Pembrolizumab Earns 2 Positive CHMP Opinions in HNSCC, Other EU Indications

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued 2 positive opinions for pembrolizumab (Keytruda).1 These recommendations include the approval of a novel formulation of pembrolizumab for subcutaneous (SC) injection across all adult indications in the European Union (EU), and a new indication for pembrolizumab as part of a perioperative regimen for the treatment of select adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC).1

Both positive opinions will now undergo review by the European Commission (EC) for final marketing authorization in the EU, Iceland, Liechtenstein, and Norway. Final decisions are anticipated in the fourth quarter of 2025.

“Building on the legacy of [pembrolizumab], we are committed to driving innovation in cancer care with new routes of administration and indications in difficult-to-treat and earlier stages of cancer,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, at Merck Research Laboratories, stated in a press release. “This is a significant step forward in our pursuit of bringing this therapy to more patients. If approved, we believe [the SC formulation of pembrolizumab] has the potential to provide meaningful benefits to patients and providers in Europe because it can offer a shorter administration time compared to [pembrolizumab] and the option to receive treatment in additional health care settings.”

What Potential Clinical Advantages Does the Subcutaneous Formulation Offer?

The proposed new formulation involves pembrolizumab combined with berahyaluronidase alfa (MK-5180), a variant of human hyaluronidase that functions as a permeation enhancer by temporarily degrading hyaluronan in the extracellular matrix. This facilitates the SC administration of pembrolizumab in dosing schedules of every 3 weeks and every 6 weeks.

A key advantage of the SC formulation is the significantly reduced administration time compared to the typical intravenous infusion, which usually takes approximately 30 minutes. If approved, the time of SC administration could be reduced to approximately 1 minute every 3 weeks (395 mg) or 2 minutes every 6 weeks (790 mg).

Which Trial Supported the CHMP Recommendation for Subcutaneous Pembrolizumab?

The marketing authorization application for SC pembrolizumab was supported by results from the pivotal, open-label phase 3 3475A-D77 trial (NCT05722015), which compared the SC and IV formulations of pembrolizumab in adult patients with newly diagnosed stage IV squamous or nonsquamous metastatic non–small cell lung cancer (NSCLC) who did not have sensitizing EGFR, ALK, or ROS1 alterations.1,2

A total of 377 participants were randomly assigned 2:1 to receive SC pembrolizumab at 790 mg every 6 weeks (n = 251) or IV pembrolizumab at 400 mg every 6 weeks (n = 126), both in combination with platinum-doublet chemotherapy. The study’s dual primary end points were pharmacokinetic (PK) exposure measures of cycle 1 area under the curve (AUC) from week 0 to week 6 and steady-state (cycle 3) trough concentrations of pembrolizumab. Of note, secondary efficacy end points of objective response rate (ORR) and progression-free survival (PFS) were assessed through descriptive analyses.

How Does Subcutaneous Pembrolizumab Compare Clinically to the IV Formulation?

The trial successfully met its primary PK end points, showing that the overall exposure and trough concentrations of SC pembrolizumab were noninferior to those of IV pembrolizumab.

The noninferiority margin for the geometric mean ratios (GMRs) of both end points was prespecified as 0.8. Key PK results included:

• The GMR for cycle 1 AUC was 1.14 (96% CI; 1.06-1.22; P < .0001).
• The GMR for steady-state trough concentration was 1.67 (94% CI; 1.52-1.84; P < .0001).

Moreover, ORR and PFS were consistent between the SC and IV regimens, respectively:

• ORR: 45.4% (95% CI, 39.1%-51.8%) vs 42.1% (95% CI, 33.3%-51.2%), for an ORR ratio of 1.08 (95% CI, 0.85-1.37).
• Median PFS: 8.1 months (95% CI, 6.3-8.3) vs 7.8 months (95% CI 6.2-9.7) for an HR of 1.05 (95% CI 0.78-1.43).

Overall survival (OS) data remain immature, though the OS event rate was comparable between arms (24.3% in SC arm vs 29.4% in IV arm).

Was the Subcutaneous Route Associated with New Safety Concerns?

The overall safety profile of SC pembrolizumab plus chemotherapy was determined to be consistent with that of the IV regimen, with no unexpected safety findings noted. The incidence of treatment-related adverse effects (TRAEs; 90.0% SC vs 96.0% IV), grade 3-5 TRAEs (47.0% SC vs 47.6% IV), and serious TRAEs (21.1% SC vs. 19.8% IV) were similar between arms.

Local reactions related to SC administration were infrequent, reported in only 6 patients (2.4%). All injection-site AEs were mild (grade 1) and nonserious, resulting in no treatment discontinuations due to these reactions. The median duration of the first event was 5.5 days (range, 2-20). The incidence of immune-mediated AEs was generally consistent between the groups, with hypothyroidism being the most common.

Moreover, health-related quality of life assessments, measured by the EORTC QLQ-C30 and the EQ-5D-5L, showed no difference between the SC and IV arms from baseline to week 24.

Who is Eligible for the Proposed Perioperative Treatment in Locally Advanced HNSCC?

