Micvotabart pelidotin produced early activity in head and neck squamous cell carcinoma as monotherapy and in combination with pembrolizumab.
Treatment with the investigational antibody-drug conjugate (ADC) micvotabart pelidotin (PYX-201) alone or in combination with pembrolizumab (Keytruda) led to antitumor activity in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), according to preliminary findings from phase 1 (NCT05720117) and phase 1/2 (NCT06795412) trials.1-3
Findings from the phase 1 monotherapy study showed that micvotabart pelidotin given at a dose of 5.4 mg/kg once every 3 weeks (n = 13) produced a confirmed overall response rate (ORR) of 46%, including 1 complete response per RECIST 1.1 criteria, and a disease control rate (DCR) of 92%, in the second- or later-line treatment of patients with recurrent/metastatic HNSCC.1 In dose-expansion arms, those in arm 1 who received prior platinum-based chemotherapy and anti–PD-L1 therapy (n = 5) experienced a confirmed ORR of 60%; those in arm 2 previously treated with an EGFR inhibitor and/or anti–PD-L1 therapy (n = 4) experienced a confirmed ORR of 25%. Responses were observed across human papillomavirus (HPV)–positive, HPV-negative, and HPV–not applicable tumors. For the lone best response of progressive disease, this patient had a verrucous HNSCC subtype, which is typically chemotherapy resistant and often managed surgically.
In the phase 1/2 combination trial, micvotabart pelidotin given at doses of 3.6 mg/kg or 4.4 mg/kg in combination with pembrolizumab at 200 mg once every 3 weeks (n = 7) generated a confirmed ORR of 71% and a DCR of 100%, with responses occurring across a range of PD-L1 combined positive scores (CPS), including in those with a CPS of at least 1 to a CPS of more than 20. Responses were also observed in patients who had progressed following prior checkpoint inhibitor therapy.
“The current paradigm for treatment of recurrent/metastatic HNSCC offers limited options and therapeutic mechanisms for our patients, so we are particularly pleased to observe a novel mechanism providing emerging evidence of such compelling benefit-risk profile,” Glenn J. Hanna, MD, director of the Center for Cancer Therapeutic Innovation and Center for Salivary and Rare Head and Neck Cancers at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School, stated in a news release.
As monotherapy, micvotabart pelidotin was generally well tolerated in the phase 1 study; no grade 4 ADC payload–related, treatment-related adverse effects (TRAEs) occurred, and no grade 5 AEs were observed. TRAEs occurred in 89% of evaluable patients (n = 18), with grade 3 or higher TRAEs reported in 56% of patients. TRAEs leading to treatment discontinuation were reported in 28% of patients; notably, all patients who discontinued treatment due to TRAEs had high body weight, defined as at least 10% above adjusted ideal body weight. Based on these findings, adjusted ideal bodyweight–based dosing, which has been associated with improved tolerability without compromising activity in other ADC programs, is planned for implementation in ongoing and future studies.
In the phase 1/2 trial, micvotabart pelidotin in combination with pembrolizumab also showed favorable tolerability. No grade 3/4 ADC payload–related TRAEs of interest and no grade 5 AEs were reported. TRAEs occurred in 86% of patients (n = 7), and no TRAEs led to treatment discontinuation. Importantly, investigators observed a lack of overlapping toxicities between micvotabart pelidotin and pembrolizumab, supporting the continued evaluation of the combination regimen.
“The preliminary data for micvotabart pelidotin as monotherapy and in combination with pembrolizumab add to the growing body of evidence supporting micvotabart pelidotin’s therapeutic potential and highlight its agility as a novel potential treatment option across the recurrent/metastatic HNSCC landscape,” Lara S. Sullivan, MD, president, chief executive officer, and chief medical officer of Pyxis Oncology, stated in a news release. “The emerging response rates and disease control observed across these studies are highly encouraging, and the lack of early disease progression supports confidence in the durability profile as we advance micvotabart pelidotin in clinical development. We look forward to sharing mature data from the ongoing trials [in 2026].”
The phase 1 monotherapy study is evaluating micvotabart pelidotin in patients at least 18 years of age with locally advanced solid tumors, including HNSCC.2 Part 1 of the study served as dose escalation, evaluating the ADC at multiple doses across different tumor types.1 In dose expansion during part 2, a cohort featured patients with recurrent/metastatic HNSCC being treated in the second line or beyond.
At data cutoff, 18 patients were treated with micvotabart pelidotin at a dose of 5.4 mg/kg once every 3 weeks. These patients received a median of 3 prior lines of therapy, and all had received prior platinum-based chemotherapy and anti–PD-L1 therapy. Prior treatment with a taxane and EGFR-targeted therapy was reported in 67% and 50% of patients, respectively.
In the phase 1/2 combination trial, investigators enrolled patients at least 18 years of age with histologically or cytologically confirmed advanced solid tumors; this included patients with first-line HNSCC and those with second- or later-line HNSCC.3
Dose escalation is ongoing in this study, and thus far, 7 patients with HNSCC have been treated with micvotabart pelidotin at 3.6 mg/kg (n = 4) or 4.4 mg/kg (n = 3) plus pembrolizumab at 200 mg once every 3 weeks.1
Among patients with first-line HNSCC (n = 4), all received prior platinum-based chemotherapy with radiation in the adjuvant or definitive settings; 1 of these patients received prior taxane therapy in the neoadjuvant setting. In the second- and later-line cohort (n = 3), all received prior platinum-based chemotherapy and anti–PD-L1 therapy, and 1 patient received a prior taxane.
Looking ahead, Pyxis Oncology is positioning micvotabart pelidotin for continued clinical maturation across both monotherapy and combination strategies, with multiple data updates anticipated in 2026. In mid-2026, the company plans to present updated results from the ongoing phase 1 monotherapy program in second- and later-line recurrent/metastatic HNSCC, which is expected to include a larger patient cohort and the first durability readouts. In the second half of 2026, Pyxis also plans to present updated findings from the ongoing phase 1/2 combination study, including data in first-line, second-line, and later-line HNSCC, and additional tumor types.
“As we look ahead to where the treatment landscape may include next-generation EGFR combination therapies as first-line options for select patients, many will still lack effective treatments, particularly in later lines, which remains a significant unmet clinical need,” Hanna added in the news release. “Micvotabart pelidotin monotherapy presents an intriguing potential option for these later-line patients, while the initial data in combination with pembrolizumab also shows promising potential synergies in [the] first line.”
