ESMO 2014: Targeted Treatments for Subsets of NSCLC Patients With Folate-Receptor-Positive, BRAF V600E-Mutant, and With Tumours Carrying HER2 Somatic Mutations

Phase II studies with vintafolide, dabrafenib and neratinib

Findings from three phase II studies revealed clinically meaningful improvement across all efficacy endpoints with vintafolide/docetaxel over single-agent docetaxel in second-line treatment of folate-receptor-positive non-small cell lung cancer (NSCLC); significant anti-tumour activity with durable objective responses and acceptable safety profile of dabrafenib in patients with BRAF V600E-mutant advanced NSCLC; and meeting efficacy criteria for neratinib with temsirolimus in patients with NSCLC carrying HER2 somatic mutations. The results were presented in two proffered paper sessions on metastatic NSCLC during ESMO Congress 2014 in Madrid, Spain.

TARGET: A phase II trial with vintafolide in second-line treatment of folate-receptor-positive NSCLC

A randomised, phase II trial comparing vintafolide vs vintafolide plus docetaxel vs docetaxel alone in second-line treatment of folate-receptor-positive NSCLC showed clinically meaningful improvement across all efficacy endpoints (overall response rate - ORR, progression-free survival – PFS, and overall survival - OS) with vintafolide/docetaxel over single-agent docetaxel treatment. The largest benefit was observed in the adenocarcinoma subgroup. The results were presented by Dr Nasser Hanna of the Department Of Medicine, Indiana University, Indianapolis, USA.

The folate receptor is expressed in many epithelial cancers, including NSCLC, and may be a useful biomarker for therapy selection.

Vintafolide, a folate-vinca alkaloid drug conjugate, is a folate receptor-targeted drug. Its companion imaging agent, 99mTc-etarfolatide, enables non-invasive imaging of folate receptor expression.

The TARGET study assessed the benefit of folate receptor-targeted therapy in 199 second-line NSCLC patients with all target lesions expressing folate receptor (100%).

Patients were randomized 1:1:1 to vintafolide, vintafolide plus docetaxel, or docetaxel alone.

Vintafolide (2.5 mg) was administered on day 1, 4, 8, and 11 and docetaxel (75 mg/m2) on day 1 of a 3-week cycle.

The primary endpoint was PFS; secondary endpoints included OS and ORR. The significance level of each PFS and OS analysis was one-sided alpha = 0.10 with no multiple testing adjustments.

The ORR in vintafolide/docetaxel arm was 22% in the overall study population; hazard ratio (HR) for PFS was 0.75 (p = 0.0696); and median OS 11,5 months. In the adenocarcinoma subgroup, the ORR was 21%, the HR for PFS 0.73 (p = 0.0899) and median OS 12,5 months.

With the pre-specified stratified analysis adjusting for baseline factors (time since last chemotherapy, best response and stage), the OS HR for vintafolide/docetaxel vs docetaxel were 0.75 (1-sided p=0.1066) for all patients, and 0.51 (1-sided p=0.0147) for the predefined adenocarcinoma patient subgroup.

Dr Giorgio Scagliotti, who discussed the study results, spoke about real-time identification of tumour lesions and response to vintafolide treatment. He said that there was no assessment of any genomic alteration in patients with adenocarcinoma. In addition, there was no information on post-study therapy. In second-line therapy there is still a huge room for improvements in terms of selecting candidate patients and treatments, he concluded.

The study was sponsored by Endocyte, Inc.

BRF113928: A phase II study with dabrafenib in patients with BRAF V600E-mutant advanced NSCLC

Dabrafenib is the first drug of its class to show activity in a prospective trial of NSCLC with BRAF mutations. Treatment of BRAF V600E mutated advanced NSCLC patients with dabrafenib demonstrated significant anti-tumour activity with durable objective responses and an acceptable safety profile in a multicenter, open-label, phase II trial. The findings were reported by Dr David Planchard of the Medical Oncology Department, Institut Gustave Roussy, Villejuif, France.

Activating BRAF V600E mutations in NSCLC are present in approximately 1.5% of tumours, primarily adenocarcinomas, offering an opportunity to test targeted therapy in this subset of patients.

This single-arm, 2-stage design, phase II study enrolled stage IV BRAF V600E-mutant NSCLC patients determined by local laboratory testing.

Patients received dabrafenib 150 mg twice daily.

The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST 1.1 criteria.

As of 30 April 2014, 84 patients (female 52%, median age 66, ECOG performance status 0–1 86%, Asian 21%, never-smoker 37%, adenocarcinoma histology 96%) were enrolled in the study since August 2011.

Median duration of treatment was 4.3 months (range, 0.3–25.2) with 21 (25%) patients still on treatment.

Six patients had not received any prior regimen for metastatic disease (first-line), 40 patients had one line and 38 patients had received ≥ 2 lines (range 2–9).

The ORR for 78 patients with more than one line of prior therapy (second-line plus patients) was 32%. All of these 25 patients experienced partial response (PR). Disease control rate (DCR) longer than 12 weeks was 56%. Median duration of response (mDoR) was 11.8 months (95% CI 5.4–not reached) with 48% of responders progressed.

Based on assessment by independent review committee, 64 second-line plus patients had measurable disease; ORR and DCR were 28% and 52% respectively, and mDoR has not been reached.

Among the six first-line patients, three patients had PR, four patients had measurable disease based on independent review committee with three PRs.

Most common (>25%) adverse events were pyrexia (36%), asthenia (30%), hyperkeratosis (30%), decreased appetite (29%), nausea (27%), cough (26%), fatigue (26%) and skin papilloma (26%). Cutaneous squamous-cell carcinomas, including keratoacanthoma, were reported in 18%.

