World Lung 2018 – Roche gives rivals a small-cell target to shoot for

Tecentriq’s long-awaited Impower-133 trial yields a highly significant though small survival benefit, setting the stage for Opdivo's Checkmate-451, Keytruda’s Keynote-604 and Imfinzi’s Caspian studies.

It is a measure of the intractability of small-cell lung cancer that a mere two-month survival benefit is enough to secure top billing at the World Congress on Lung Cancer.

This was the honour bestowed on the Impower-133 study of Roche’s Tecentriq at today’s plenary session in Toronto. And Georgetown University’s Dr Stephen Liu did not mince his words when presenting the data, calling Impower-133 “the first study in over 30 years to show a clinically meaningful improvement in overall survival over the current standard of care” in this cancer.

The trial was already known to have read out positively for both its primary endpoints – median progression-free and overall survival – but the magnitude of the benefit was being kept back for the World Lung meeting.

The headline numbers showed 12.3 months of median overall survival for Tecentriq-treated subjects, versus 10.3 for standard of care alone, translating into a 30% reduction in risk of death (p=0.0069). Median time to progression was just 5.2 months for Tecentriq, against 4.3 months for control patients (p=0.017).

Dr Liu accepted that a two-month survival benefit might not seem like much, but said the median measure was just one aspect. The 30% reduction in risk of death across the whole trial was more meaningful, he argued, and represented a "tremendous achievement". 

Impower-133 is only the third SCLC trial of a checkpoint-blocking antibody to yield data, and is the first in front-line disease. Based on remissions seen in the Checkmate-032 trial, Bristol-Myers Squibb’s Opdivo secured US approval for third-line SCLC last month.

However, it is Merck & Co and Astrazeneca that might be most interested in Roche’s Impower-133 data. These companies’ first-line SCLC studies, the Keynote-604 trial of Keytruda and the Caspian study of Imfinzi, are due to yield results in January and March respectively.

Bristol should reveal results of a separate SCLC trial, Checkmate-451, any day now, and the 940 subjects enrolled into this study received Opdivo plus Yervoy while still responding to front-line chemo.

Subgroup effects?

Merck, meanwhile, already has second-line data for Keytruda, courtesy of the single-arm Keynote-158 trial in relapsed SCLC. In this study 36% of PD-L1-positive patients responded to Keytruda monotherapy, but there was virtually no activity in PD-L1-negatives (Asco 2018 – Small cell lung data underwhelm but big readouts approach, June 5, 2018).

One of the key questions after the Keynote-158 result was how PD-L1 expression might influence outcomes for first-line patients. Impower-133 randomised 403 subjects irrespective of PD-L1 status, and the survival curves revealed today at World Lung showed a relatively late separation, suggesting that the benefit might have been driven by subgroups.

However, an analysis by PD-L1 expression was not provided. Dr Lui said that, while tissue samples were available for 80% of Impower-133 subjects, the quality of these samples was in many cases inadequate for any kind of analysis. "We will look further to identify biomarkers to find out who is driving the benefit," he told a World Lung press conference today. "We simply don’t have that [data] yet, but it will be forthcoming." 

Among subgroups analysed, there seemed to be a particular separation favouring Tecentriq in subjects with no brain metastases, and in patients over 65 years of age.

Whatever the drivers, given the statistical strength of the all-comers result, and the lack of other options for SCLC patients, the Impower-133 data look sufficient for submission to regulators. Roche also wants to separately secure Tecentriq as a treatment for first-line NSCLC, and an FDA action date of December 5 has been set.

Dr Liu stated confidently that the Impower-133 results suggested that Tecentriq plus carboplatin and etoposide was a new standard of care for first-line, extensive-stage SCLC.

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