Remarkable Six Months for Treatment Options in NSCLC

http://www.targetedonc.com/publi ... nt-options-in-nsclc

An impressive array of newly approved treatments, as well as investigational agents, for non–small cell lung cancer (NSCLC) emerged in the first 6 months of 2015. In addition, researchers continued the investigation of biomarkers to identify patients for the increasing range of targeted therapies and to uncover the early emergence of resistance.

Checkpoint Inhibitors
Nivolumab
In March 2015, the US Food and Drug Administration (FDA) approved Bristol-Myers Squibb’s checkpoint inhibitor nivolumab for NSCLC. Its clinical trial results led the FDA to approve the treatment for patients with metastatic squamous NSCLC with progression on or after platinum-based chemotherapy.1 Approval was based on data from a phase II trial (CheckMate-063 single arm)2 and a phase III trial (CheckMate-017, nivolumab vs docetaxel). Patients treated with nivolumab experienced statistically significant overall survival (OS) versus patients treated with docetaxel. At ASCO 2015, results of the phase III CheckMate 057 trial showed statistically significant improvement in OS for nivolumab versus docetaxel in patients with nonsquamous NSCLC who failed previous platinum-based chemotherapy.3 It is now approved in Europe for the treatment of patients with squamous NSCLC based on the results of the CheckMate 063 and 017 trials.

Pembrolizumab
On April 19, 2015, Merck filed for FDA approval of pembrolizumab for the treatment of patients with advanced NSCLC based on the results of its phase I 001 trial.4 The trial recruited 495 patients. Programmed cell death ligand 1 (PD-L1) expression was assessed in tumor samples from a validation group. The objective response rate (ORR) was 19.4%, median duration of response (DOR) was 12.5 months, and median duration of progression-free survival (PFS) was 3.7 months for all patients. In patients with PD-L1 expression in at least 50% of tumor cells, the response rate was 45.2%, and the median PFS was 6.3 months.5,6 A decision from the FDA is expected on October 2, 2015.

Atezolizumab
Data were presented at ASCO 2015 on single-agent atezolizumab (Roche, previously known as MPDL3280A). The FIR study recruited patients with metastatic NSCLC who were previously treated with other therapies and who were chemotherapy naïve. The ORR was greater in patients who had tumors with high PD-L1 expression.7 At the same meeting, the results of the POPLAR study showed that atezolizumab versus docetaxel improved OS, PFS, and ORR in previously treated patients with squamous or nonsquamous NSCLC. Once again, response was most evident in patients with high expression of PD-L1.8

Combination of MEDI4673 and tremelimumab
A phase Ib study shows that the combination of Astra Zeneca’s MEDI4673, a monoclonal antibody to PD-L1, and tremelimumab, an anti-cytotoxic T-lymphocyte–associated protein-4 (CTLA-4), is safe and demonstrates clinical activity in patients with advanced NSCLC. Activity was noted in PD-L1–negative and PD-L1–positive tumors, and the combination will move into phase III.9


Anti-EGFR, Anti-VEGF
Necitumumab
An FDA committee met on July 9, 2015, to consider data on necitumumab, an anti-EGFR antibody. In a press release, Lilly said it was encouraged by the discussions it had with the FDA regarding the risk-benefit profile of the drug. The combination of necitumumab  with gemcitabine and cisplatin demonstrated a significant improvement in OS over chemotherapy alone, specifically in the first-line setting.10,11

Bevacizumab
The results have been published of a randomized, open-label, phase II study of bevacizumab, an established anti-VEGF-A agent, with erlotinib versus erlotinib alone as first-line therapy in patients with advanced NSCLC with EGFR mutations.12 The median PFS was 16 months (95% confidence interval [CI], 13.9-18.1) for the combination versus 9.7 months (95% CI, 5.7-11.1). OS data have not matured, and the authors state that a randomized phase III trial will be needed to confirm the efficacy of the combination.


Small Molecule Inhibitors
Motesanib
Early in 2015, Takeda announced the failure of its phase III study (MONET-A) testing motesanib (AMG 706) to meet its primary endpoint of PFS. Motesanib, an orally administered inhibitor of VEGF receptors, platelet-driven growth factor receptors, and stem cell growth factor, was administered to patients with advanced nonsquamous NSCLC in combination with carboplatin and paclitaxel.13

Rociletinib
Encouraging data for rociletinib, a third-generation inhibitor of EGFR, was published in the New England Journal of Medicine.14 Rociletinib (CO-1686) has activity against NSCLC that has developed resistance to EGFR therapy, usually mediated by T790M resistance mutation. A phase I/II study demonstrated that patients who had failed prior EGFR treatment, and had the T790M mutation, achieved an ORR of 59%. Ongoing trials include Tiger 1 (NCT02186301), a phase II versus erlotinib; Tiger 2 (NCT02147990), a phase II as second-line treatment in mutated NSCLC; and a phase III Tiger 3 (NCT02322281) versus chemotherapy in patients who have previously failed EGFR therapy. Clovis Oncology hopes to submit a new drug application some time in 2015.15