The second CHMP opinion recommends the approval of pembrolizumab monotherapy for patients with locally advanced HNSCC whose tumors exhibit PD-L1 expression with a combined positive score of 1 or greater.1 The recommended treatment schedule would consist of pembrolizumab as neoadjuvant treatment, then continued as adjuvant treatment in combination with radiation therapy with or without concomitant cisplatin, and then as monotherapy in adults.

If approved by the EC, this regimen would be established as the first perioperative anti–PD-1 treatment option available for select patients with resectable HNSCC in the EU.

Which Trial Supported the CHMP Recommendation for Perioperative Pembrolizumab in HNSCC?

The recommendation for resectable LA-HNSCC is based on results from the phase 3 KEYNOTE-689 trial (NCT03765918).1,3 In this open-label trial, 714 patients with LA-HNSCC were randomly assigned 1:1 to receive either pembrolizumab at 200 mg every 3 weeks for 2 cycles as neoadjuvant therapy and for 15 cycles as adjuvant therapy plus standard surgery and adjuvant radiotherapy with or without cisplatin, or the standard of care (SOC) alone.

The primary end point of the study was event-free survival (EFS). Secondary end points included OS, major pathological response (mPR), pathological complete response, and safety.

Findings from KEYNOTE-689 supported the FDA approval of perioperative pembrolizumab for this patient population in June 2025.4

What Was the Efficacy of the Perioperative Pembrolizumab Regimen in KEYNOTE-689?

At the first prespecified interim analysis, after a median follow-up of 38.3 months, the perioperative pembrolizumab-based regimen demonstrated a statistically significant and clinically meaningful improvement in EFS vs the SOC alone.1,3 This reduction in the risk of EFS events was as follows:

• PD-L1 CPS of 10 or greater: 34% reduction in the risk of EFS events (HR, 0.66; 95% CI, 0.49-0.88; P = .0022)
• PD-L1 CPS of 1 or greater: 30% reduction (HR, 0.70; 95% CI, 0.55-0.89; P = .0014)
• Intention-to-treat (ITT) population: 27% (HR, 0.73; 95% CI 0.58-0.92; P = .0041)

The median EFS with perioperative pembrolizumab vs SOC alone was as follows:

• PD-L1 CPS of 10 or greater: 59.7 months (95% CI, 41.1-not reached [NR]) vs 26.9 months (95% CI, 18.3-51.5)
• PD-L1 CPS of 1 or greater: 59.7 months (95% CI, 37.9-NR) vs 29.6 months (95% CI, 19.5-41.9)
• ITT population: 51.8 months (95% CI, 37.5-NR) vs 30.4 months (95% CI, 21.8-50.1)

A trend toward improved OS was observed in the CPS of 10 or greater population (HR, 0.72; 95% CI, 0.52-0.98), but this did not reach statistical significance at the interim analysis.

Crucially, the study confirmed that the addition of neoadjuvant pembrolizumab did not negatively affect the feasibility or completeness of surgical procedures. Surgery was completed in approximately 88% of patients in both the pembrolizumab and the control groups.

What Should Be Known About the Safety Profile of the Perioperative Pembrolizumab Regimen in KEYNOTE-689?

The safety profile of pembrolizumab in KEYNOTE-689 was consistent with previously reported studies, and no new safety signals were identified. Grade 3 or higher TRAEs occurred in 44.6% of patients receiving the perioperative regimen compared with 42.9% in the control group. TRAEs led to death in 4 patients receiving the perioperative regimen vs 1 patient receiving the SOC.

References

1. Merck receives two positive EU CHMP opinions for KEYTRUDA (pembrolizumab), for subcutaneous (SC) administration and for new indication for earlier-stage head and neck cancer. News release. Merck. September 19, 2025. Accessed September 19, 2025. https://www.merck.com/news/merck-receives-two-positive-eu-chmp-opinions-for-keytruda-pembrolizumab-for-subcutaneous-sc-administration-and-for-new-indication-for-earlier-stage-head-and-neck-cancer/
2. Felip E, Rojas CI, Schenker M, et al. Subcutaneous versus intravenous pembrolizumab, in combination with chemotherapy, for treatment of metastatic non-small-cell lung cancer: the phase III 3475A-D77 trial. Ann Oncol. 2025;36(7):775-785. doi:10.1016/j.annonc.2025.03.012
3. KEYTRUDA (pembrolizumab) as perioperative treatment with standard of care (SOC) adjuvant therapy significantly improved event-free survival (EFS) compared to SOC alone in patients with resectable locally advanced head and neck squamous cell carcinoma. News release. Merck. April 27, 2025. Accessed September 19, 2025. https://www.merck.com/news/keytruda-pembrolizumab-as-perioperative-treatment-with-standard-of-care-soc-adjuvant-therapy-significantly-improved-event-free-survival-compared-to-soc-alone-in-patients-with-resectable-loca/
4. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. FDA. June 12, 2025. Accessed September 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-and-adjuvant-pembrolizumab-resectable-locally-advanced-head-and-neck