Grade ≥ 3 adverse events occurred in 45% with one event of grade 5 intracranial haemorrhage.

Dr Enriqueta Felip, who discussed the study results, said that BRAF V600E mutations are present in 1.5% of NSCLC and are mutually exclusive to other driver alterations. BRAF mutations identified in NSCLC are V600E (50%), G469A (40%), D594G (10%). In this study, dabrafenib showed clinically meaningful anti-tumour activity in BRAF V600E mutated NSCLC.

Dr Felip highlighted the recommendation from the 2nd ESMO Consensus Conference on Lung Cancer about optimal treatment for patients with ROS1, RET, BRAF or HER2 genomic alterations after standard treatment: Specific targeted treatments should be discussed with the patients and may be considered in individual patients based on expected risk-benefit, biological plausibility, preclinical data, and limited clinical efficacy data for authorised therapies in different indications.

Dr Felip questioned if in patients with uncommon alterations there is a need for randomised trials if there are good results from phase II trials.

Next steps for researchers would be identification of acquired resistance mechanisms to BRAF inhibitors, testing anti-PD1 and anti-PDL1 strategies and combination of targeted therapies. In the latest one, there is a trial in which a cohort B with dabrafenib/trametinib is actively recruiting.

The study was sponsored by GlaxoSmithKline.

A phase II study of neratinib with or without temsirolimus in patients with NSCLC carrying HER2 somatic mutations

In a phase II international randomised study of neratinib with or without temsirolimus in patients with NSCLC and tumours carrying HER2 somatic mutations, the combination therapy with neratinib/temsirolimus met the efficacy criteria in stage 1 study and has been subsequently expanded into stage 2. The results were presented by Dr Benjamin Besse of the Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France.

Somatic HER2 mutations occur in approximately 2-4% of patients with NSCLC.

In vivo data suggest that combined HER2/mTOR inhibition has synergistic effects in HER2-driven lung tumours. In a phase I study, 5 of 7 HER2-mutated NSCLC patients showed tumour regression (partial response – PR / stable disease - SD) after treatment with neratinib, an irreversible pan-HER tyrosine kinase inhibitor and mTOR inhibitor, temsirolimus. However, the effects of neratinib alone are unknown.

This randomized 2-stage phase II study compared neratinib with or without temsirolimus in patients with stage IIIB/IV NSCLC and HER2 somatic mutations.

Patients whose tumours had a documented HER2 mutation were randomised 1:1 to receive oral neratinib 240 mg once daily continuously with or without temsirolimus i.v . 8 mg/week, escalated to 15 mg/week after one 3-week cycle if tolerated.

Addition of temsirolimus was permitted in patients assigned to neratinib alone after progression.

High-dose loperamide prophylaxis for diarrhoea was mandatory throughout cycle 1.

The primary endpoint was overall response rate (ORR). Secondary endpoints included: clinical benefit rate, progression-free survival (PFS), and safety.

It was foreseen if ≥ 2 of 13 patients in each arm have a response at 12 weeks in stage 1, a further 26 patients per arm will be enrolled in stage 2.

In stage 1, 27 patients were enrolled (13 in the neratinib arm and 14 in the combined neratinib/temsirolimus arm) with approximately 12 weeks between randomisation of last patient and data cut-off.

Baseline characteristics of these 27 patients included in stage 1 were: male/female 52%/48%; median age 65 year; never smokers 63%. Two patients, both in the neratinib/temsirolimus arm, had not received prior anticancer medications.

In stage 1, the ORR was 21% in neratinib/temsirolimus arm vs 0% in neratinib arm. The partial response was observed in 3 patients in the combined arm and none in the neratinib arm alone. The stable disease was recorded in 6 patients in the combined arm and 4 patients in the neratinib arm.

Median PFS was 4.0 months in the neratinib/temsirolimus arm and 2.9 months in the neratinib arm.

In all 27 patients, most common all-grade adverse events were diarrhoea, constipation, nausea, dyspnoea, asthenia, and vomiting. Most common grade 3/4 adverse events were dyspnoea, diarrhoea (grade 3 only), vomiting, and nausea.

Grade 3 diarrhoea was recorded in 2 patients in the neratinib/temsirolimus arm and 1 patient in the neratinib arm. It was not a limiting toxicity with aggressive upfront management.

Dr Enriqueta Felip, who discussed the study results, said thatNSCLC is divided in subsets by the presence of molecular alterations (EGFR, ALK, KRAS, ROS1, RET, HER2, BRAF, NTRK1, FGFR, among others). Challenges are reflected  in genotyping, some molecularly defined subsets are rare and a clear effort is required to identify these patients. There are few trials in these uncommon molecular alterations and directing the patients to targeted trials requires collaboration.

HER2 mutations are present in 2% of NSCLC. They are mutually exclusive with other driver alterations. Potential synergistic effect of combined HER2 and mTOR inhibition has been observed in preclinical models of HER2 mutated NSCLC. In this study encouraging results were seen with the inhibition of both the HER2 and the PI3K pathway. She concluded that neratinib/temsirolimus combination deserves further development in HER2 mutated NSCLC.

The study sponsor was Puma Biotechnology, Inc.

References:

LBA 40 TARGET: A randomized, phase II trial comparing vintafolide versus vintafolide plus docetaxel, versus docetaxel alone in second-line treatment of folate-receptor-positive non-small cell lung cancer (NSCLC) patients

LBA 38  Dabrafenib in patients with BRAF V600E-mutant advanced Non-Small Cell Lung Cancer (NSCLC): a multicenter, open-label, Phase II trial (BRF113928)

LBA 39 Neratinib with or without temsirolimus (TEM) in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: An international randomized phase II study