Studies Confirm Ceritinib’s Benefit in ALK-Positive Patients



For patients with advanced non–small cell lung cancer (NSCLC) harboring the ALK gene rearrangement, ceritinib (Zykadia) provided longer progression-free survival than chemotherapy in patients previously treated with chemotherapy and crizotinib (Xalkori), but gastrointestinal toxicity was troublesome, according to a study presented at the 2016 European Society for Medical Oncology (ESMO) Congress.


Progression-free survival was significantly lengthened with ceritinib compared to chemotherapy. The benefit was quite striking.
— Giorgio V. Scagliotti, MD, PhD

Ceritinib is a second-generation inhibitor of anaplastic lymphoma kinase (ALK). While crizotinib, the first-approved ALK inhibitor, is effective in patients with ALK-positive disease, most patients develop resistance and eventually experience disease progression. Ceritinib has a 20-fold greater potency than crizotinib and more intracranial activity, according to Giorgio V. Scagliotti, MD, PhD, Head of the Department of Oncology at the University of Turin, Italy, who presented the results of the phase III ASCEND-5 trial.1

“The results of ASCEND-5 open up a new treatment paradigm after crizotinib failure,” said Dr. Scagliotti. “It would be logical now to give a sequence of active drugs, starting with crizotinib in the first-line setting and moving to ceritinib in the second line.”


Ceritinib results in a robust response rate, remarkably prolonged progression-free survival and overall survival, with long-term follow-up in ALK inhibitor–naive patients from the ASCEND-3 study who had previously received up to three lines of chemotherapy.
— Enriqueta Felip, MD, PhD

Ceritinib also performed well as the initial ALK-inhibiting agent in patients with disease progression after chemotherapy, according to long-term follow-up of the phase II ASCEND-3 study reported by Enriqueta Felip, MD, PhD, of Vall d’Hebron University Hospital in Barcelona.2 Its activity was robust in patients with brain metastases at baseline.

ASCEND-5 Trial

“This was the first phase III study to assess whether the second-generation ALK inhibitor ceritinib was superior to chemotherapy after progression on crizotinib,” said Dr. Scagliotti.

The open-label ASCEND-5 study included 231 patients with NSCLC previously treated with crizotinib. Patients were randomly assigned to ceritinib at 750 mg once daily or chemotherapy (pemetrexed [Alimta] or docetaxel), with crossover to ceritinib allowed. The primary endpoint was progression-free survival assessed by a blinded independent review committee. Intracranial efficacy was a secondary endpoint [these data to be presented later].

Median progression-free survival was 5.4 months with ceritinib compared to 1.6 months with chemotherapy (hazard ratio [HR] = 0.49; P < .001). Ceritinib also increased overall response rates compared to chemotherapy (39.1% vs 6.9%) and the disease control rate (76.5% vs 36.2%). Virtually all subgroups benefited from ceritinib, Dr. Scagliotti reported.

Overall survival data were immature and also possibly confounded by the high number of control subjects who ultimately received ceritinib (n = 75). As of the data cutoff, median overall survival was 18.1 months with ceritinib and 20.1 months with chemotherapy.

“Progression-free survival was significantly lengthened with ceritinib compared to chemotherapy. The benefit was quite striking,” Dr. Scagliotti commented. “We did not observe an improvement in overall survival with ceritinib, probably because the patients who crossed over diluted the potential benefit.”

ASCEND-3 Trial

The open-label, single-arm phase II ASCEND-3 study included 124 ALK inhibitor–naive, chemotherapy-pretreated patients. At ESMO, Dr. Felip presented the long-term follow-up data (> 2 years), reporting that the objective response rate was 68%, the disease control rate was 90.3%, and 94.7% of patients demonstrated reductions in tumor burden.

Ceritinib in ALK-Positive Advanced NSCLC

  • Studies presented at the 2016 ESMO Congress found benefit for the second-generation ALK inhibitor ceritinib in patients previously treated or never treated with crizotinib.
  • In ASCEND-5, in previously treated patients, median progression-free survival was 5.4 months with ceritinib vs 1.6 months with chemotherapy (HR = 0.49; P < .001), response rates were 39.1% vs 6.9%, and disease control rates were 76.5% vs 36.2%.
  • In the single-arm ASCEND-3 trial, in ALK inhibitor–naive patients, the response rate was 68% and the disease control rate was 90.3%. Median progression-free survival was 16.6 months by investigator review and 18.4 months by blinded independent radiologic review. Estimated 18-month progression-free survival was 49.1%, and 24-month overall survival was 67.5%.
  • Gastrointestinal toxicity—diarrhea and nausea—are problems with ceritinib, at least with the 750-mg/d dose.

Median progression-free survival was 16.6 months by investigator review and 18.4 months by blinded independent radiologic review, with an estimated 18-month progression-free survival of 49.1%. Median overall survival was not reached, but the 24-month survival rate was 67.5%.

“Ceritinib results in a robust response rate, remarkably prolonged progression-free survival and overall survival, with long-term follow-up in ALK inhibitor–naive patients from the ASCEND-3 study who had previously received up to three lines of chemotherapy. Ceritinib was also active in patients with brain metastases,” she said.

Among 13 patients with measurable brain involvement at baseline, the intracranial response rate was 61.5%. Median progression-free survival was 10.8 months in patients developing brain metastases and 19.6 months in those without.

Gastrointestinal Toxicity

In ASCEND-5, patients taking ceritinib had similar toxicities to those observed in phase I and II studies. The most frequent grade 3/4 adverse events with ceritinib were nausea (7.8%), vomiting (7.8%), and diarrhea (4.3%) and with chemotherapy were neutropenia (15.5%), fatigue (4.4%), and nausea (1.8%).

Ceritinib significantly improved patient-reported outcomes, including lung cancer–specific symptoms and overall health status, compared to chemotherapy (P < .05). “But while the majority of symptoms measured with the EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 [Quality of Life version 3.0] questionnaire improved with ceritinib treatment, some deterioration was observed in two scales for gastrointestinal symptoms, ie, diarrhea, nausea, and vomiting,” Dr. ­Scagliotti added.

In ASCEND-3, patients showed improvements in symptom burden, especially the lung cancer–specific score, and maintained quality of life according to the EORTC QLQ-C30 instrument. ■

Disclosure: Dr. Scagliotti is a consultant for Eli Lilly and has received honoraria from Eli Lilly, AstraZeneca, Pfizer, Roche, and Clovis Oncology. Dr. Felip reported no potential conflicts of interest.

References

1. Scagliotti G, Kim TM, Crino L, et al: Ceritinib vs chemotherapy in patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer previously treated with CT and crizotinib: Results from the confirmatory phase 3 ASCEND-5 study. 2016 ESMO Congress. Abstract LBA42_PR. Presented October 9, 2016.

2. Felip E, Orlov S, Park K, et al: Phase 2 study of ceritinib in previously treated ALKi-naive patients with ALK+ NSCLC: Whole-body efficacy in all patients and in patients with baseline brain metastases. 2016 ESMO Congress. Abstract 1208O. Presented October 9, 2016.


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