First-Line Ceritinib Extends ALK-Rearranged Advanced NSCLC PFS

Anaplastic lymphoma kinase-rearranged advanced non-small-cell lung cancer patients derive progression-free survival benefit from first-line ceritinib over platinum-based chemotherapy

medwireNews: ASCEND-4 trial findings support the use of first-line ceritinib for the treatment of patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC).

The selective oral ALK inhibitor given at a dose of 750 mg/day almost doubled the duration of progression-free survival (PFS) in treatment-naïve patients with stage IIIB/IV disease compared with four cycles of a conventional regimen of cisplatin or carboplatin plus pemetrexed, followed by maintenance pemetrexed.

When assessed by a blinded independent review committee, PFS was a median of 16.6 months in the 189 patients given open-label ceritinib versus 8.1 months for the 187 patients given platinum-based chemotherapy, giving a significant hazard ratio (HR) of 0.55, report Jean-Charles Soria, from Institut Gustave Roussy in Villejuif, France, and co-workers.

PFS findings favoured ceritinib in most predefined patient subgroups except for 19 patients who had previously received adjuvant chemotherapy and 18 who were recruited from South America – both of these groups showed “large variability due to a small sample size”, the researchers comment.

A significant PFS benefit with ceritinib over chemotherapy was found for the 126 patients without brain metastases at baseline, at 26.3 versus 8.3 months and a HR of 0.48. And among 121 patients with brain metastases at the start of the study, a nonsignificant trend supporting ceritinib was detected, at 10.7 versus 6.7 months and a HR of 0.70.

Overall survival (OS) data are not mature, the authors note in The Lancet, and the study did not cross the efficacy stopping boundary in the current analysis; median OS was unreached in the ceritinib-treated patients versus 26.2 months for those given chemotherapy.

“The overall response with ceritinib was high, rapid, and prolonged”, Jean-Charles Soria et al write, adding that compared with chemotherapy, ceritinib was also associated with significant improvements in quality of life and a longer time to deterioration of lung cancer-specific symptoms.

Ceritinib was associated with diarrhoea (85%), nausea (69%), vomiting (66%) and elevated alanine aminotransferase (60%), while nausea (55%), vomiting (36%) and anaemia (35%) were the most common side effects with chemotherapy. Grade 3 or 4 adverse events suspected to be treatment-related occurred in 65% of ceritinib-treated patients versus 40% of the chemotherapy group.

But the researchers emphasize that the ceritinib-associated gastrointestinal symptoms were generally grade 1 or 2 and “manageable with supportive concomitant medication, dose interruption or adjustments”, allowing patients to manage a median 66.4 weeks of treatment with a relative dose intensity of 78.4%.

They conclude: “Overall, ceritinib should be considered as a new first-line therapeutic option in patients with ALK-rearranged NSCLC.”

The author of a linked comment notes that the study is limited by its use of chemotherapy as the comparator rather than the ALK inhibitor crizotinib, which became the standard first-line therapy following PROFILE 1014 results, reported not long after ASCEND-4 was launched.

“Nonetheless, the positive results of this study reinforce PROFILE 1014 in demonstrating that patients with ALK-rearranged NSCLC should receive initial therapy with an ALK inhibitor rather tha[n] chemotherapy and establishes ceritinib as an additional option for first-line therapy”, writes Benjamin Solomon, from the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Ongoing or planned trials for newer generation ALK inhibitors “will inform choices for optimal first-line therapy and potentially affect how ALK tyrosine kinase inhibitor therapy is sequenced in patients, many of whom have tumours that remain ALK-dependent even beyond progression on first-line ALK tyrosine kinase inhibitors”, he adds.

References

Soria J-C, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet; Advance online publication 23 January 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(17)30123-X

Solomon B. First-line treatment options for ALK-rearranged lung cancer. Lancet; Advance online publication 23 January 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(17)30124-1

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