Lung squamous cell carcinoma (SCC) accounts for approximately 25% of all cases of
non-small cell lung cancer (NSCLC). Treatments vary a great deal between SCC and non-SCC.
Platinum-based chemotherapy is the main treatment for lung SCC, and targeted therapies,
such as epidermal growth factor receptor (EGFR) inhibitors and anaplastic lymphoma
kinase (ALK) inhibitors, are effective for lung adenocarcinoma but not lung SCC; therefore,
new treatment strategies for lung SCC are required. Novel tumor immunotherapies are
becoming potential treatments for cancer patients. The results of the KEYNOTE-407
study on lung SCC are exciting. In this paper, we interpret and analyze the clinical
implications of the KEYNOTE-407 study.
The KEYNOTE-407 study (1) is a multicountry, randomized, double-blind, placebo-controlled,
phase III trial in treatment-naïve patients with stage IV squamous NSCLC (sq-NSCLC),
including patients with negative expression of programmed death-ligand 1 (PD-L1).
The primary endpoints are overall survival (OS) and progression-free survival (PFS).
The secondary endpoints include overall response rate (ORR) and duration of response
(DOR). A total of 559 eligible patients were randomly assigned at 1:1 to receive pembrolizumab
200 mg or placebo Q3W, for 35 cycles, combined with 4 cycles of carboplatin, area
under curve (AUC) 6 mg/mL/min Q3W, and researchers’ choice of either paclitaxel (PTX)
200 mg/m2 Q3W or nab-PTX100 mg/m2 QW.
The results showed that pembrolizumab combined with carboplatin and PTX or nab-PTX
significantly improved ORR (57.9% vs. 38.4%), OS [hazard ratio (HR) 0.64, 95% confidence
interval (CI): 0.49–0.85, P=0.0008), and PFS (HR 0.56, 95% CI: 0.45–0.70, P<0.0001)
relative to placebo combined with carboplatin and PTX or nab-PTX. Regardless of the
PD-L1 tumor proportion score (TPS), patients benefited from additional pembrolizumab
therapy. In addition, pembrolizumab combined with carboplatin and PTX or nab-PTX showed
a manageable safety profile.
In this study, we explore and analyze the effect of researchers’ choice of either
PTX (60.1%) or nab-PTX (39.9%), one of the stratification factors, on efficacy. Patients
who received PTX or nab-PTX showed similar baseline characteristics. Pembrolizumab
combined with carboplatin improved the outcomes, regardless of whether patients received
PTX or nab-PTX. For the comparison between pembrolizumab combined with carboplatin
and carboplatin only, the median OS (mOS) was 14.0 vs. 10.3 months for patients with
PTX, with an HR of 0.67 (0.48–0.93), and were NR vs. 12.6 months for patients with
nab-PTX, with an HR of 0.59 (0.36–0.98); the median PFS (mPFS) was 6.4 vs. 4.4 months
for patients with PTX, with an HR of 0.52 (0.40–0.68), and were 6.5 vs. 5.9 months
for patients with nab-PTX, with an HR of 0.65 (0.45–0.94); and the ORRs were 57.4%
vs. 37.7% for patients with PTX and were 58.7% vs. 39.5% for patients with nab-PTX.
For the comparison between pembrolizumab combined with carboplatin and placebo combined
with carboplatin, in terms of grade 3–5 adverse events (AEs), the incidence rates
were 63.9% vs. 59.3% for patients with PTX and 78.9% vs. 81.4% for patients with nab-PTX;
in terms of treatment discontinuation, the rates were 13.6% vs. 8.4% for patient with
PTX and 12.8% vs. 3.5% for patients with nab-PTX; in terms of immune-related AEs,
the incidence rates were 29.6% vs. 9.6% for patients with PTX and 27.5% vs. 7.1% for
patients with nab-PTX; and in terms of steroids, the usage rates were 99.4% vs. 99.4%
for patients with PTX and 88.1% vs. 86.7% for patients with nab-PTX. As first-line
treatment for metastatic lung SCC, pembrolizumab combined with carboplatin and PTX
was superior to placebo combined with carboplatin and PTX and significantly improved
OS, PFS, and ORR, regardless of the specific type of PTX. Moreover, pembrolizumab
combined with PTX or nab-PTX was well tolerated.
