Geneva, Switzerland — A new oral angiogenesis inhibitor for the treatment of lung cancer could be edging closer to the market: Approval application for nintedanib (Boehringer Ingelheim) has been filed in Europe and is being prepared for the United States.
The data for nintedanib come from the phase 3 trial known as LUME-Lung-1, recently published in the Lancet Oncology(2014;15:143-155).
The data were also presented in a poster and discussed here at the European Lung Cancer Conference (ELCC) 2014 by principal investigator, Martin Reck, MD, PhD, head of thoracic oncology at the Lungen Clinic, Grosshansdorf, Germany.
The trial was conducted in 1314 previously treated patients with stage 3B or 4 or recurrent non-small cell lung cancer (NSCLC), who were given docetaxel as second-line therapy. Adding nintedanib significantly improved the progression-free survival to 3.4 months vs 2.7 months with docetaxel alone (hazard ratio [HR], 0.79; P = .0019).
The improvement in overall survival (OS) for all participants did not reach significance (10.1 vs 9.1 months; P = .27).
However, the survival difference was significant in 2 patient subgroups that were prespecified, Dr. Reck noted. The survival difference was significant in the subgroups of patients with adenocarcinoma histology (about half of all the participants)—12.6 vs 10.3 months (HR, 0.83; P = .0359)—and also in the subgroup of patients with adenocarcinoma and fast-growing tumors (who progressed within 9 months of starting therapy)—10.9 vs 7.9 months (HR, 0.75; P .0073).
Dr. Reck said that adenocarcinoma histology can act as a clinical biomarker for patients who are likely to benefit from this approach.
He noted that to date, no targeted agent has shown an improvement in survival when added to second-line chemotherapy in lung cancer.
Boehringer Ingelheim said that in its filing with the European regulatory authorities, it has specified use of nintedanib in adenocarcinoma NSCLC.
However, some lung cancer experts are not impressed by the data.
The improvement in progression-free survival (PFS) was only 0.7 month (about 3 weeks), which may be statistically significant but is not clinically significant, said Pasi Janne, MD, PhD, from the Dana Farber Cancer Center in Boston, Massachusetts, during a discussion of the poster presentation. He also emphasized that there was no OS difference in the overall intention-to-treat population, only in a subgroup of patients.
To Medscape Medical News, he commented that emphasizing the OS survival in a subgroup of the participants was "data dredging." He was skeptical over whether nintedanib would get approved, and noted that several previous oral angiogenesis inhibitors have been tested in lung cancer and failed, including vandetanib, sunitinib, and sorafenib.
The trial with vandetanib also included docetaxel in very similar patients (Lancet Oncol. 2010;11:619-626) and showed a "similarly not very impressive PFS improvement and no improvement in overall OS," he said.
In his discussion, Dr. Janne said, "One of the issues is that we have chemotherapy in both treatment arms, and unless the clinical effect is dramatic it's really hard to see an improvement."
Need for a Biomarker
It is not clear that it is worth pursuing this line of clinical development of oral angiogenesis inhibitors with chemotherapy in lung cancer in the absence of a biomarker, Dr. Janne said. "The angiogenesis field has been crying out for a biomarker for years, and yet there is nothing that has been clearly identified so far, and it is not clear in my mind that it is worth pursuing this strategy without some additional biology," he said.
A similar point was made by Roy Herbst, MD, PhD, Ensign professor of medicine and chief of medical oncology at the Yale Cancer Center, New Haven, Connecticut, who was approached for comment. "I would feel much more confident with this in future trials or in the clinic if there was a biomarker," he told Medscape Medical News.
Dr. Herbst noted that the results were similar to those seen in the vandetanib trial (which he headed), but those data were not submitted for approval — a decision that he was not involved with, he noted — but he did say "we were looking for meaningful outcomes."
The nintedanib trial "was positive for PFS, although quite modestly, and it did meet a survival endpoint, albeit in a subgroup of patients, but that was prespecified," he said. "My feeling is that there is a signal here, but I would feel much better about it if we could find a biomarker to enhance this effect and bring the hazard ratio down to 7 or better."
"In the era of patient-tailored therapy, biomarkers are crucial to enrich the patient population that benefit and reduce the number of patients who have substantial adverse reactions with no improvement in the clinical outcome," Dr. Herbst wrote with coauthors in an editorial that accompanied the publication.
Adverse Effects Manageable
Dr. Reck reported that the adverse-effect profile of nintedanib was manageable. Adverse events that were more common in the nintedanib plus docetaxel group included diarrhea and transient elevation of liver enzymes. The incidence of bleeding events was low (with no severe pulmonary bleeding), as was the incidence of hypertensive events (with no severe hypertension), he said.
To Medscape Medical News, Dr. Reck commented that nintedanib appears to have a milder adverse-effect profile than that seen with bevacizumab (Avastin, Genentech), which to date is the only angiogenesis inhibitor approved for use in lung cancer, but in the first-line setting. In particular, "bleeding is not a problem" with nintedanib, he said, not even in patients with squamous histology, for whom bevacizumab is contraindicated because of the high risk for bleeding.
A second trial with nintedanib, known as LUME-Lung 2, was recently stopped early for "futility" after an interim analysis of the data, based on investigator review, suggested there would be no significant difference between the treatment groups: nintedanib with pemetrexed (Alimta, Lilly) vs pemetrexed alone. However, a later analysis, which was an independent review and included a few more events, did find a significant improvement in median PFS (4.4 vs 3.6 months; P = .0435), Dr. Reck said. Details of the LUME-Lung 2 trial were reported in a poster at the 2013 American Society of Clinical Oncology annual meeting.
These studies were funded by Boehringer Ingelheim, manufacturer of nintedanib, and several of the coauthors are company employees.
European Lung Cancer Conference (ELCC) 2014. Abstract 97PD. Presented March 28, 2014.