AstraZeneca's new anticancer Zactima fails to impress in lung cancer
This article was originally published in Scrip
Three Phase III trials testing AstraZeneca's new oral targeted anticancer Zactima (vandetanib) as a second-line therapy in non-small cell lung cancer (NSCLC) failed to impress experts at the recent ASCO meeting in Orlando, Florida, who called for the testing of biomarkers which would predict which patients benefited most from the drug.
AstraZeneca previously announced in November that Zactima had met its primary progression-free survival (PFS) endpoint in one Phase III trial but failed in two others to meet this (scripnews.com, November 21st, 2008). It did not reveal specific data at that time. A fourth Phase III trial, ZEPHYR, in EGFR pre-treated NSCLC, is ongoing and is expected to report data in the second-half. There are no ongoing Phase III first-line trials in NSCLC.
Despite the mixed data, AstraZeneca still plans to file Zactima in the first half of this year in combination with chemotherapy in the second-line; two of the studies presented (ZODIAC and ZEAL) were in combination with two different chemotherapies, while one (ZEST) tested the drug as monotherapy.
Currently, standard second-line therapy in NSCLC consists of either single-agent chemotherapy or a single-agent EGFR inhibitor.
Zactima is the most advanced of AstraZeneca's experimental anticancers in development. It inhibits VEGFR-2, EGFR and RET kinase. The latter is an important growth driver in certain types of thyroid cancer, AstraZeneca says. The drug is in late-stage development for thyroid cancer, with Phase III data expected in the second-half, and in earlier development for a number of other tumour types.
No drug on the market currently combines an inhibitor of VEGF or a VEGF receptor, which would work to inhibit angiogenesis, with inhibition of EGFR, to block tumour growth. Roche/Genentech's VEGF-targeted Avastin (bevacizumab) is approved as a first-line therapy for non-squamous NSCLC after improving overall survival by two months in one of two pivotal trials. Lilly's (ImClone)/Merck KGaA's Erbitux (cetuximab), an EGFR inhibitor, improved overall survival by one month in one of two pivotal trials in first-line NSCLC, and has been filed for approval. Finally, two other EGFR-targeted drugs, Roche (Genentech's) Tarceva (erlotinib) and AstraZeneca's Iressa (gefitinib) are approved for use in pre-treated NSCLC.
One Phase III trial, BeTa Lung, failed to show that the combination of Avastin and Tarceva improved overall survival compared with Tarceva alone in the second-line setting in advanced NSCLC, raising doubts about the benefits of combined VEGF/EGFR blockade (scripnews.com, October 10th, 2008). This strategy also failed in a Phase III trial in advanced colorectal cancer combining Avastin and Erbitux.
ZODIAC
The 1,391-patient Phase III ZODIAC trial was the only Zactima trial reported at the meeting that met its primary PFS endpoint. It tested Zactima as a second-line therapy in combination with the chemotherapy agent docetaxel comparing this with docetaxel alone.
Median PFS was improved by only a few weeks (four months for the combination vs 3.2 months for docetaxel alone). The hazard ratio was 0.79, with a p-value of <0.001. there="" was="" no="" significant="" improvement="" in="" overall="" survival,="" a="" secondary="" endpoint,="" with="" median="" os="" 10.6="" months="" vs="" 10="" months.="" the="" hazard="" ratio="" was="" 0.91,="" with="" a="" p-value="" of="">
There was a significant improvement in time to deterioration of symptoms as measured on the FACT-L lung cancer subscale. The hazard ratio was 0.77, with a p-value of <>
As has been seen with other EGFR inhibitors, Zactima resulted in higher grade 3 or more rash (9% vs 1%).
There was no increase in pulmonary haemoptysis, with one fatal case in each arm, and patients with both squamous-cell and non-squamous cell NSCLC appeared to do similarly. This is in contrast with Avastin, which is not used in squamous NSCLC because of the risk of fatal pulmonary haemoptysis.
ZEAL
The 534-patient ZEAL trial tested Zactima as a second-line therapy in combination with the chemotherapy agent pemetrexed (Lilly's Alimta), comparing this with pemetrexed alone.
Neither the PFS or OS endpoints were met, while once again there was improvement in time to deterioration of symptoms on the FACT-L lung cancer subscale.
Median PFS was 17.6 weeks vs 11.9 weeks, with a hazard ratio of 0.86 and p-value of 0.10. Median OS was 10.5 vs 9.2 months, with a hazard ratio of 0.86, p=0.22. The data suggested no benefit for squamous cell patients.
Median time to deterioration of symptoms was 18.1 weeks vs 12.1 weeks.
ZEST
The 1,240-patient ZEST tested Zactima as monotherapy after failure of at least one prior therapy, comparing it with Tarceva. About twothirds of patients had one prior chemotherapy regimen and one-third had two.
The trial failed to meet both PFS and OS endpoints. Median PFS was 11.3 vs 8.9 months, with a hazard ratio of 0.98 and a p-value of 0.72. Median OS was 6.9 vs 7.8 months, and the hazard ratio was 1.0 with a p-value of 0.83.
A pre-planned non-inferiority analysis demonstrated equivalent efficacy, with 83% of Tarceva's efficacy retained for PFS and at least 55% for OS.
There was more grade 3 or higher toxicity for Zactima (50% vs 40%) and treatment-related death (5.6% vs 2.9%).
Analysis
Dr Martin Edelman of the University of Maryland Greenebaum Cancer Center, who discussed the ZODIAC trial, said that it represented a "small incremental gain" and he hoped that with greater use of predictive markers we would have greater gains. It is likely that there is a specific population, such as patients with EGFR mutations or KRAS wild-type patients, that can be identified as more likely to benefit from Zactima, he said.
In the trial, a large proportion of patients were not analysed for EGFR status; EGFR mutations have correlated with benefit with EGFR-targeted drugs in NSCLC, such as Iressa and Tarceva. There was apparently no benefit for KRAS-mutated patients; KRAS mutations have correlated in several studies with no benefit with EGFR-targeted drugs.
Dr Gregory Kalemkerian of the University of Michigan, who discussed the ZEAL and ZEST trials, said that the absolute benefit in ZODIAC and ZEAL was similar, but the larger patient population in ZODIAC may have been the reason that it met its primary PFS endpoint. However, he questioned whether a three-week improvement in PFS was clinically meaningful. This was is "not what we should be aiming for," he said.
He concluded that the results of ZODIAC, ZEST and ZEAL do not justify use Zactima's use alone or in combination with chemotherapy in unselected patients with relapsed NSCLC, and like Dr Edelman called for biomarkers to predict which patients would benefit most from the drug.