Cohen, MD

The bispecific antibody petosemtamab (MCLA-158) delivered responses with a manageable safety profile in patients with advanced head and neck squamous cell carcinoma (HNSCC), according to findings from the cohort expansion portion of a phase 1/2 study that were presented at the 2023 AACR Annual Meeting.

Petosemtamab treatment led to an overall response rate (ORR) of 37.2% (n = 16/43; 95% CI, 23.0%-53.3%), with 1 patient with a complete response (CR), 15 patients with a partial response (PR), including 1 patient with p16-positive disease in the oropharynx, and 15 patients achieving a best response of stable disease (SD). The disease control rate was 72.1% (n = 31/43; 95% CI, 56.3%-84.7%).¹

“We observed clinically meaningful activity and durable responses in this cohort of patients with advanced and quite refractory HNSCC who had been previously treated with both immunotherapy and platinum-based chemotherapy,” lead study author Ezra Cohen, MD, of the University of California San Diego Moores Cancer Center, said in a presentation of the data.

Petosemtamab, which targets EGFR and LGR5, previously elicited tumor growth inhibition in patient-derived organoid models of epithelial tumors with high EGFR expression and minimal toxicity toward healthy LGR5-positive colon stem cells.²

To be eligible for this trial, patients needed to have incurable recurrent or metastatic HNSCC that had progressed on or was intolerant to PD-1 or PD-L1 inhibitors and platinum-based chemotherapy, as well as measurable disease and an ECOG performance score (PS) of 0 or 1.1

In the completed dose escalation portion of this study, no dose-limiting toxicities were reported, and the recommended phase 2 dose (RP2D) of 1500 mg once every 2 weeks was selected based on the safety, pharmacokinetics, and predicted receptor occupancy of petosemtamab. In the cohort expansion portion, patients received intravenous petosemtamab at the RP2D in 28-day cycles until progressive disease (PD) or toxicity, with tumor assessments every 8 weeks. After discontinuing treatment, patients were followed for survival for up to 18 months.

As of the data cutoff date of February 1, 2023, 49 patients had enrolled in the trial, 43 of whom were evaluable for efficacy. Six patients were excluded per protocol, 5 of whom withdrew on day 1 because of infusion-related reactions, and 1 who deviated from the exclusion criteria.

The primary end point of this trial was investigator-assessed ORR per RECIST v1.1 criteria. Key secondary end points included ORR per central review, duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, pharmacokinetics, immunogenicity, and biomarkers.

The enrolled patients had a median age of 63 years (range, 31-77), most were male (78%; n = 38), most had an ECOG PS of 1 (71%; n = 35), and most had squamous cell carcinoma (SCC) histology (98%; n = 48). In total, 35% (n = 17), 31% (n = 15), 16% (n = 8), 10% (n = 5), and 8% (n = 4) had primary tumors in the oropharynx, oral cavity, larynx, other sites, and hypopharynx, respectively.

A total of 35 patients had EGFR mutations, with a median H-score of 170 (range, 0-300). Regarding PD-L1 status, 41% (n = 20), 18% (n = 9), and 41% (n = 20) patients were PD-L1 positive (combined positive score ≥1), negative, and unknown, respectively. Of the patients with primary tumors in the oropharynx, p16 status was evaluable in 9, 35% (n = 6) of whom were p16-positive, and 18% (n = 3) of whom were p16-negative.

Patients in this trial had a median of 2 prior lines of therapy (range, 1-4), including a PD-1 or PD-L1 inhibitor (96%; n = 47), chemotherapy (94%; n = 46), platinum-based chemotherapy (92%; n = 45), and cetuximab ([Erbitux] 4%; n = 2). Patients’ last therapies prior to petosemtamab were immunotherapy (55%; n = 27), immunotherapy plus chemotherapy (29%; n = 14), chemotherapy (14%; n = 7), and an investigational therapy (2%; n = 1).

At the time of data cutoff, 25% of patients (n = 12) were still receiving petosemtamab therapy. Of the 37 patients who discontinued treatment, 63% (n = 31), 8% (n = 4), and 4% (n = 2) did so because of disease progression, related adverse effects (AEs), and other reasons, respectively. Patients received petosemtamab for a median of 4.1 months (range, 0.5-20.8).

Patients had a median time to response of 1.8 months (range, 0.8-3.5). “The majority of patients who did respond had that response early,” Cohen said.

Of the patients who responded, the median DOR was 6.0 months (95% CI, 3.7-not calculable), and 63% of responders (n = 10) had ongoing responses at the data cutoff date.

The median PFS in the efficacy-evaluable population, with 14 patients censored, was 5.3 months (95% CI, 3.7-6.8). In total, 29 patients progressed.

In the overall population, the median OS was 11.5 months (95% CI, 7.2-20.6), and 29 patients were still alive at the data cutoff date.

