After Decades, New Standard of Care in Small Cell Lung Cancer

Pam Harrison

September 28, 2018

TORONTO — For the first time in decades, overall survival (OS) has been shown to improve in patients with extensive-stage small cell lung cancer (ES-SCLC) when concurrent immunotherapy is added to standard chemotherapy in the first-line setting. The finding comes from the IMpower133 study.

"This is a highly lethal subtype of lung cancer with a 5-year survival of only about 1% to 3%," Stephen Liu, MD, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, told a press briefing here.

"Most patients respond at first, but as much as we expect a response, we also know it's transient, and median survival remains about 10 months," he added.

Immunotherapy with programmed cell death inhibitors has already made an impact on the treatment of non–small cell lung cancer (NSCLC), and the investigators were hoping that this trial would show a benefit in patients with SCLC.

"We showed that the concurrent administration of atezolizumab (Tecentriq, Genentech) to chemotherapy helped people live longer, with a median OS of 12.3 months compared with 10.3 months with chemotherapy alone, so we had a 30% reduction in the risk of death," Liu said. The difference was significant (P = .007).

"We really think these data suggest that atezolizumab plus carboplatin and etoposide is a new standard of care for the initial treatment of ES-SCLC," he added.

The new results were presented here at the 19th World Conference on Lung Cancer (WCLC) and were simultaneously published online September 25 in the New England Journal of Medicine.

Asked by Medscape Medical News whether a 2-month improvement in OS is clinically meaningful, Liu noted that a more important way to look at the results is to see the absolute gain of 2 months in OS as a hazard ratio (HR).

At an HR of 0.70, "a reduction in the risk of death by 30% meets our bar for significant improvement," Liu said.

Despite having tried more than 60 different drugs during past decades, "many trials in ES-SCLC have failed to move the needle forwards," he added.

Many trials in ES-SCLC have failed to move the needle forwards. Dr Stephen Liu

"This is a very difficult disease to show advances in," Liu reminded the press.

"And here we note that the addition of atezolizumab increases survival by 30%, so I really think that a reduction in the risk of death is a tremendous achievement," he concluded.

Commenting on the study, discussant Natasha Leighl, MD, Cancer Clinical Research Unit, Princess Margaret Cancer, Toronto, Canada, reminded delegates that it is well recognized that SCLC is a recalcitrant cancer for which survival is currently very limited.

"Any progress that we've made is related to cigarette consumption, rather than our therapeutic efforts," she said.

Given this, Leighl absolutely agreed with Liu that atezolizumab should be considered a new standard of care for stage IV SCLC, based on a clear, unmet need for better treatments for this disease and nearly 4 decades without virtually any progress.

"We have a long way to go to catch up with NSCLC," Leighl noted.

We have a long way to go to catch up with NSCLC. Dr Natasha Leighl

"But that progress starts today," she said, adding, "SCLC is still a preventable disease, and we need to take urgent steps towards tobacco control to help us eradicate it."

Study Details

In the IMpower 133 study, concurrent atezolizumab or placebo was added to standard-of-care carboplatin plus etoposide as initial treatment for patients with ES-SCLC.

Some 201 patients were assigned to the group that received the immune checkpoint inhibitor, and 202 were assigned to the group that received placebo.

Patients could have brain metastases at the time of study enrollment, Liu noted.

"All patients received carboplatin at an area under the curve (AUC) of 5 [mg/mL/min] on day 1, and etoposide, at a dose of 100 mg/m2 intravenously on days 1 through 3," Liu explained.

Patients were then randomly assigned to receive concurrent atezolizumab at a dose of 1200 mg on day 1 of each cycle or placebo for a total of four 21-day cycles of induction therapy, followed by maintenance atezolizumab or placebo given every 3 weeks until progression or loss of clinical benefit, he added.

During the maintenance phase, prophylactic cranial irradiation was permitted, although thoracic irradiation was not.

Only 22 patients in each group received prophylactic cranial irradiation during the study interval.

The coprimary endpoints were OS and progression-free survival (PFS).

At 1 year, 51.7% of patients in the additional atezolizumab group were still alive, compared with 38.2% of control patients who received placebo.

Moreover, PFS was 23% longer in the immune checkpoint inhibitor arm, at a median of 5.2 months, compared with 4.3 months for the control arm (HR for progression or death, 0.77; P = .02).

"There was also a doubling of the 12-month PFS rate from 5.4% in the control arm to 12.6% in the atezolizumab arm," Liu added.

Nearly all subgroups who were treated with atezolizumab benefited from the additional therapy, with the exception of patients with treated brain metastases, Liu observed.

On the other hand, "objective response rates and median duration of response were similar in the two groups," the investigators note.

Adverse Events

Adverse events were primarily hematologic in nature and are well known for the chemotherapy regimen that was used in IMpower133, the researchers said. The addition of atezolizumab did not significantly alter hematologic toxicity rates.

As expected, however, immune-related adverse events — primarily mild rash — were more common in the atezolizumab arm. The incidence of pneumonitis was similar in the two arms, at 2% in the atezolizumab arm and 2.5% in the control arm.

The study was funded by Hoffmann-La Roche/Genentech. Dr Liu reports receiving fees as a speaker or as an advisory board participant from Genentech, Pfizer, Takeda, Celgene, Eli Lilly, Taiho, Bristol-Myers Squibb, AstraZeneca, and Ignyta and has received research grants from Genentech, Pfizer, Threshold, Clovis, Corvus, Esanex, Bayer, OncoMed, Ignyta, Merck, Lycera, AstraZeneca and Molecular Partners. Dr Leighl reports receiving research grants from Novartis and honoraria from Merck and Bristol-Myers Squibb. She reports other relevant financial relationships with Novartis, AstraZeneca, Bristol-Myers Squibb, Merck, and Pfizer.

19th World Conference on Lung Cancer (WCLC). Abstract PL02.07, presented September 25, 2018.

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

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