Necitumumab plus chemotherapy improved PFS, OS in squamous NSCLC

Issue: August 10, 2014

CHICAGO — The addition of necitumumab to gemcitabine and cisplatin significantly improved PFS and OS in patients with stage IV squamous non–small cell lung cancer, according to results of the phase 3 SQUIRE trial presented at the ASCO Annual Meeting.

Perspective from Mark G. Kris, MD

“Squamous cell lung cancer is an important part of the lung cancer profile, accounting for 25% to 30% of our patients,” investigator Nick Thatcher, MD, professor of oncology at University of Manchester, said during a presentation. “There’s been very limited progress over the last few years compared to non-squamous lung cancer. There are basically no relevant oncogenic drivers that can help us with our treatment, at least at the moment. However, we do have some information from cetuximab in the FLEX trial, which did show some benefit is the squamous subpopulation.”

Thatcher and colleagues evaluated data from 1,093 patients. They assigned 548 patients to 1,250 mg/m2 gemcitabine on days 1 and 8 plus 75 mg/m2 cisplatin on day 1 for up to six 21-day cycles. The other 545 patients received the chemotherapy combination plus 800 mg IV necitumumab (IMC-11F8, Eli Lilly) on days 1 and 8.

Almost half of patients (51%) assigned the combination received four additional cycles of necitumumab alone.

Chemotherapy exposure between the arms was similar. Patients received a median 86% dose intensity for gemcitabine and 95% for cisplatin.

Overall, necitumumab was associated with significantly longer median OS (11.5 months vs. 9.9 months; HR=0.84) and PFS (5.7 months vs. 5.5 months; HR=0.85).

Improvement with necitumumab was observed across subtypes.

The overall response rate was comparable between the arms (31% vs. 29%; P=.4); however, significantly more patients assigned necitumumab achieved disease control (82% vs. 77%; P=.043).

More grade ≥3 adverse events (72% vs. 61.6%) and adverse events with outcomes of death (12.3% vs. 10.5%) occurred in the necitumumab arm.

“SQUIRE is the largest randomized phase 3 trial in the first line treatment for metastatic squamous NSCLC,” Thatcher said. “The results are an important advance in the search for a new treatment for patients with metastatic squamous NSCLC, and it’s the first time we’ve seen benefit in this group of patients over the last 20 to 25 years.”

For more information:

Thatcher N. Abstract #8008. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.

Disclosure: The researchers report consultant/advisory roles with and honoraria/research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ImClone, Lilly, Pfizer, PPD Hungary Ltd and Roche.

Perspective

Mark G. Kris, MD

Necitumumab targets EGFR, and EGFR is overexpressed in a vast majority of squamous lung cancers. Also, the combination of gemcitabine and cisplatin is one standard for patients with squamous cancers. So if you want to improve outcomes for patients with squamous cancers, this is the kind of trial you would run.
Clearly, though, people were hoping for more — more tumor shrinkage, survival improvements in terms of years rather than months, and disease control in terms of months rather than weeks.
The bottom line, though, is that these trials are difficult to put in context.
This was a large, multicenter, randomized trial. You can consider this the benchmark for the next trial, so it is useful in that way.
Another issue is, you don’t always know how useful a treatment can be in different settings. One example is pemetrexed (Alimta, Lilly). The first trial of pemetrexed in lung cancer compared it with docetaxel. Pemetrexed was better tolerated, but there was no difference in important outcomes, such as response rate, PFS or OS. However, when pemetrexed was used in other settings — such as initial therapy with cisplatin — it made cisplatin easier to take, and it showed superior benefit, particularly in the adenocarcinoma cohort compared with the squamous cohort.
That is just one example in which a trial that showed no difference in main outcomes ultimately led to the identification of uses for a drug in other settings. Perhaps a positive result from the SQUIRE trial opens the door to a similar possibility. There may be other situations for patients with squamous lung cancer in which this regimen could be useful. Still, I think regulators and individual physicians are going to have a difficult time knowing how to integrate this into any kind of standard of care.
Crizotinib (Xalkori, Pfizer) — a drug that shrinks cancer 75% of the time and has shown obvious benefit in every trial — still is not approved in every country. When we have drugs with dramatic benefits that can’t always be put in the hands of patients, I have to wonder where necitumumab will be. That is what we are wrestling with. Even after this presentation, despite the numbers being “significant,” people are unsure how to move this forward with regard to care, research and regulatory approvals.

Mark G. Kris, MD

William and Joy Ruane chair in thoracic oncology

Memorial Sloan-Kettering Cancer Center

Disclosures: The SQUIRE trial included patients at Memorial Sloan-Kettering Cancer Center. Kris serves as principal investigator on a Pfizer-led trial unrelated to crizotinib.