Cohen shared 2 case studies demonstrating the clinical activity of petosemtamab. The first was of a 57-year-old male with stage IVA, incurable, locally recurrent oral cavity SCC and an ECOG PS of 1 at baseline. This patient had previously received surgery followed by cisplatin plus radiotherapy followed by carboplatin plus paclitaxel and durvalumab (Imfinzi), to which they achieved a best response of PR and progressed 6 months after their first dose. In this trial, they received 6 cycles of petosemtamab, were still receiving treatment at data cutoff, and achieved a PR with 53% tumor reduction.

The second case study was of a 73-year-old female with stage III incurable, locoregional, p16-positive oropharynx SCC and an ECOG PS of 1 at baseline. This patient had previously received radical surgery followed by radiotherapy followed by pembrolizumab (Keytruda) plus a TLR9 agonist, to which they achieved a best response of PD. In this trial, they received 10 cycles of petosemtamab, were still receiving treatment at data cutoff, and achieved a PR with 71% tumor reduction.

An evaluation of intratumoral and peritumoral immune cell infiltrates in biopsy H&E slides at baseline and day 1 of cycle 2 showed increased infiltration in some patients with PR or SD. Patients with PD at cycle 2 day 1 did not have immune cell infiltration. However, baseline immune cell presence was not correlated with response.

The safety analysis population included the 80 total patients who received petosemtamab at the recommended phase 2 dose across both the dose escalation and cohort expansion portions of the trial. All patients experienced at least 1 AE, regardless of causality, 53% of patients (n = 42) had grade 3-5 AEs regardless of causality, and 33% of patients (n = 26) had grade 3-5 AEs suspected to be related to petosemtamab treatment.

The EGFR inhibition–associated toxicities of suspected relation to petosemtamab were rash (all-grade, 36%; grade 3-5, 0%), dermatitis acneiform (25%; 1%), and decreased blood magnesium (16%; 4%). Other common AEs suspected to be related to petosemtamab were hypotension (25%; 6%), infusion-related reaction (20%; 13%), erythema (19%; 0%), nausea (18%; 0%), dyspnea (16%; 4%), pruritis (14%; 0%), skin fissures (14%; 0%), dry skin (10%; 0%), stomatitis (10%; 0%), flushing (10%; 3%), headache (9%; 0%), hypoxia (9%; 1%), diarrhea (9%; 0%), fatigue (6%; 0%), asthenia (6%; 1%), pyrexia (4%; 0%), and constipation (3%; 0%). No treatment-related grade 5 AEs occurred.

The most frequent AEs were signs and symptoms of infusion-related reactions. A total of 74% and 21% of patients had grade 1-4 and grade 3-4 infusion-related reactions, respectively. The most common infusion-related reactions were hypotension (all-grade, 24%; grade 3-4, 6%), infusion-related reactions (21%; 13%), dyspnea (15%; 4%), erythema (14%; 0%), nausea (13%; 0%), flushing (10%; 3%), hypoxia (9%; 1%), chills (5%; 0%), hyperhidrosis (5%; 1%), pruritis (5%; 0%), tachycardia (5%; 0%), vomiting (5%; 0%), back pain (4%; 1%), bradycardia (4%; 3%), headache (4%; 0%), syncope (4%; 1%), and throat irritation (4%; 0%).

These infusion-related reactions mainly occurred during the first infusion, and all were resolved. Six patients discontinued petosemtamab on day 1 because of grade 3-4 infusion-related reactions. However, all petosemtamab rechallenges in patients who experienced infusion-related reactions were successful. Overall, the infusion-related reactions were manageable with prolonged infusion or prophylaxis on day 1.

“We developed and learned along the way how to manage and [use] prophylaxis for these infusion-related reactions, and those became quite feasible and did not interfere with ongoing therapy,” Cohen emphasized.

Further research is investigating petosemtamab either as monotherapy in patients with recurrent or metastatic HNSCC in the phase 1/2 MCLA-158-CL01 trial (NCT03526835) or in combination with pembrolizumab as first-line systemic therapy in those with recurrent or metastatic disease.

Disclosures: Dr Cohen reports consultant roles with Adagene, Astellas, Cidara, Eisai, Genmab, Gilboa, iTeos, Eli Lilly, MSD, Merck, Nectin Tx, Novartis, Nykode, Pangea Therapeutics, PCI Biotechn Replimune, Roche, Soteria, Tempus, and Viracta; stock/equity in Kinnate Biopharma and Primmune Therapeutics; board of directors participation with Akamis Bio; scientific advisory board participation with Kinnate Biopharma and Pangea Therapeutics; and data and safety monitoring board participation with Kura.

References

1. Cohen EEW, Fayette J, Daste A, et al. Clinical activity of MCLA-158 (petosemtamab), an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced head and neck squamous cell carcinoma (HNSCC). Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT012.
2. Herpers B, Eppink B, James MI, et al. Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR x LGR5 bispecific antibody with efficacy in epithelial tumors. Nat Cancer. 2022;3(4):418-436. doi:10.1038/s43018-022-00359-0