Could a pembro + CRT combo improve outcomes in locally advanced head and neck SCC?

Combining pembrolizumab with chemoradiation therapy (CRT) showed a trend toward improved event-free survival (EFS) compared with CRT alone in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), primary results of the phase III KEYNOTE-412 trial showed.

Participants were 804 treatment-naïve patients (median age 59 years, 82 percent male) with newly-diagnosed, unresected locally advanced (stage 3–4) HNSCC* and ECOG performance status 0–1 who could receive definitive high-dose cisplatin-based CRT. They were randomized 1:1 to receive intravenous pembrolizumab (200 mg Q3W) or placebo plus CRT**. Patients in the respective groups then received pembrolizumab or placebo maintenance therapy. Patients received a total of 17 doses (pembrolizumab/placebo priming dose 1 week pre-CRT, followed by two doses during CRT and 14 doses of maintenance therapy post-CRT).

Eighty-four and 86 percent of patients in the pembrolizumab and placebo groups, respectively, had PD-L1 ≥1 percent, with 36 percent of each group having PD-L1 ≥20. Twenty-seven and 26 percent of the respective groups were human papillomavirus (HPV)-positive. Eighty-six percent of each group were current or former smokers. Patients received pembrolizumab or placebo for a median 11.1 months, and 46.1 and 52.5 percent of patients in the pembrolizumab and placebo groups, respectively, received ≥300 mg/m² cisplatin.

At a median 47.7 months follow-up, there was a trend toward improved EFS with pembrolizumab vs placebo in the intention-to-treat population (median not reached [NR] vs 46.6 months; hazard ratio [HR], 0.83, 95 percent confidence interval [CI], 0.68–1.03; p=0.0429). [ESMO 2022, abstract LBA 5]

However, the between-group difference did not achieve statistical significance, said Professor Jean-Pascal Machiels from the Cliniques Universitaires Saint Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), UCLouvain, Brussels, Belgium, who presented the results at ESMO 2022. “We did not meet the primary endpoint but we have a favourable trend for CRT + pembrolizumab.”

Two- and 3-year EFS was 63.2 percent vs 56.2 percent (pembrolizumab vs placebo) and 57.4 percent vs 52.1 percent, respectively.

Overall survival (OS) was also not significantly improved with pembrolizumab vs placebo (median NR in either group; HR, 0.90, 95 percent CI, 0.71–1.15), with 2- and 3-year OS rates of 77.9 percent (pembrolizumab) vs 76.8 percent (placebo) and 71.9 percent vs 70.1 percent, respectively.

The benefits with pembrolizumab over placebo were consistent in patients with PD-L1 ≥1 percent (EFS: median NR vs 45.2 months; HR, 0.80, 95 percent CI, 0.64–1.00; OS: median NR in both groups; HR, 0.88, 95 percent CI, 0.68–1.14), with 2- and 3-year EFS rates of 63.7 percent vs 56.3 percent and 58.0 percent vs 51.8 percent, respectively, and OS rates of 77.7 percent vs 76.9 percent and 71.4 percent vs 70.2 percent, respectively.

Post hoc analysis showed a particular benefit with pembrolizumab vs placebo in patients with PD-L1 ≥20 (EFS: median NR in both groups; HR, 0.73, 95 percent CI, 0.49–1.06; OS: median NR in both groups; HR, 0.67, 95 percent CI, 0.43–1.04), with 2- and 3-year EFS rates of 71.2 percent vs 62.6 percent and 66.7 percent vs 57.2 percent, respectively, and OS rates of 83.3 percent vs 79.9 percent and 79.1 percent vs 73.0 percent, respectively.

Grade 3–5 adverse events (AEs) were reported in 92.2 and 88.4 percent of pembrolizumab and placebo recipients, respectively. Of these, 8.8 and 7.0 percent, respectively, were grade 5 AEs. There were four and six treatment-related deaths in the respective groups. AEs led to discontinuation of any treatment in 41.2 and 33.2 percent, respectively. Grade 3–5 immune-mediated AEs and infusion reactions were reported in 8.3 and 2.3 percent, respectively, with one grade 5 event in the pembrolizumab group. These AEs led to discontinuation of any treatment in 7.0 and 2.3 percent, respectively.

“No new safety signals [were observed] with the combination of pembrolizumab + CRT,” noted Machiels.

Why the need for new treatments?

The standard therapy in unresected, locally advanced HNSCC is high-dose cisplatin plus CRT, which results in 5-year survival rates of approximately 50 percent, said Machiels. “We clearly need to improve that,” he said in an interview with The ASCO Post. [https://ascopost.com/videos/esmo-congress-2022/jean-pascal-machiels-on-head-and-neck-cancer-recent-data-on-pembrolizumab-and-chemoradiation-therapy/, accessed 18 October 2022] “We know that pembrolizumab improves survival in the recurrent and metastatic setting,” he continued.

The apparent benefit noted in patients with higher PD-L1 expression suggests the need to streamline potential treatment recipients. “Clearly in the future, we need to try to individualize the treatment and to select the right patients for this kind of trial,” said Machiels.

Varying the delivery of pembrolizumab + CRT, such as in an adjuvant or neoadjuvant setting, may also produce different results than concomitant delivery, he concluded.