The oral, triple angiokinase inhibitor nintedanib has been approved in the European Union and other countries in combination with docetaxel for the treatment of advanced adenocarcinoma of the lung after first-line chemotherapy. It works by targeting vascular endothelial growth factor (VEGF) receptors 1-3, platelet-derived growth factor (PDGF) receptors α/β and fibroblast growth factor (FGF) receptors 1-3, as well as RET [1, 2].
Given the changing treatment landscape in advanced NSCLC, the activity of nintedanib plus docetaxel is of particular interest in patients who have previously received immune checkpoint inhibitor (ICI) therapy. The optimal sequence after progression on this therapy has not yet been elucidated, although the underlying tumor biology can contribute to guiding the selection of treatment.
Angiogenesis plays a role in ICI resistance as excessive VEGF release can create an immunosuppressive tumor microenvironment [3, 4]. Therefore, anti-angiogenic strategies involving the inhibition of VEGF, PDGF and FGF might support vessel normalization and improve access of immune cells to the tumor. This might tip the balance towards an immunosupportive tumor microenvironment in the so-called angio-immunogenic switch.
Nintedanib plus docetaxel after ICI therapy
At the ASCO Congress, Grohé et al. reported updated results from 57 patients included in the Cohort B of the ongoing, non-interventional, prospective VARGADO trial . In this cohort, patients with locally advanced, metastatic or locally recurrent adenocarcinoma of the lung received nintedanib plus docetaxel after first-line chemotherapy and second-line ICI treatment.
The updated analysis continued to demonstrate encouraging clinical benefit and a manageable safety profile of nintedanib plus docetaxel. From the start of third-line therapy, patients remained progression-free for a median of 6.5 months and survived for a median of 12.4 months. OS from the start of first-line therapy was 34.5 months. Twenty patients responded to the treatment, which translated to an ORR of 50 % (Table). One patient experienced a complete response. In 65 %, treatment-related AEs occurred, with the most common events being diarrhea (all grades, 37 %) stomatitis (12 %) and decreased white blood cell count (11 %). At least one dose reduction was performed in 26 % and 19 % for nintedanib and docetaxel, respectively. Treatment-emergent AEs led to discontinuation of study treatment in 30 % of patients.
As the authors noted, these data are consistent with the ICI-pretreated subgroup analysis of the LUME-BioNIs study evaluating nintedanib plus docetaxel  and previous data from the nintedanib named patient use program . Rational sequencing of an anti-angiogenic agent after ICI therapy might be a promising approach that warrants further investigation.
RELAY+: ramucirumab combined with gefitinib
Preclinical and clinical studies have demonstrated activity of dual inhibition of the VEGF and EGFR pathways in EGFR-mutant NSCLC [8-11]. In the phase III RELAY study, the anti-VEGFR2 antibody ramucirumab in combination with the EGFR TKI erlotinib gave rise to prolonged PFS compared to erlotinib alone (19.4 vs. 12.4 months; HR, 0.59) . As gefitinib is more commonly used in Japan than erlotinib, the exploratory open-label RELAY+ cohort evaluated ramucirumab 10 mg/kg every 2 weeks plus gefitinib 250 mg daily in 80 patients with previously untreated, EGFR-mutant, stage IV NSCLC .
The 1-year PFS rate, which constituted the primary exploratory objective, was similar between the ramucirumab plus gefitinib regimen (65 %) and the ramucirumab plus erlotinib regimen in RELAY (71.9 %) . This also applied to ORR (71 % and 76 %, respectively) and DCR (99 % and 95 %, respectively). Moreover, the 1-year PFS rates were similar when viewed according to EGFR mutation subtype within the RELAY+ group (63 % and 67 % for L858R mutations and exon 19 deletions, respectively). Ramucirumab in combination with gefitinib proved tolerable, and the overall safety profile was consistent with the established safety profiles for each agent in EGFR-mutation–positive metastatic NSCLC.
NEJ026: no OS effect with bevacizumab plus erlotinib
The randomized, open-label, phase III NEJ026 trial tested bevacizumab plus erlotinib against single-agent erlotinib in patients with non-squamous, stage IIIB/IV or postoperatively recurrent NSCLC harboring activating EGFR mutations. PFS was significantly in favor of bevacizumab plus erlotinib (16.9 vs. 13.3 months; HR, 0.605; p = 0.016) . However, the superiority of the combined strategy waned over time. The combination showed only slightly improved activity in terms of PFS2, which was defined as the time on second-line therapy after the first progression (28.6 vs. 24.3 months; HR, 0.773; p = 0.205) . Finally, regarding OS, the addition of bevacizumab to erlotinib provided no further benefit (50.7 vs. 46.2 months; HR, 1.007). No subgroup appeared to derive a significant survival benefit from the regimen. These observations coincide with those from the phase II JO25567 study that revealed significant PFS improvement with bevacizumab plus erlotinib over erlotinib but showed comparable results for the two arms with respect to OS .
