Cabozantinib, Vandetanib Roles Explored In Select NSCLC Patients

Cabozantinib alone or with erlotinib may extend progression-free survival in EGFR wild-type nonsquamous NSCLC patients, while RET rearrangements may indicate benefit from cabozantinib or vandetanib

medwireNews: Results from three phase II trials highlight the potential for cabozantinib in patients with EGFR wild-type advanced non-small-cell lung cancer (NSCLC) and the possible efficacy of targeted therapy with the multi-targeted tyrosine kinase inhibitors cabozantinib or vandetanib in patients with RET fusion-positive disease.

In the first of three articles, Joel Neal, from Stanford Cancer Institute in California, USA, and co-authors report that patients with EGFR wild-type, nonsquamous NSCLC who had received one or two prior treatments had significantly longer progression-free survival (PFS) when given cabozantinib alone (n=38) or alongside erlotinib (n=35) than when treated with erlotinib monotherapy (n=38).

Median PFS was 4.3 and 4.7 months versus 1.8 months, respectively, with hazard ratios (HRs) of 0.39 and 0.37 against erlotinib alone, and corresponding overall survival (OS) HRs of 0.51 and 0.68, they write in The Lancet Oncology.

The most common grade 3 or 4 side effect was diarrhoea, affecting 8% of patients in the single cabozantinib and erlotinib groups and 28% of those given combined treatment. Hypertension (25%, 0% and 3%, respectively), fatigue (15%, 13% and 15%) and oral mucositis (10%, 0% and 3%) were also common. One case of fatal respiratory failure in the cabozantinib group and one fatal case of pneumonitis in the combined treatment group were considered to be possibly related to treatment.

“Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable”, the researchers write, noting that the US Food and Drug Administration has now modified the indication for erlotinib to restrict use to patients with EGFR mutations only.

Analysis of tissue samples from 86 patients showed that MET protein expression was not a significant predictor of PFS regardless of whether the patient received cabozantinib, which is known to target this biomarker. AXL or VEGFR2, which are also targeted by cabozantinib, may instead explain the agent’s efficacy, the authors suggest.

A second, single-arm study published in The Lancet Oncology investigated the efficacy of cabozantinib 60 mg/day in 26 patients with RET-rearranged, metastatic or unresectable NSCLC, the majority (62%) of whom had the KIF5B-RET fusion.

The primary endpoint of overall response was 28%, with seven of 25 assessable patients achieving a RECIST confirmed partial response, say Alexander Drilon, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-authors.

Describing the responses as “brisk and durable”, with median PFS and OS of 6 and 10 months, respectively, they believe this reported activity “defines RET rearrangements as actionable drivers in patients with lung cancers”.

But the team admits that dose reductions were required by 73% of patients because of drug-related adverse events. Grade 3 elevations of lipase (15%), alanine aminotransferase (8%) and aspartate aminotransferase (8%) were among the most common side effects experienced.

Writing in a comment published in The Lancet Oncology, Rafael Rosell and Niki Karachaliou, from Germans Trias i Pujol Sciences Research Institute in Badalona, Spain, say the study by Drilon et al paves the way for tailored treatment in patients with RET fusion-positive NSCLC.” But they note that “clinical benefit of this treatment was small compared with benefits obtained by targeted treatment in other subclasses of NSCLC driven by EGFR mutations or ALK or ROS fusions.”

The commentators add that cabozantinib’s lack of specificity for RET and side effect profile could point to use of alternative RET inhibitors, such as vandetanib, lenvatinib, sunitinib and ponatinib.

Kiyotaka Yoh, from the National Cancer Center Hospital East in Kashiwa, Japan, and co-authors report the outcome of the oral agent vandetanib in patients with previously treated RET-rearranged, EGFR mutation-negative advanced NSCLC.

The open-label LURET study findings, published in The Lancet Respiratory Medicine, showed a confirmed partial response rate to vandetanib 300 mg/day of 53% in 17 patients who met the study’s full eligibility criteria.

In the intention-to-treat group of 19 patients, including two patients with low potassium levels, 47% achieved an objective response, 90% disease control and 11% stable disease. Indeed, 84% of patients had some tumour shrinkage, with 37% showing a tumour reduction of at least 50%.

The team notes that the KIF5B-RET fusion was the most common rearrangement, in 53% of patients, while the CCDC6-RET fusion occurred in 31%; objective responses occurred in 20% and 83% of these patients, respectively.

Median PFS was 4.7 months and median OS was 11.1 months in the overall group and again appeared to differ between the KIF5B-RET fusion and CCDC6-RET fusion groups, at 2.9 versus 8.3 months.

“Although further large confirmatory studies are warranted, our results have important implications for RET-directed therapy in patients with NSCLC”, the authors summarise.

Rafael Rosell and Niki Karachaliou comment on this finding, noting that “[i]t is plausible that different types of RET fusions have different sensitivities to RET inhibitors, as has been shown in EGFR-mutant NSCLC”.

“Preclinical studies have identified specific RET mutations that are resistant to vandetanib, and other RET inhibitor drugs, such as ponatinib have been shown to overcome this resistance”, they observe.

“Moreover, preclinical studies of another RET inhibitor, alectinib, which also inhibits ALK, have suggested that cells with RET fusion mutations undergo adaptive resistance in the presence of alectinib.”

References

Neal JW, Dahlberg SE, Wakelee HA, et al. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled open-label, multicentre, phase 2 trial. Lancet Oncol; Advance online publication 4 November 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30561-7

Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2 single-arm trial. Lancet Oncol; Advance online publication 4 November 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30562-9

Rosell R, Karachaliou N. RET inhibitors for patients with RET fusion-positive and RET wild-type non-small-cell lung cancer. Lancet Oncol; Advance online publication 4 November 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30557-5

Yoh K, Seto T, Satouchi M, et al. Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Resp Med; Advance online publication 4 November 2016. DOI: http://dx.doi.org/10.1016/S2213-2600(16)30322-8

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