Nintedanib-docetaxel: tolerable and effective for patients with advanced adenocarcinoma NSCLC failing on first line chemoimmunotherapy

Nowadays, immune checkpoint inhibition (ICI) with or without chemotherapy is considered standard of care for advanced NSCLC patients without oncogenic driver mutations. However, data on the optimal subsequent treatment for patients failing on this first-line treatment are limited. Real-world results of the VARGADO trial now demonstrate meaningful clinical activity of second line nintedanib plus docetaxel in patients with failure on first line immunochemotherapy (ICT), with a tolerable safety profile. As such, nintedanib plus docetaxel should be considered as a treatment option in patients with adenocarcinoma of the lung following ICT failure.

Over the last five years we have witnessed a dramatic change in the first-line treatment paradigm for patients with advanced non-small cell lung cancer (NSCLC) without oncogenic driver mutations. Nowadays, the standard first-line treatment for these patients consists of immune checkpoint inhibition (ICI) with or without chemotherapy, depending on the level of PD-L1 expression. However, data on the optimal treatment strategy for patients with disease progression on this first line treatment are limited. Previously, the phase III LUME-Lung 1 trial demonstrated that the addition of the angiokinase inhibitor nintedanib to docetaxel significantly improves the overall (OS) and progression-free survival (PFS) of patients with advanced adenocarcinoma NSCLC who progress on first line chemotherapy. To date, however, little is known on the efficacy and safety of this combination following disease progression on first line ICT. The German VARGADO study is a prospective, non-interventional study evaluating nintedanib plus docetaxel after first line chemotherapy in a real-world setting. During ESMO 2021, results were presented for cohort C of this trial specifically looking at the efficacy and safety of nintedanib-docetaxel following first line ICT. In addition, subgroup analysis was conducted to study the potential effect of time since the start of first line treatment and KRAS mutation status.

Nintedanib-docetaxel: tolerable and effective after first line ICT

Cohort C of the VARGADO trial included a total of 137 patients with advanced adenocarcinoma NSCLC and disease progression following first line ICT. Patients in the trial were treated with docetaxel (IV, 75 mg/m2) on day 1 plus nintedanib (oral, 200 mg, BID) on days 2–21 of each 21-day cycle. The primary endpoint of the study consists of the OS rate at 12 months after the initiation of nintedanib plus docetaxel, while secondary objectives include PFS, OS, objective response rate (ORR), disease control rate (DCR), and safety.

The median age of patients in the study was 63 years, 58.4% was male and 71.6% had an ECOG performance status (PS) of 0-1. Most patients had stage IV disease at baseline (86.1%) with one out of five patients having brain metastases (19.7%). The most common first line treatment regimen consisted of pembrolizumab-pemetrexed-platinum (87.6%). None of the patients in the study obtained a complete response to first-line ICT, 27% had a partial response and 20.4% experienced disease stabilization. For 27.7% progressive disease was the best response to the ICT. For two thirds of patients, the treatment with nintedanib-docetaxel was initiated within 9 months after the start of the first-line treatment (65%)

At the time of the presented analysis, the median follow-up was 4.2 months. At that timepoint, results on OS were still immature. The median PFS was reported at 4.77 months, with an ORR of 37.5% (1.3% complete, 36.2% partial response). As an additional 35% of patients obtained disease stabilization, the investigators reported a DCR of 72.5%. No significant difference in PFS was seen between patients who progressed early (<9 months) or late (≥9 months) on first line ICT (median PFS: 4.08 vs. 5.26 months, respectively; p= 0.1441). Similarly, no association was seen between KRAS mutation status and PFS (median PFS 6.41 and 4.77 months for patients with wild-type and mutant KRAS, respectively; p=0.4784).

No unexpected safety signals were seen in the study, Grade ≥3 treatment emergent adverse events (TEAEs) were observed in 45.3% of patients (serious TEAEs in 36.5%). Nintedanib dose reductions and therapy interruptions were reported in 33.6% and 21.9% of patients, respectively. Docetaxel dose reductions and interruptions were reported in 13.1% and 16.1% of patients, respectively. Finally, 40 (29.2%) patients had to stop their treatment due to TEAEs.

Conclusions

Based on these results, the investigators conclude that second line nintedanib plus docetaxel has clinically meaningful efficacy following failure of first-line ICT, with a median PFS of 4.8 months and disease control in almost three quarters of patients (DCR: 72.5%). This efficacy of nintedanib plus docetaxel was seen regardless of the time since the start of first-line treatment and the KRAS mutation status. The treatment also proved to be tolerable without any unexpected safety signals. As such, nintedanib plus docetaxel should be considered as a treatment option in patients with adenocarcinoma of the lung following failure of ICT.

Reference

Grohé C, et al. Second-line nintedanib + docetaxel for patients with lung adenocarcinoma after first-line chemo-immunotherapy treatment: Updated efficacy and safety results from VARGADO Cohort. Presented at ESMO 2021; Abstract 1330P.

SC-BE.-00446 09/2021