The authors surmised that the loss of efficacy of the combined regimen might be related to the long post-progression survival and the initiation of second-line osimertinib at the end of study treatment. Osimertinib was superior to treatment without osimertinib in both arms of the trial. According to liquid biopsy studies, bevacizumab plus erlotinib elicited T790M resistance mutations as frequently as first-generation EGFR TKIs did.
Meta-analysis: anti-angiogenesis plus erlotinib vs. erlotinib
Landre et al. performed a meta-analysis of five randomized trials comparing VEGF inhibition plus erlotinib with erlotinib alone in the first-line treatment of advanced NSCLC harboring EGFR mutations . The analysis included the NEJ026, ARTEMIS, RELAY, and J025567 studies, as well as the US-based trial by Stinchcombe et al. RELAY was conducted with ramucirumab in addition to erlotinib, while all of the others used bevacizumab as the anti-angiogenic partner of the EGFR TKI. For all studies, PFS had been defined as the primary endpoint.
According to the results, the combined inhibition of VEGF and EGFR is associated with significantly improved PFS and duration of response compared to erlotinib alone. However, mature data for OS are required to confirm the benefit of this strategy. Moreover, the outcomes suggested that the combination might slow the emergence of resistance to EGFR TKIs. In the ARTEMIS trial, at the time of progression, patients in the combination arm showed fewer acquired resistance mutations, such as T790M, than the patients in the monotherapy arm. The same trend was observed in RELAY.
VEGR inhibition with anlotinib
The TKI anlotinib is an anti-angiogenic drug that targets multiple receptor tyrosine kinases including VEGFR2 and VEGFR3. Due to its oral route of administration, anlotinib offers advantages over bevacizumab and ramucirumab, which are administered intravenously. Huang et al. conducted a single-arm study to investigate the activity of anlotinib combined with the oral EGFR TKI icotinib in untreated patients with EGFR-mutated, IIIB, IIIC or IV non-squamous NSCLC . Thirty-five patients were evaluated for toxicity, and 30 of these were evaluable for efficacy.
Anlotinib plus icotinib demonstrated encouraging efficacy in the first-line setting. Overall, 21 patients (70.0 %) responded, with all of them achieving partial remission. PRs were obtained by 11 patients with exon 19 deletions (73.3 %) and 10 of those with L858R mutations (66.7 %; Figure). Disease control resulted in 96.7 %, as another eight patients experienced disease stabilization. Eighteen patients harbored additional aberrations regarding oncogenic drivers (PIK3CA or AKT1) and/or tumor suppressors (TP53, RB1, PTEN); here, the ORR was 83.3 %. Anlotinib plus icotinib was well tolerated, and AEs proved manageable. The most common AEs included hypercholesterolemia, hypertriglyceridemia, hypertension, diarrhea, and rash. Among grade-3 AEs, hypertension (17 %) and hypertriglyceridemia (6 %) occurred most frequently. The only grade-4 event was hypertriglyceridemia (6 %). PFS and OS outcomes are awaited as longer follow-up is required for further evaluation.
VEGF/Ang-2 blockade and checkpoint inhibition
Another potential combination strategy based on anti-angiogenesis consists in the inhibition of VEGF/Angiopoietin-2 (Ang-2) together with an immunotherapeutic approach. A phase Ib trial established preliminary antitumor activity of the VEGF/Ang2-blocking nanobody® BI 836880 combined with the anti-PD-1 antibody BI 754091 at doses of 720 mg and 240 mg, respectively, three-weekly . Ten of 12 patients with locally advanced or metastatic non-squamous NSCLC achieved partial remissions or disease stabilization. Two thirds of them had already received ICI therapy prior to enrollment. Changes in target lesions were observed in both ICI-pretreated and ICI-naïve patients.
The combination showed a manageable safety profile. All-grade AEs comprised hypertension, vomiting, nausea, and asthenia. No grade-4 events occurred. Expansion cohorts are ongoing, and further results can be expected.