Changing Paradigms for NSCLC in Personalized Therapy Era

In the era of personalized medicine, paradigms for treating nonsmall cell lung cancer (NSCLC) are evolving. With the discovery of mutation drivers for NSCLC—including EGFR, KRAS, and EMLA 4-ALK—targeted therapies directed to those mutations are beginning to make a difference. While more work needs to be done to improve outcomes, advances thus far were discussed by Chandra P. Belani, MD, deputy director of the Penn State Hershey Cancer Institute in Pittsburgh, Pennsylvania.

Lung cancer is still the leading cause of death in 2011. NSCLC currently accounts for about 87% of all cases and small cell lung cancer (SCLC) for about 13%.

Adjuvant chemotherapy is now the standard of care for early resectable (<4 cm) NSCLC, Belani said. Adjuvant chemotherapy has improved overall survival (OS) from 4.1% to 15%.

Cisplatin/vinorelbine has been the most common doublet used in all clinical trials, but up to 50% of patients are not able to get the recommended 4 cycles, and there is a clear need to reduce toxicity, improve dose delivery, and improve compliance. An adjuvant therapy trial by Winton et al compared standard cisplatin/vinorelbine versus cisplatin/pemetrexed. The feasibility of cisplatin/pemetrexed compared favorably with that of cisplatin/vinorelbine, with fewer toxicities and fewer dose delays. This regimen has been incorporated into the ECOG1505 trial for nonsquamous NSCLC, which will compare 1 of 4 chemotherapy regimens with no bevacizumab versus chemotherapy plus bevacizumab in the adjuvant setting.

“Maintenance therapy for NSCLC has become the new paradigm for about 50% of physicians, based on available data,” Belani continued. The other 50% are skeptics, he added. “The criticism [of maintenance therapy] is that about 40% of patients are unable to receive it. If we are going to change the paradigm from acute disease to chronic disease in stage IV NSCLC, we need to give less toxic maintenance therapy,” he stated.

Two strategies have been studied: switch maintenance therapy and continuation maintenance therapy. Switch maintenance with pemetrexed following initial therapy with a platinum-containing regimen improves survival in all patients. Switch maintenance with erlotinib also improves overall survival. However, only patients with good performance status are candidates for maintenance therapy.

Continuation maintenance therapy was studied in the PARAMOUNT trial, in which patients with stage IV NSCLC who responded to front-line cisplatin/ pemetrexed were randomized to continuation pemetrexed or placebo. Progression- free survival (PFS) was improved with pemetrexed continuation maintenance; OS data have not yet been presented.

“Pemetrexed continuous maintenance has had similar results to switch maintenance therapy, and we await the overall survival data,” Belani said.

ECOG 5508 is accruing 1282 patients with stage IV nonsquamous NSCLC who respond to 4 cycles of carboplatin/paclitaxel/bevacizumab and randomizing them to pemetrexed, bevacizumab, or the combination of pemetrexed/bevacizumab, following carboplatin, paclitaxel, and bevacizumab therapy.

“The next step is to personalize maintenance therapy using molecular selection. Patients with EGFR mutations can get erlotinib,” Belani continued. Research by the Lung Cancer Mutation Consortium looked at 10 driver mutations in patients with stage IV adenocarcinoma. Fifty-four percent of patients had 1 or more of these mutations; the most common ones were KRAS (22%), EGFR (17%), and EMLA 4-ALK (7%).

“These mutations were almost all mutually exclusive, since 97% of patients had only one of them. This work just scratches the surface, because lung cancer is a heterogeneous disease,” Belani explained.

The European Randomized Trial of Tarceva vs Chemotherapy (EURTAC) trial compared front-line chemotherapy with a platinum-based doublet versus erlotinib in 174 patients with EGFR mutations (EGFR ). Erlotinib was superior for PFS, and all subsets of patients with EGFR status benefited from erlotinib. There was no improvement in OS, but Belani said that this was attributable to the fact that patients in the chemotherapy arm received second-line erlotinib.

“The new treatment paradigm is to test patients with NSCLC adenocarcinoma for EGFR-mutated status and treat with erlotinib if EGFR mutations are present,” he said.

Newer targeted therapies are being studied. Crizotinib (an ALK and MET inhibitor) is approved for ALK-positive NSCLC, representing a second targeted approach. Afatinib (HER-1 and -2 inhibitor) plus cetuximab shows promise in patients with EGFR status who develop resistance to EGFR tyrosine kinase inhibitors. This drug is not yet approved.

There is a long list of other novel personalized agents in earlier phases of development, including MetMAb, ARQ 197, Hsp90 inhibitors, talactoferrin, farletuzumab, and hedgehog inhibitors.