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www.thelancet.com/oncology Vol 15 May 2014 e203

Published OnlineMarch 28, 2014 http://dx.doi.org/10.1016/S1470-2045(13)70565-5

For the study see N Engl J Med 2014; published online March 27. DOI:10.1056/NEJMoa1311107

Ceritinib: a safe and potent alternative to crizotinibNew research has shown that ceritinib is an eff ective treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC).

ALK shows genetic rearrangement in roughly 5% of cases of NSCLC, and these ALK-positive tumours have high sensitivity to ALK inhibitors (eg, crizo-tinib). Previous studies have shown that in patients with advanced ALK-posi-tive NSCLC given crizotinib, about 60% show a response and have a med ian progression-free survival of 8–10 months.

“The fi rst generation ALK inhibitor crizotinib is currently the only approved therapy for ALK-positive lung cancer”, said investigator Alice Shaw (Massachusetts General Hospital Cancer Center, MA, USA). “However, patients invariably develop resistance to crizotinib, typically within the fi rst 12 months”, she added.

Shaw and colleagues did a phase 1 trial of 130 participants with

ALK-positive tumours to examine the safety, tolerability, and anti-tumour act ivity of ceritinib, a new ALK inhib-itor that showed greater anti-tumour potency than crizotinib in preclinical studies. Participants received oral ceritinib at doses of 50–750 mg once daily, with a maximum tolerated dose of 750 mg. Dose-limiting toxic eff ects were diarrhoea, vomiting, dehydration, elevated concentrations of alanine aminotransferase, and hypo phosphataemia.

Shaw and colleagues noted that in 114 patients with NSCLC who were given at least 400 mg of ceritinib per day, the overall response rate was 58% (95% CI 48–67). In 80 patients who had received crizotinib previously, the response rate was 56% (45–67). In patients with NSCLC who had had at least 400 mg of ceritinib per day, median progression-free survival was 7 months (95% CI 5·6–9·5).

“In this study”, said Shaw, “ceritinib was highly eff ective in patients with advanced ALK-positive lung cancer. In particular, in patients who had become resistant to previous crizotinib, ceritinib was able to re-induce remission in the majority of patients. “Thus, this study establishes a new paradigm in the management of ALK-positive NSCLC”, she added.

Arnab Sengupta (Calcutta Medical College, Kolkata, India) commented, “Although crizotinib has shown im-pressive results in patients with advanced ALK-positive NSCLC, devel-op ment of resistance is a major problem with this drug. Ceritinib, the new ALK inhibitor, can be a safe and potent alternative to crizotinib, particularly in patients for whom crizotinib is no longer an eff ective treatment option.”

Sanjeet Bagcchi

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Companion imaging drug for treatment of ovarian cancerA new study has identifi ed an imaging procedure that could bene fi t patients with ovarian cancer given vintafolide by identifying the ex pression of folate receptors in cancer cells.

Vintafolide is a therapeutic folate-drug conjugate combining folate with microtubule destabilising drug desacetylvinblastine monohydrazide.Folate receptor is a folate-bind ing protein expressed in high concen-trations in ovarian, non-small-cell lung, and other epithelial tumours, but minimally distributed in normal cells. Etarfolatide is a 99m Technetium molecularly targeted imaging drug that detects lesions expressing folate receptor. Patients were categorised according to the proportion of folate-receptor-positive target lesions, and were grouped as folate receptor (100%), (10–90%), or (0%).

The phase 2 study was a single-group, multicentre clinical study that

enrolled 49 patients with advanced ovarian cancer who were heavily pretreated and had large-volume disease. Of 139 assessable tumours, 110 (79%) tumours were folate-receptor positive and 29 (21%) were receptor negative. Tumour response was recorded in 56% of folate-receptor-positive tumours compared with 21% of receptor-negative tumours (p<0·001). Disease control correlated positively with folate-receptor status: 57% (90% 32·5–79·4) of receptor (100%) patients had disease control versus 36% (19·6–56·1) of receptor (10–90%) patients and 33% (11·7–86·5) in receptor (0%) patients. Receptor (100%) patients had the highest median overall survival of 14·6 months versus 9·6 months and 3 months for receptor (10–90%) and receptor (0%) patients, respectively.

Study author Robert T Morris (Wayne State University, MI, USA)

said “Our study shows that by utilising the cell’s folate receptors, vintafolide imaging is able to identify ovarian cancer patients who have a signifi cant chance to respond to folate targeted therapy.” He adds “folate targeted therapy is becoming an important target, and vintafolide imaging is now a validated selection process for patients with a susceptibility to folate targeted therapy.”

Stefano Dellalonga (Università dell’Aquila, Coppito, Italy) agrees that the study provides convincing evidence that patients with higher folate-receptor positivity could be more responsive to vintafolide, even those who have been heavily treated. He added “Further studies could evaluate the lower limit of detection for [folate-receptor] positivity with respect to the lesion size.”

Sharan Prakash Sharma

Published OnlineApril 11, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70158-5

For the study see Ann Oncol 2014; 25: 852–58.

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