ESMO pre-"research" news Locally advanced head and neck squamous cell carcinoma immune combined with chemoradiotherapy and chemotherapy still takes time

The 2022 European Society of Medical Oncology (ESMO) Annual Meeting will be held
in Paris on September 9~13, local time.
As the most prestigious and influential oncology conference in Europe, ESMO Annual Conference covers basic research, translational research and the latest clinical research progress, providing a broad and excellent academic platform
for clinical practice and multidisciplinary discussions.
The KEYNOTE-048 study established the classic status of pembrolizumab as the first-line treatment of relapsed metastatic head and neck squamous cell carcinoma (HNSCC), and the results
of a 5-year follow-up were presented at this ESMO meeting.
In locally advanced HNSCC, pembrolizumab has not been explored, and new data have been announced
at the ESMO annual meeting.

Locally advanced head and neck squamous cell carcinoma

The Phase 3, randomized, double-blind, KEYNOTE-412 study (NCT03040999) was designed to evaluate the efficacy and safety
of pembrolizumab + chemoradiotherapy (CRT) versus placebo + CRT in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC).

The study included newly diagnosed, pathologically confirmed treatment-new patients with LAHNSCC (T3-T4 [N0-N3] or any N2a-3[T1-T4] laryngeal/hypopharyngeal/oral/p16-negative oropharyngeal carcinoma and T4 or N3p16-positive oropharyngeal carcinoma) randomized to pembrolizumab 200 mg Q3W + CRT (70 Gy/35F + cisplatin 100 mg/m2 Q3W), Pembrolizumab maintenance therapy or placebo Q3W + CRT, followed by placebo maintenance therapy
.
Pembrolizumab/placebo initiating doses were given 1 week before CRT, followed by 2 doses during CRT and 14 doses of maintenance therapy after CRT for a total of 17 doses
.
The primary endpoint was event-free survival (EFS) (efficacy cut-off, unilateral P = 0.
0242).

Overall survival (OS) and safety/tolerability were secondary endpoints
.

A total of 804 patients were randomized (402 patients per group).

Overall, baseline feature balance is comparable
between groups.
At the data cut-off of the final analysis (31 May 2022), the median time from randomization to data cut-off was 47.
7 months (range, 37.
0-61.
4).

CRT plus pembrolizumab had a trend towards EFS improvement compared with placebo (HR 0.
83, P = 0.
0429; table), but the difference did not reach statistical significance
.
The incidence of grade 3 AEs ≥ pembrolizumab was 92.
2% in the pembrolizumab group and 88.
4% in the placebo group; The proportion of discontinuation in the pembrolizumab group was 41.
2% compared with 33.
2% in the placebo group; Treatment-related AEs resulted in 1.
0% and 1.
5%
of deaths, respectively.

The results of the KEYNOTE-412 study showed a trend towards improvement in EFS in patients with LA-HNSCC compared with placebo + CRT, but the difference did not reach statistical significance
.
No new safety signals were observed
.

Recurrent metastatic head and neck squamous cell carcinoma

KEYNOTE-048 is a global, multicenter, prospective phase III clinical study comparing pembrolizumab/pembrolizumab combination chemotherapy with the classical standard of care EXTREME (cetuximab + platinum + fluorouracil) regimen for the first-line treatment of patients with
relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
。 OS, progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR)
were assessed in the ITT population, PD-L1CPS≥1, PD-L1CPS≥20, and general population.

Long-term follow-up (4 years) confirmed that pembrolizumab monotherapy or combination chemotherapy versus first-line treatment with EXTREME regimen confers long-term survival benefits
in patients with R/M HNSCC.
In patients with PD-L1 combined with a positive score (CPS) ≥1, pembrolizumab significantly prolonged
OS compared with patients with EXTREME regimens.
Given that pembrolizumab monotherapy for CPS≥1 or combination chemotherapy for first-line treatment of R/M HNSCC is the standard regimen in the United States, the results of long-term follow-up are expected
.
The ESMO meeting presented the results of a 5-year follow-up of all patients in the
KEYNOTE-048 study.

As of 21 February 2022, the median follow-up was 69.
2 months (range, 61.
2-81.
6 months) in the pembrolizumab monotherapy group and 68.
6 months (range, 61.
2-82.
1 months)
in the combination group with pembrolizumab.

In the population with CPS≥20, the 5-year OS rate was 19.
9% in the pembrolizumab monotherapy group and 7.
4% with the EXTREME regimen; The 5-year OS rate can reach 23.
9% in the pembrolizumab combination chemotherapy group and 6.
4% in the EXTREME regimen;

In the CPS≥1 population, the 5-year OS rate was 15.
4% in the pembrolizumab monotherapy group and 5.
5% with the EXTREME regimen; The 5-year OS rate can reach 18.
2% in the pembrolizumab combined chemotherapy group and 4.
3% in the EXTREME regimen;

In the general population, the 5-year OS rate was also 14.
4% in the pembrolizumab monotherapy group and 6.
5% with the EXTREME regimen; The 5-year OS rate can reach 16.
0% in the pembrolizumab combination chemotherapy group and 5.
2%
with the EXTREME regimen.

The 5-year OS rate and PFS rate, ORR and DOR are listed in the table
.
The incidence of grade 3 to 5 TRAEs was 17.
0% in the pembrolizumab monotherapy group, 71.
7% in the pembrolizumab combination chemotherapy group, and 69.
3%
in the EXTREME regimen group.

After 5 years of extended follow-up, first-line pembrolizumab and pembrolizumab combination chemotherapy continue to show durable antitumor activity and controlled safety
in R/MHNSCC.
These results further support pembrolizumab monotherapy and combination chemotherapy as the first-line standard of care for
R/M HNSCC.

References:

1.
J-P.
Machiels，et al.
Primary results of the phase III KEYNOTE-412 study:Pembrolizumab (pembro) with chemoradiation therapy(CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma ( HNSCC).
2022 ESMO.
Abstract LBA5.

2.
M.
Tahara，et al.
Pembrolizumab with or without chemotherapy for first-line treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): 5-year results from KEYNOTE-048.
2022 ESMO.
Abstract 659MO.