Search for Curative Therapies Continues in Lung Cancer

Silas Inman @silasinman
Published: Friday, Aug 01, 2014

Dr. Paul Bunn

Paul A. Bunn Jr, MD

Curative strategies for patients with advanced lung cancer remain elusive despite several exciting advancements, according to Paul A. Bunn Jr, MD, and Primo N. Lara Jr, MD, who delivered keynote lectures during the 15th Annual International Lung Cancer Congress.

Survival has been substantially prolonged by new treatment strategies for patients with advanced non–small cell lung cancer (NSCLC). However, these advances have not yet culminated in a cure for patients, said Bunn, a professor of Lung Cancer Research at the University of Colorado School of Medicine in Denver and a winner of a 2014 Giants of Cancer Care award. Similarly, despite progress in small cell lung cancer (SCLC), extensive disease remains incurable, suggested Lara, the associate director of Translational Research at the UC Davis Comprehensive Cancer Center.

Progress in NSCLC

In his talk, Bunn highlighted three primary approaches that have been utilized in the search for cure in NSCLC: large trials in unselected patients, molecular-based studies, and studies exploring immunotherapy with checkpoint inhibitors.

For the first point, Bunn drew on evidence from the phase III SQUIRE trial that explored the addition of necitumumab to gemcitabine and cisplatin compared with the chemotherapy alone among 1093 patients with squamous cell NSCLC.1 In this study, the addition of necitumumab significantly improved overall survival (OS) and progression-free survival (PFS).

The median OS with necitumumab was 11.5 versus 9.9 months with chemotherapy alone (HR = 0.84; P = .012). The median PFS was 5.7 versus 5.5 months (HR = 0.85; P = .02) and the overall response rate (ORR) was 31% versus 29% (P = .40), for necitumumab and gemcitabine-cisplatin, respectively.

In a similar scenario, the phase III REVEL study randomized 1253 patients with NSCLC to receive either second-line ramucirumab added to standard docetaxel or docetaxel alone.2 The addition of the VEGFR2 inhibitor improved OS by 1.4 months versus docetaxel alone (HR = 0.857; P = .0235). The median OS was 10.5 months in the ramucirumab arm versus 9.1 months in the docetaxel-alone arm. The survival benefit was upheld across most patient subgroups, including both squamous and nonsquamous histology.

"It’s easy to see that after many, many randomized trials in unselected patients that were either negative or with a tiny advantage that we're not going to cure patients by doing that type of trial," Bunn said. "That doesn't mean those trials shouldn't be done, but you're not going to cure anybody."

In selected populations, several clinical trials exploring tyrosine kinase inhibitors (TKIs) in NSCLC have demonstrated extensions in OS. However, resistance is common with these therapies, warranting the need for next-generation resistance-targeted agents.

For the 21% of patients with EGFR mutations, third-generation inhibitors have shown promise in early studies. The selective inhibitors of the EGFR T790M acquired resistance mutation, AZD9291 and CO-1686 have demonstrated impressive early results. Based on this early promise, both therapies have received the FDA's breakthrough therapy designation.

“Resistance is universal, and cells largely escape from the original TKI by a secondary gatekeeper mutations that changes the TKI binding pocket or by activating another signaling pathway,” Bunn said. “It is certainly interesting that third-generation EGFR TKIs that don’t bind to wild-type but do bind to the T790M gatekeeper mutations have shown very high response rates and very long durations of response.”

In a large phase I study, AZD9291 demonstrated an ORR of 64% without inducing dose-limiting toxicities in patients with T790M-mutant NSCLC.3 The median duration of response had not been reached at the time of the analysis, with the longest duration of response being >8 months.

In phase I and II studies looking at CO-1686, the ORR was 58% across all dose levels in trial participants with biopsy-confirmed T790M mutations.4 Additionally, both compounds did not induce the skin rash and diarrhea commonly associated with earlier generations of EGFR inhibitors.

For the 8% of patients with ALK mutations, crizotinib is an established frontline standard of care. Adding to this, the ALK inhibitor ceritinib (Zykadia) gained FDA approval for patients with NSCLC who progressed on crizotinib in April 2014. In the phase I ASCEND-1 trial, the ORR was 54.6% with ceritinib in patients who received prior crizotinib (n = 163).5 Additionally, the median duration of response to ceritinib was 7.4 months and the median PFS was 6.9 months (95% CI, 5.4-8.4) among previously treated responders.


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