'Transformational' Results in Squamous Cell Lung Cancer

Pam Harrison

October 02, 2018

TORONTO — Pembrolizumab (Keytruda, Merck) plus chemotherapy extends overall survival (OS) in squamous non–small cell lung cancer (NSCLC), a difficult-to-treat malignancy for which there is a real need of a more effective regimen, according to new data from a phase 3 trial.

It's another example of a combination of immunotherapy and chemotherapy creating a new standard in the treatment of lung cancer, said experts.

Results from the KEYNOTE-407 study indicate that the median overall survival (OS) in a pembrolizumab-plus-chemotherapy arm was 15.9 months, compared with 11.3 months in a combination chemotherapy arm.

The findings were reported by Balazs Halmos, MD, Montefiore Medical Center, New York City, here at the 19th World Conference on Lung Cancer (WCLC).

The study was simultaneously published online September 25 in the New England Journal of Medicine.

"In this particular subset of squamous NSCLC patients, there has been very little real progress made in many years despite the introduction of targeted agents, which are rarely used, and antiangiogenics, which also have very little activity [in this setting]," Halmos told Medscape Medical News.

"So this really is a transformational event, to make major progress in the frontline management of squamous NSCLC, and the progress made here is not just measured by an improved response rate or an improved progression-free survival but a very significant improvement in overall survival, which is what we need to see in these studies," he added.

This should absolutely be the standard of care. Dr Balazs Halmos

"As of the publication of this study, this should absolutely be the standard of care that future regimens need to be measured against," Halmos stressed.

Commenting on the study, discussant Antoinette Wozniak, MD, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, agreed with Halmos that KEYNOTE-407 was an important "practice-changing" trial.

The new results echo findings in another difficult-to-treat lung cancer that were also presented here.

Earlier at the meeting, other researchers showed that concurrent administration of atezolizumab (Tecentriq, Genentech) — another immune checkpoint inhibitor — with chemotherapy significantly extended median OS compared with chemotherapy alone in patients with extensive-stage, small cell lung cancer (ES-SCLC).

Given the improvement in OS, the first in decades, the investigators suggested that atezolizumab plus carboplatin and etoposide be considered the new standard of care for first-line treatment of ES-SCLC.

Immune checkpoint inhibitors such as atezolizumab and pembrolizumab inhibit the programmed death receptor–1 and its ligand (PD-L1) and have now shown to be effective in the treatment of squamous and nonsquamous NSCLC.

KEYNOTE-407 Design

In the four-arm clinical trial, 559 patients with untreated, metastatic, squamous NSCLC all received carboplatin plus either paclitaxel or nanoparticle albumin–bound (nab)-paclitaxel (Abraxane, Celgene) for the first four cycles.

Carboplatin was given at a dose calculated to produce an area under the concentration-time cure of 6 mg/mL/min on day 1; and either paclitaxel, 200 mg/m2, was given on day 1, or nab-paclitaxel, 100 mg/m2, was given on days 1, 8, and 15.

Patients were then randomly assigned to receive 200 mg of pembrolizumab or placebo for up to 35 cycles.

All treatments were given intravenously in 3-week cycles, the investigators point out.

Patients in the placebo arm were permitted to cross over to active immunotherapy upon disease progression.

Those assigned to paclitaxel were also premedicated with a glucocorticoid and an antihistamine. Those assigned to nab-paclitaxel in theory did not require premedication, although almost all of them received glucocorticoid treatment for the prevention of nausea.

Treatment was continued until radiographic disease progression or unacceptable toxicity.

The overall response rate (ORR) was improved by 20% with the addition of pembrolizumab, Halmos noted.

Median PFS was 44% longer for the patients who received additional pembrolizumab, at 6.4 months compared with 4.8 months in the chemotherapy-plus-placebo arm (P < .001), he added.

At 1 year, an estimated 65.2% of patients treated with the immunotherapy-chemotherapy combination were still alive, compared with 48.3% of patients in the chemotherapy-alone arm.

The OS benefit was consistent, regardless of the level of PD-L1 expression, the investigators note.

In an exploratory analysis, which he presented at the meeting, Halmos examined outcomes by the choice of the taxane used to see whether either paclitaxel or nab-paclitaxel had a more favorable influence on OS, PFS, or ORR.