On November 23, 2019, Prof. Ying Cheng of Jilin Cancer Hospital presented the results
of an interim analysis of the KEYNOTE-407 China extension study, including extension
cohorts, at the 2019 European Society for Medical Oncology in Asia (ESMO Asia) conference
(2).
A total of 125 treatment-naïve patients in China with histologically confirmed stage
IV sq-NSCLC and no symptomatic brain metastases were enrolled at Chinese centers and
randomly assigned at 1:1 to receive 4 cycles of pembrolizumab (200 mg, Q3W) + carboplatin
(AUC 6, Q3W) + PTX (200 mg/m2, Q3W)/nab-PTX (100 mg/m2, QW) or placebo + carboplatin
+ PTX/nab-PTX, followed by maintenance therapy with pembrolizumab or placebo. Patients
with cancer progression in the control group could crossover to receive pembrolizumab
monotherapy. The primary endpoints were PFS and OS, and the secondary endpoint was
ORR. Moreover, protocol-defined subgroup analyses were performed to analyze OS, PFS,
and ORR per PD-L1 tumor expression status (TPS ≥50% vs. 1% to 49% vs. <1%) to evaluate
the benefits of pembrolizumab combined with carboplatin in the Chinese population
and to compare with the results of the global population.
After a median follow-up of 10.4 months, the results showed that mOS was 17.3 months
in the pembrolizumab group and 12.6 months in the control group, indicating that pembrolizumab
combined with carboplatin reduced mortality by 56%; for mPFS, the figures were 8.3
and 4.2 months, respectively, indicating that pembrolizumab combined with carboplatin
reduced the risk of progression or mortality by 68%. Moreover, pembrolizumab combined
with carboplatin improved the ORR by 36.8% (78.5% vs. 41.7%). As of May 2019, 35 patients
in the control group crossed over to receive pembrolizumab monotherapy, and 31 patients
(48%) in the pembrolizumab group and 4 patients (7%) in the control group were still
receiving treatments.
The overall incidence of AEs (any grade) was 100% in both groups; for grade 3–5 AEs,
the rates were similar in the two groups, 89% and 87%. Major immune-related AEs included
hyperthyroidism, hypothyroidism, infusion reactions, myositis, pneumonitis, thyroiditis,
and type 1 diabetes.
The results of the KEYNOTE-407 China extension study are consistent with those of
the global KEYNOTE-407 study. First-line treatment with pembrolizumab combined with
carboplatin significantly improves the OS and PFS of patients with metastatic sq-NSCLC
and demonstrates a manageable safety profile, indicating that the regimen brings more
benefits to Chinese patients with lung SCC.
It should be noted that taxanes are used in the KEYNOTE-407 study. Our analysis of
conventional PTX vs. nab-PTX showed that nab-PTX achieved similar outcomes and caused
fewer adverse reactions; more importantly, it eliminated steroid pretreatment, a step
required for conventional PTX. Currently, there is no definitive evidence to suggest
that high-dose steroids affect the efficacy of immunotherapy; however, some retrospective
analyses and basic research have shown that steroids may negatively affect immunotherapy.
Thus, eliminating this risk can improve the confidence of patients and physicians
regarding the regimen. Moreover, this study does not use gemcitabine, a standard treatment
for SCC, or radiotherapy, which eliminates the risk of radiation injury.
In summary, as first-line treatment for metastatic lung SCC, pembrolizumab combined
with carboplatin and PTX/nab-PTX, significantly improves OS, PFS, and the ORR and
is well tolerated. For the Chinese population, first-line treatment with pembrolizumab
combined with carboplatin and PTX/nab-PTX significantly improves the OS and PFS of
patients with metastatic sq-NSCLC with a manageable safety profile.
Supplementary
The article’s supplementary files as
10.21037/tlcr.2020.03.12