October 2018

By James Spicer, Professor of Experimental Cancer Medicine and Consultant in Medical Oncology

ALTA1: brigatinib vs crizotinib in ALK-rearranged non-small cell lung cancer
The initial results of this comparison of brigatinib with the first generation drug crizotinib were presented at the World Lung meeting. Brigatinib is already associated with high response rates in ALK-driven disease, including in patients with CNS metastases. This was a randomised phase 3 trial of first line ALK-targeted therapy; up to one prior line of chemotherapy was allowed. The randomisation in this trial was stratified according to the presence or absence of untreated brain mets.

The hazard ratio for progression-free survival (PFS) was an impressive 0.49 in favour of brigatinib. This effect size was similar in all subgroups including patients with baseline CNS disease.

The median PFS for crizotinib was 9.8 months, as would be expected, but is not yet reached for brigatinib. In this respect these results are reported rather early, and it is not yet possible to compare the performance of brigatinib against alectinib, the other next-generation ALK inhibitor to be tested against crizotinib. A median PFS of 34 months was reported for alectinib in the ALEX trial updated at this year’s ASCO. We are not yet in a position to determine which is the “best” next-generation ALK inhibitor.

More gastrointestinal and liver function side effects were observed with crizotinib, and by contrast asymptomatic laboratory abnormalities were commoner with brigatinib (CPK, amylase, lipase). Reassuringly, early onset pneumonitis in this first line setting was lower than previously reported for brigatinib (3%).

The ALTA1 results presented in Toronto were published simultaneously in the New England Journal of Medicine. Brigatinib is clearly a very active drug in this patient population, and superior to crizotinb. It is too early to be able to rank the newer ALK inhibitors, however.

IMPower-133: addition of atezolizumab anti-PDL1 checkpoint inhibitor to first line chemotherapy for small cell lung cancer

Atezolizumab was combined with conventional carboplatin and etoposide first line chemotherapy in this randomised trial, with chemotherapy alone offered in the control arm. The combination arm included maintenance atezolizumab. The presence of brain metastases was allowed in this pragmatic design.

Response rates were very similar in the 2 arms, but a statistically significant difference in overall survival (OS) was seen. The OS was 12.3 months in the atezolizumab combination arm compared with 10.3 months in the control arm, with a hazard ratio of 0.70 (p=0.0069).

The effect size was not different in subgroups divided according to blood tumour mutational burden (TMB).

As would be expected, the combination arm was somewhat more toxic, with discontinuation rates due to side effects of 11% in the combination, versus 3% in control arm.

It has been decades since the last positive small cell trial in this setting, and appropriately this trial was published simultaneously in the New England Journal of Medicine. The clinical significance of a 2 month survival benefit is open to discussion, however, and the cost effectiveness of atezolizumab in this setting may be too easy to question. Nevertheless, the trial demonstrates in principle that immune checkpoint inhibition can work in small cell lung cancer, as might have been hoped, given the high TMB characteristic of this most smoking-associated form of lung cancer.