Halmos pointed out that 60% of patients in the study were treated with paclitaxel, and the remaining 40% of patients received nab-paclitaxel.

The two taxane groups were well balanced except for the fact that a somewhat higher percentage of patients from East Asia received nab-paclitaxel, he noted.

"In both groups of patients, OS was very significantly improved with additional pembrolizumab, at an HR [hazard ratio] of 0.67 with paclitaxel and an HR of 0.59 with nab-paclitaxel," Halmos reported.

Similarly, PFS rates were also improved with the addition of pembrolizumab, at an HR of 0.52 for paclitaxel and an HR of 0.65 for nab-paclitaxel.

ORRs were also very similar in both taxane groups.

Table. Outcomes Stratified by Baseline Taxane Use

  Caboplatin Plus Paclitaxel Carboplatin Plus Nab-Paclitaxel
  Pembrolizumab + Chemotherapy Placebo + Chemotherapy Pembrolizumab + Chemotherapy Placebo + Chemotherapy
Median OS 14.0 months 10.3 months Not reached 12.6 months
Median PFS 6.4 months 4.4 months 6.5 months 5.9 months
ORR 57.4 months 37.7 months 58.7 months 39.5 months


Adverse Events

In the overall trial, the incidence of adverse events (AEs) of grade 3 or higher was virtually identical in the immunotherapy-plus-chemotherapy arm, at 69.8%, as in the placebo-chemotherapy arm, at 68.2%.

However, AEs prompted more discontinuations of any treatment component in almost one quarter of the immunotherapy-chemotherapy arm, at 23.4%, vs 11.8% for the control arm. The rate of discontinuations of all treatment components was also higher in the pembrolizumab-chemotherapy group, at 13.3%, vs 6.4% in the placebo-chemotherapy group.

AE rates leading to death were relatively similarly, however, at 8.3% in the additional pembrolizumab group compared with 6.4% in the control arm.

Stratified by the choice of taxane, AEs led to discontinuation of any treatment in 19.5% of the immunotherapy-chemotherapy arm for patients given paclitaxel, compared with 13.2% for the chemotherapy-alone arm, 29.4% of the pembrolizumab-chemotherapy group treated with nab-paclitaxel, and 9.7% of the chemotherapy-alone group treated with nab-paclitaxel.

Rates of immune-mediated AEs were relatively similar in both taxane groups.

"Certainly there could have been potential differences, even if subtle, between the two different regimens in terms of how they each synergized with immunotherapy," Halmos explained.

"But since the actual analysis did not suggest that this was the case, then I think these results are very reassuring for physicians, in that they can pick whatever their favorite regimen is or the better one for a particular patient at hand, because the choice of the carboplatin-taxane-based chemotherapy regimen does not adversely impact the outcome of these patients," he concluded.

No Evidence of Influence of Steroids

In commenting on the study, discussant Wozniak wondered whether the steroids that were required as pretreatment prior to the administration of paclitaxel influence the efficacy of immunotherapy.

A much earlier study suggested that response rate to carboplatin plus either paclitaxel or nab-paclitaxel was superior in those patients with squamous cell NSCLC who did not require premedication with steroids.

"However, in KEYNOTE-407, the use of premedication steroids was pretty much the same between the two groups, as steroids were routinely given to prevent nausea from carboplatin, which was used in both taxane groups," Wozniak noted.

"So at least in this study, the use of steroids does not appear to influence the results of the trial," she added.

Dr Halmos reports receiving speakers or advisory board fees from AstraZeneca, Boehringer Ingelheim, Genentech, Pfizer, Eli Lilly, Foundation Medicine, Guardant Health, Takeda, Novartis, Merck Bristol-Meyers Squibb as well as research grants from Merck, AstraZeneca, Mirati Therapeutics, Boehringer Ingelheim, Pfizer, Takeda, Novartis and Eli Lilly. He also reports receiving honoraria from many of the same companies. Dr Wozniak reports receiving speakers or advisory board fees from AstraZeneca, Takeda, Boehringer Ingelheim, HUYA, and BeyondSpring, as well as research grants from Boehringer Ingelheim.

19th World Conference on Lung Cancer (WCLC). Abstract MA10.08, presented September 25, 2018.

N Engl J Med. Published online September 25, 2018. Full text


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