乌鸦传媒

CHICAGO -- The novel kinase inhibitor nintedanib may slightly delay relapse of non-small cell lung cancer (NSCLC) when added to chemotherapy, with perhaps greater benefit in adenocarcinomas, the LUME-Lung 1 trial showed.

The angiogenesis-targeted agent prolonged progression-free survival (PFS) by an average of 3 weeks, a 21% improvement over the median 2.7 months with docetaxel alone (P=0.0019), Martin Reck, MD, PhD, of Hospital Grosshansdorf, Germany, and colleagues found.

Overall survival (OS) wasn't impacted for the entire population unselected by molecular or any other tumor characteristic in the second-line setting, the group reported here at the American Society of Clinical Oncology meeting.

But in the adenocarcinoma subset, the addition of nintedanib significantly boosted PFS by 1.2 months and OS by 2.3 months.

"Further investigations are warranted to identify molecular and clinical benefit for nintedanib in NSCLC," Reck told attendees at the session.

Trial discussant Benjamin Besse, MD, PhD, of Institut Gustave Roussy in Paris, was largely critical of the findings and trial design, pointing to the fact that the limited positive impact on PFS came from what was not formally an intent-to-treat analysis.

The PFS results were based on only 86% of the study population because of the event-driven analysis and thus haven't been updated for more than 2 years, he cautioned.

The companion LUME-Lung 2 trial testing nintedanib with a different chemotherapy drug, pemetrexed (Alimta), in nonsquamous cell NSCLC was stopped for futility at its interim analysis.

But the combination appeared to have a significant impact on PFS among the patients that were enrolled when followed out longer term (median 4.4 months versus 3.6 on pemetrexed alone, P=0.0435), as reported at a poster session at the conference.

"For nonsquamous NSCLC, we really favor pemetrexed as the primary treatment," Bruce Roth, MD, of Washington University in St. Louis, commented in an interview with 乌鸦传媒.

Docetaxel didn't "underperform" in LUME-Lung 1 compared with prior trials, Besse noted.

But other treatments in this setting have looked better in clinical trial results he cited.

Bevacizumab (Avastin), a VEGF-targeted monoclonal antibody, produced a 3.9 month OS advantage in NSCLC adenocarcinoma in the Eastern Cooperative Group Study E4599. Nintedanib inhibits fibroblast growth factor and platelet-derived growth factor receptors along with the VEGF receptor.

Whether the benefit in the adenocarcinoma group with nintedanib would remain after bevacizumab exposure remains an open question, Besse said.

Another question is how this molecular targeted agent performed by molecular characterization of the tumors treated, although no biomarker study was planned for the LUME-Lung patients, he added.

"Moving forward the question is did we look at the right population, did we ask all the right questions in the beginning," Roth agreed. "The problem is to try to ask the best questions we know at the time of study, but at the end of the study, a lot of times you wish you had asked a slightly different question."

The LUME-Lung 1 trial included 1,314 patients with locally advanced or metastatic or recurrent NSCLC who had progressed after first-line chemotherapy in the adjuvant or neoadjuvant setting randomized to docetaxel at 75 mg/m2 IV on 21 day cycles with placebo or 200-mg nintedanib given orally twice a day.

Half of the population had adenocarcinoma, 42% had squamous cell carcinoma, and the rest had other histology.

Overall PFS came out at a median 3.4 months with the combination treatment compared with 2.7 months in the control group.

For the adenocarcinoma subgroup, the medians were 4.0 versus 2.8 months, for a hazard ratio of 0.77 for death or progression compared with docetaxel alone (P=0.0193).

For the squamous cell carcinoma subgroup, the hazard ratio came out the same but with a lower median of 2.9 months on nintedanib versus 2.6 months without it (P=0.0200).

OS came out similar between groups, with a median of 10.1 months with the nintedanib combination versus 9.1 months in the comparator group, for a hazard ratio of 0.94 (P=0.2720).

Among the adenocarcinoma cases, the hazard ratio favored nintedanib more at 0.83, with a median of 12.6 months compared with 10.3 months in the docetaxel alone group (P=0.0359).

No OS difference was seen in the squamous cell carcinoma setting (median 8.6 versus 8.7 months, P=0.8907), although the only complete response actually occurred in a patient with squamous cell carcinoma in the docetaxel alone group.

Partial responses were most common, at 56%, in the nintedanib combination group with adenocarcinoma followed by 45% in the nintedanib group with squamous cell carcinoma. The docetaxel alone groups had rates of 40% in adenocarcinoma and 33% in squamous cell carcinoma.

Disease control rates followed a similar pattern.

Systemic therapy after the study treatment was similar between groups, although somewhat more common with adenocarcinoma than squamous cell carcinoma.

Adverse event rates didn't differ between treatment groups overall, although diarrhea and liver enzyme increases were more common with nintedanib.

Incidence of grade 3 or worse events typical with VEGF or VEGFR inhibitors was low and not much different between groups, including 2% bleeding, 1% venous thromboembolism, and less than 1% GI perforation in both treatment groups.

While there was no toxicity signal in the study, Besse cautioned that the trial included a highly-selected population.

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