Four ongoing, early stage trials evaluate novel agents in NSCLC patients with ALK-positive and EGFR mutated tumours
Four new pharmacological interventions show promise in crizotinib naive patients or in overcoming resistance to ALK and tyrosine kinase inhibitors
- Date : 29 Sep 2012
- Topic : Lung and other thoracic tumours
Four new therapeutic agents, currently being tested, show considerable clinical benefit with acceptable toxicity in non-small cell lung cancer (NSCLC) patient populations that were distinct, either regarding presence of mutations or prior treatments. Further investigation is required in patients who are refractory to ALK and tyrosine kinase inhibitors. The results of these four studies were presented during the proffered papers session of the Developmental therapeutics programme track at ESMO 2012 Congress in Vienna.
Translocations of the anaplastic lymphoma kinase (ALK) gene are present in 3 to 8% of NSCLC cases. Resistance to tyrosine kinase inhibitors (TKIs) due to activating EGFR mutations (EGFR-mut) is seen in 10–20% of NSCLCs. Four ongoing, early stage trials are evaluating four new agents and this article summarizes the presented findings.
AUY922 blocks HSP90 chaperone activity of ALK+ and EGFR-mut and is therefore active against both mutations. AUY922 is being tested in a phase II trial in patients with ALK-rearranged (ALK+) or EGFR-mut advanced NSCLC who progressed following at least one line of chemotherapy; most (61%) patients had received three or more prior treatments. At the April 6, 2012 cutoff, 121 patients had received once-weekly 70 mg/m2 AUY922. Partial response was seen in 6 of 22 (29%) ALK+ patients and 7 of 35 (20%) EGFR-mut patients. Of the 6 ALK+ responders, four were crizotinib-naive and 2 had received crizotinib. No partial response was seen in 28 patients with KRAS-mutation, 33 EGFR/KRAS/ALK wild-type and 3 mutation undetermined patients. Median progression-free survival rates at 18 weeks were 42% in ALK+ and 34% in EGFR-mut patients. Median progression-free survival (PFS) rate at 18 weeks was greatest in EGFR-mut patients who had progressed after EGFR tyrosine kinase inhibitor therapy compared to tyrosine kinase inhibitor-naive patients; 45% versus 21%, respectively. The most frequent adverse events were grades 1/2, with higher grade adverse events occurring in 10% of patients that included eye disorders, diarrhoea and nausea (46%), which were reported in 77%, 74% and 46% of patients, respectively. The results were presented by Dr E. Felip on behalf of international study team.
Dr S. Gettinger and colleagues reported results from a first-in-human phase I/II dose-finding study of AP26113, a new, orally-active, dual inhibitor of ALK+ and EGFR-mut activity. AP26113 is a tyrosine kinase that inhibits ALK+ and EGFR-mut and is also active against other tyrosine kinase inhibitor resistant forms, including L1196M (ALK) and T790M (EGFR), but does not affect wild type EGFR. AP26113 was administered daily to 15 patients with advanced malignancies; 11 with NSCLC, and one patient each with pancreatic, colon, cholangiocarcinoma and adenocarcinoma of unknown primary. Ten patients were documented ALK+ and 5 were EGFR-mut. All patients had been heavily pretreated; 4 ALK+ NSCLC patients failed prior crizotinib and 4 EGFR-mut patients had failed prior EGFR targeted therapy. Three, 3, 5 and 4 patients received AP26113 at 30, 90 mg and 120 mg, respectively and achieved measurable blood levels. All 4 ALK+ patients achieved partial responses, one patient at 60 mg and the remaining 3 at the 90 mg dose. Anti-tumour activity and safety at 120 mg remains to be evaluated. The trial was discontinued by 8 patients due to disease progression, and by one patient due to investigator discretion; however, no treatment related serious events were observed. The most commonly reported adverse events were fatigue and nausea. No dose-limiting toxicity was recorded. A phase II expansion is planned that will test AP26113 in four cohorts; two groups of patients with ALK+ NSCLC who are naive or resistant to prior ALK-targeted therapy; patients with EGFR-mut NSCLC resistant to EGFR-targeted therapy and a fourth group of patients with other cancers with abnormalities in ALK or other AP26113 targets.
Dr A. Shaw and colleagues reported results of the study in which 51% of patients showed a response to LDK378, a small molecule ALK inhibitor that had shown activity in ALK+ NSCLC xenografts. This ongoing trial enrolled patients with ALK+ advanced solid tumours; 50 patients with primary NSCLC, 4 with primary breast cancer and two patients with other ALK+ cancers, of whom 88% were ECOG performance status 0/1. Of the 50 lung cancer patients, 37 had been refractory to prior crizotinib. All patients received LDK378 at doses of 50 to 750 mg/day. Response was seen in 42 of 47 patients with ALK+ NSCLC (FISH positive in ≥15%) evaluable for response (per investigator). A stronger response was seen in patients with NSCLC who had progressed following crizotinib and were treated at ≥400 mg/day with LDK378, where 21 of 23 (81%) patients responded. Dose limiting toxicities of diarrhoea, vomiting, nausea, dehydration, and ALT elevation were recorded in 2 of the 14 patients who received LDK378 at 400 mg/day, 2 of 9 patients at 600 mg/day, and in 1 of the 9 patients dosed at 750 mg/day. The maximum tolerated dose was 750 mg/day. At the 25 April, 2012 cut-off date, 36 (64%) patients continued treatment. One (2%) patient left study due to adverse events and 19 (34%) patients discontinued because of disease progression. The most frequent adverse events (all grades) were nausea, vomiting, and diarrhoea, which were reported by 59%, 54% and 48% of patients, respectively. Grade 3/4 adverse events diarrhoea occurred in 5 (9%) patients. Oral LDK378 was quickly absorbed with a half-life of about 36 hours.
Dr M. Nishio and colleagues reported interim safety and efficacy results from the phase II portion of a phase I/II trial of CH5424802, an oral ALK inhibitor, in patients with ALK+ NSCLC. Phase I results that showed promising efficacy and acceptable safety with CH5424802 were previously reported at ASCO 2012. As of March 23, 2012, 34 patients with ALK-positive NSCLC, measurable disease, and no prior ALK inhibitor therapy were enrolled and treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity. The majority (62%) of patients were never-smokers with ECOG performance score 0/1. Patients had received up to four prior chemotherapies. Among the first 15 patients receiving CH5424802, one patient achieved complete response and 10 patients showed partial responses, with a response rate of 73.3%. At the time of abstract submission, 30 patients remain on study (range 1-8 months). Most treatment-related adverse events were grade 1, with two cases of grade 3 neutropenia reported; no dose reductions were made. Just one case of treatment-related eye disorder, blurred vision, was reported, in contrast to the number of eye disorders frequently reported with crizotinib.
In conclusion, AUY922 had activity in both ALK+ and EGFR-mut patients, especially in EGFR-mut patients who progressed following treatment with TKIs. The response was seen in all treated patients with ALK+ NSCLC, whether they had failed or never received crizotinib.
Remarkable activity was observed with two ALK specific agents in patients with ALK+ NSCLC: Just over half of the patients receiving LDK378 showed a response and an 81% response rate was seen in patients who had failed crizotinib, while CH5424802 demonstrated clinically meaningful antitumour activity in a cohort of patients who had not received prior ALK inhibitor therapy.
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