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A chemotherapy-free regimen combining the investigational therapy eftilagimod alpha with pembrolizumab (Keytruda) showed promising efficacy in a small cohort of patients with recurrent or metastatic PD-L1–negative head and neck squamous cell carcinoma (HNSCC).

The combination led to an objective response rate (ORR) of 35.5% as first-line treatment among 31 HNSCC patients with a PD-L1 combined positive score (CPS) less than 1, according to results of the reported by Robert Metcalf, MBCHB, PhD, of the Christie NHS Foundation Trust in Manchester, England.

"This response rate compares very favorably to historical results where a response rate in the region of 5% would be expected," Metcalf said during the European Society for Medical Oncology (ESMO) . "Certainly, based on the encouraging response rate described, and the unmet clinical need, particularly in the PD-L1 CPS<1 population, further investigation of this combination is warranted."

Metcalf also observed the combination appeared to be safe, with no new safety signals.

ESMO discussant Marc Oliva, MD, of the Institut Català d' Oncologia in Barcelona, Spain, agreed that the regimen showed "promising and encouraging overall response rates, and most importantly, a good safety profile."

However, he cautioned, overall response rates don't always translate into a survival benefit in later trial phases.

For example, he pointed to the LEAP-010 phase III trial in which adding lenvatinib (Lenvima) to pembrolizumab substantially improved the ORR (46.1% vs 25.4%) in first-line therapy for patients with recurrent/metastatic HNSCC, but a later analysis showed actually poorer median overall survival with the combination (15 vs 17.9 months).

"We don't know whether this will be the case for [TACTI-003], but definitely we need to consider that [while] response rates might be exciting in early studies, we need to increase the number of patients and also see a translation into PFS [progression free survival] and overall survival benefits," Oliva said.

In the pre-immunotherapy era, the standard of care for recurrent or metastatic HNSCC was platinum-based chemotherapy with the epidermal growth factor receptor inhibitor cetuximab (Erbitux). However, on the basis of the KEYNOTE-048 trial, pembrolizumab is now recommended as first-line treatment for recurrent/metastatic HNSCC as monotherapy in PD-L1–positive disease, or with platinum plus fluorouracil independent of PD-L1 status.

However, an of KEYNOTE-048 participants with PD-L1 CPS <1 status showed that neither pembrolizumab monotherapy nor pembrolizumab-chemotherapy demonstrated benefit over cetuximab-chemotherapy. The ORR was only 4.5% for pembrolizumab versus 42% for cetuximab and chemotherapy, with a median overall survival of 7.9 months and 11.3 months in the two groups, respectively.

Eftilagimod alpha is a soluble LAG-3 protein and major histocompatibility complex class II agonist that has demonstrated after failure of first-line chemotherapy and in first-line treatment for patients with .

TACTI-003 was a multicenter, randomized, open-label phase IIb trial with two cohorts. Cohort A included patients with CPS ≥1 who were randomized to receive eftilagimod plus pembrolizumab or pembrolizumab alone, but it was not included in the current analysis.

Cohort B comprised 33 patients who were recruited at 14 sites across six countries. The 31 patients evaluable for efficacy had a median age of 64 years and were mostly male, ECOG 1 status, and current or ex-smokers. They were treated with subcutaneous eftilagimod (30 mg) every 2 or 3 weeks and IV pembrolizumab (400 mg) every 6 weeks for up to 24 months.

Of the 31 patients, a complete response was observed in three patients, a partial response in eight, and stable disease in seven, translating into a disease control rate of 58.1%. Twenty-two (71%) patients remained on treatment for at least 6 months, and about half for 6 or more months.

Regarding safety, treatment-emergent adverse effects (TEAEs) were observed in 72.7% of patients in the safety population of 33 patients, with just 15.2% of patients experiencing grade 3 or higher events and 9.1% leading to treatment discontinuation.

Immune-mediated AEs were observed in 39.4% of patients, of which 9.1% were grade 3. Local injection site reactions occurred in 18.2% of patients, all of which were grade 1.

The most frequently observed TEAEs included fatigue (21.2%), weight loss (18.2%), hypothyroidism (18.2%), pyrexia (15.2%), arthralgia (15.2%), gamma-glutamyl transferase increase (15.2%), and anemia (15.2%).

As for the next step for eftilagimod, "we've seen a good signal of activity in this subgroup," said Metcalf. "We now want to know whether that translates into an overall survival gain."

Oliva observed that this will take a phase III study, "but pembrolizumab alone cannot be a comparator, so we need to think about combinations such as chemo plus cetuximab or chemo plus pembrolizumab in this subgroup."

"We might also have to consider other endpoints and co-primary endpoints that actually inform us on the best treatment sequence," Oliva added. "Because we are starting to see that despite some PFS benefit, that might not translate into overall survival in the end."

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