Inhibrx Biosciences’ INBRX-106 Combo Tops KEYTRUDA Alone in Phase 2 Cancer Study

Key Points

• INBRX-106 plus KEYTRUDA outperformed KEYTRUDA alone in an interim randomized Phase 2 study in first-line PD-L1-positive head and neck squamous cell carcinoma. Among evaluable patients, the combo produced a 44% confirmed objective response rate versus 21.4% for pembrolizumab alone, including three complete responses.
• Inhibrx said the data were supported by strong pharmacodynamic evidence, with much higher CD8 and CD4 T-cell proliferation and activation in the combination arm, suggesting INBRX-106 is functioning as a T-cell costimulator.
• The company described safety as manageable with mostly low-grade adverse events and no treatment-related deaths, and plans to start the Phase 3 portion of HexAgon in the third quarter while also expanding into lung cancer studies.

Inhibrx Biosciences NASDAQ: INBX reported interim randomized Phase 2 data for INBRX-106 in combination with Merck’s KEYTRUDA in first-line PD-L1-positive head and neck squamous cell carcinoma, with Chief Executive Officer Mark Lappe saying the results showed a higher confirmed response rate and deeper tumor reductions versus KEYTRUDA alone.

The update came from the Phase 2 portion of the HexAgon study, which is evaluating INBRX-106, an OX40 agonist, in combination with pembrolizumab compared with pembrolizumab alone. Lappe said the trial was modeled after KEYNOTE-048 and enrolled patients with high PD-L1 expression, defined as a combined positive score of at least 20.

The interim analysis included 53 evaluable patients as of a May 7 data cutoff: 25 patients in the INBRX-106 combination arm and 28 patients in the KEYTRUDA control arm. Patients were considered evaluable if they had confirmed disease progression or death, or had completed at least two on-study tumor assessments. Lappe said another 15 patients had not yet reached the maturity threshold for response confirmation or were not evaluable at the time of the cutoff and were not included in the analysis.

Combination Arm Shows Higher Confirmed Response Rate

In the evaluable population, 11 of 25 patients, or 44%, in the INBRX-106 plus KEYTRUDA arm achieved a confirmed objective response, compared with six of 28 patients, or 21.4%, in the KEYTRUDA-alone arm. Lappe said that represented a 22.6-percentage-point absolute increase in confirmed responses.

The company also reported three complete responses in the INBRX-106 combination arm and none in the pembrolizumab-alone arm. Lappe said complete responses in first-line head and neck cancer remain uncommon and are generally associated with more durable outcomes.

“We believe we don’t just have more responders, but better responders,” Lappe said, noting that the company’s investor materials included a waterfall plot showing depth of response. He said the majority of responders in the combination arm had more than 50% tumor shrinkage.

Lappe cautioned that data from the randomized study are still maturing, and said longer follow-up will be needed to assess durability and progression-free survival. He said the company expects to present a more complete mature dataset, including longer-term endpoints such as progression-free survival, in the fourth quarter.

Pharmacodynamic Data Point to T Cell Expansion

Inhibrx said the clinical findings were supported by pharmacodynamic data showing up to a 15-fold increase in peripheral CD8 and CD4 T cell proliferation and up to a four-fold increase in activation in patients treated with INBRX-106 plus KEYTRUDA. That compared with up to a 2.5-fold increase in proliferation and 1.5-fold increase in activation among patients receiving KEYTRUDA alone.

Lappe said those findings supported INBRX-106’s role as a T cell costimulator and differentiated it from earlier OX40 agonist programs. In response to an analyst question, he said prior OX40 programs had generally shown modest T cell expansion in the 2x to 5x range in selected patients, without meaningful clinical responses.

“The alignment between the biological activity and the clinical responses increases our confidence that this signal is real and potentially reproducible across indications,” Lappe said.

Safety Described as Manageable

Lappe said the combination of INBRX-106 and pembrolizumab was “generally manageable,” with a safety profile consistent with immune activation in the setting of checkpoint blockade. The most common treatment-related adverse events were rash, diarrhea, fatigue and infusion reaction, which he said were predominantly low grade. No treatment-related deaths were reported in either arm.

During the question-and-answer session, Lappe said more than 200 patients have been exposed to INBRX-106 across the company’s clinical development program. He said rash has been the most frequent on-target finding associated with OX40 agonism. He also noted that the overall safety data had not yet been fully quality-controlled, but said top-line rates appeared “incredibly similar” to single-agent pembrolizumab safety data from KEYNOTE-048.

Company Plans Phase 3 and Additional Studies

Based on the interim results, Inhibrx plans to begin the Phase 3 portion of the HexAgon study in head and neck cancer during the third quarter of this year. Lappe said the seamless Phase 2/3 design means the company’s sites are active and ready to begin the Phase 3 portion. In response to an analyst question, he said the company expects to complete enrollment by 2029 at the latest, while also planning to expand the number of active sites.

The company also plans to initiate a study later this quarter in the perioperative non-small cell lung cancer setting. Lappe said Inhibrx believes OX40 agonism may have the greatest potential in earlier-stage disease, where patients typically retain a more active immune system. He said the planned perioperative lung cancer study is designed to closely mirror elements of Merck’s KEYNOTE-671 framework, which showed an approximately 18% complete pathological response rate.

Lappe also said Inhibrx is beginning to plan for studies in frontline metastatic non-small cell lung cancer, which are expected to begin next year. He said the company has already generated safety and tolerability data in heavily pretreated non-small cell lung cancer patients using INBRX-106 with pembrolizumab and chemotherapy regimens used for squamous and non-squamous disease, and has not observed new or unexpected safety signals beyond those typically anticipated from the treatment backbone.

Outside checkpoint inhibitor combinations, Lappe said Inhibrx plans to explore INBRX-106 with agents that could benefit from T cell costimulation, including vaccines, T cell engagers and CAR-T therapies.

About Inhibrx Biosciences NASDAQ: INBX

Inhibrx, Inc, headquartered in La Jolla, California, is a clinical-stage biotechnology company focused on the discovery and development of next-generation protein therapeutics. The company's proprietary protein engineering platform enables the design and production of multispecific and multivalent biologics with tailored binding characteristics and favorable pharmacokinetic properties. By leveraging high-throughput screening and structure-based design, Inhibrx aims to create molecules that address challenging targets in oncology, regenerative medicine and other areas of unmet medical need.

The company's lead candidate, INBRX-109, is a tetravalent agonist of the receptor tyrosine kinase ROR2 designed to stimulate tissue repair and regeneration.

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