Antitumor activity
In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.
In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.
“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.
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Dr. Leora Horn
But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.
“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.
She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.
“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.
The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”
In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.
“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.
She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.
SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.