AZD9291
AZD9291 (AstraZeneca) is another third-generation EGFR inhibitor with activity against the T790M resistance mutation. Encouraging results of a phase I/II study demonstrated therapeutic benefit in patients with NSCLC who harbored the T790M mutation and who had failed previous anti-EGFR therapy with a tyrosine kinase inhibitor. A response rate of 61% was reported in patients with the mutation.16

Afatinib versus erlotinib
In a phase III study, treatment with afatinib (Boehringer Ingelheim) resulted in significantly superior PFS and OS versus erlotinib in patients with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after ≥4 cycles of platinum-based chemotherapy.17 The study authors concluded that afatinib could be an option for patients with squamous cell carcinoma of the lung. Afatinib was approved in 2013 for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.18

Alectinib
A media release in May 2015 from Roche announced that the company had plans to submit its phase I/II data to the FDA as part of a new drug application for alectinib for the treatment of ALK-positive NSCLC. Alectinib, an ALK inhibitor that can cross the blood-brain barrier, has been granted breakthrough therapy designation.19 The data were presented at ASCO 2015. In the phase II study, the ORR for patients with central nervous system metastases was high, at 68.8%.20

Dabrafinib and trametinib combination
Data from a phase II trial supporting the combination of dabrafenib and trametinib in patients with BRAF V600E-mutated metastatic NSCLC were presented at ASCO 2015. The ORR was 68% by independent review, superior (by indirect comparison) to dabrafenib monotherapy. A financial statement released by Novartis stated that the combination has been granted breakthrough therapy status by the FDA.21,22

Gefitinib
In July, the FDA approved gefitinib (AstraZeneca) for the first-line treatment of patients with metastatic EGFR-positive NSCLC expressing the most common EGFR mutations (exon 19 deletions or exon 21 L858R substitution gene mutations). The FDA also approved the therascreen® EGFR RGQ PCR Kit to permit identification of candidate patients for treatment with gefitinib.23 The approval was based on the results of the phase IV IFUM trial (NCT01203917).24

Crizotinib
Pfizer announced it had received breakthrough therapy designation from the FDA for crizotinib. The designation was based on the results of a phase I study of patients with ROS1-positive NSCLC. The trial recruited 50 patients with advanced ROS1+ NSCLC and achieved an ORR of 72% and median PFS of 19.2 months.25,26

Veliparib
Poly ADP ribose polymerase (PARP) inhibitors are in development for NSCLC.  At the ASCO 2015 meeting, data were presented from a phase II trial of veliparib (AbbVie) with carboplatin (C) and paclitaxel (P), versus placebo with C and P, showing that smoking was a strong predictor of veliparib efficacy. These results are important because outcomes for tobacco-related NSCLC are poor. A phase III trial has been initiated in patients with a history of smoking.27


Novel Developments
With immunotherapy enjoying a high profile, interest in vaccines for NSCLC is emerging. The Roswell Park Institute in Buffalo, New York, announced in May that it will be the first US medical institution to offer a vaccine to treat lung cancer. The vaccine, called CIMAvax EGF, was developed by the Center for Molecular Immunology in Cuba. It acts by making circulating EGF immunogenic so that it is depleted by the immune system, thus depriving  tumor cells of this growth factor. The vaccine will undergo clinical development for FDA approval in the US.28,29

The therapeutic options regarding immunotherapy  will increase when pembrolizumab, MEDI4673, tremelimumab, and atezolizumab are approved, which in addition to the developing small molecule inhibitors greatly increases opportunities to tailor therapies for patients.

Hand in hand with these newer agents in development is the search for improved biomarkers to identify appropriate patients, to detect disease earlier, and to elucidate the development of resistance. Progress is being made with regard to the status of PD-L1 on tumor cells as markers of the efficacy of immune checkpoint inhibitors.8 A protein encoded by a cancer/testis gene called AKAP4 has recently been found to be a potential circulating biomarker for NSCLC, which could greatly facilitate very early detection of the disease.30

Details of a potential new test for the development of resistance to first-generation anti-EGFR tyrosine kinase inhibitors were presented at ASCO 2015. By monitoring urinary circulating tumor DNA it was possible to detect acquisition of the EGFR T790M resistance mutation. On further analysis, in some patients, urinary EGFR T790M could be detected 1 to 3 months before progression was detected radiographically.31 - See more at: http://www.targetedonc.com/publi ... thash.Z2WrIlWd.dpuf

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