Unprecedented Progress in the Treatment of NSCLC

A record number of drugs reached the clinic in a short time, and more are in late phase pipeline

Generic chemotherapy such as antitubulins and antimetabolites form the backbone of treatment for the majority of patients with non-small cell lung cancer (NSCLC), often in combination with platinum-based regimens. However, in recent years NSCLC has evolved into a highly segmented indication defined by tumour histology and molecular status; targeted branded therapies have shaped the treatment algorithm. These include bevacizumab, an inhibitor of angiogenesis, the first-generation epidermal growth factor receptor (EGFR) inhibitor erlotinib, and the anaplastic lymphoma kinase (ALK) inhibitor crizotinib. In 2015, the US Food and Drug Administration (FDA) approved six additional therapies for NSCLC, more than for any other oncology indication in that year; the situation was also accompanied by a shift in standard of care.

The programmed cell death protein 1 (PD1) inhibitor nivolumab became the first immunotherapy and immune checkpoint inhibitor to enter the NSCLC market, gaining approval for previously treated patients with metastatic squamous cell carcinoma in the United States (March 2015) and Europe (July 2015). The FDA label was expanded in October 2015 to include non-squamous NSCLC. In both histologies, nivolumab demonstrated significant overall survival improvements over docetaxel, a standard of care. A second PD1 inhibitor, pembrolizumab, was approved in October 2015, together with a companion diagnostic (PD-L1 IHC22C3 pharmDx), for previously treated patients with NSCLC whose tumours express PD1 ligand 1 (PDL1). Pembrolizumab is under regulatory review for NSCLC in Europe. Several phase III trials are ongoing for nivolumab and pembrolizumab to expand their use to earlier lines of therapy.

Gefitinib, another first-generation EGFR inhibitor, was granted FDA approval in July 2015 as a first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib is the first agent to launch specifically for patients whose tumours harbour the EGFR-T790M mutation, which is associated with drug resistance. Osimertinib was approved in the United States in November 2015 under accelerated approval and in Europe in February 2016 under conditional approval. Unlike the FDA label, the European label does not restrict the use of osimertinib to patients who have received prior EGFR TKI therapy.

The anti-EGFR recombinant monoclonal antibody necitumumab was granted approval in the United States in November 2015 and in Europe in February 2016 as a first-line therapy for metastatic squamous NSCLC, in combination with gemcitabine and cisplatin. The triplet combination demonstrated a statistically significant but modest 1.6-month improvement in median overall survival compared with gemcitabine plus cisplatin.

First approved in Japan in July 2014, the ALK inhibitor alectinib was granted accelerated approval by the FDA in December 2015 for patients with ALK-positive metastatic NSCLC who received prior treatment with crizotinib on the basis of early phase data. An European marketing authorisation application submitted in September 2015 is under review. The Japanese phase III J-ALEX trial, which evaluated alectinib versus crizotinib in ALK inhibitor naive patient, was stopped early in February 2016 for meeting its primary endpoint, progression-free survival. A similarly designed phase III trial (ALEX) is ongoing in the Unites States and other countries.

Late phase pipeline

Most excitement surrounds immune checkpoint inhibitors and their combination.  Several PD1 inhibitors are in phase III development for NSCLC, including atezolizumab, durvalumab and avelumab. Atezolizumab is being evaluated as a monotherapy and in combination with other agents, including bevacizumab and chemotherapy. Durvalumab is being evaluated as a monotherapy and in combination with tremelimumab – which targets cytotoxic T lymphocyte antigen 4 (CTLA4) – and to date is the only immune checkpoint inhibitor in phase III development for unresectable stage III NSCLC. Like pembrolizumab, atezolizumab and durvalumab are also in late phase development as adjuvant therapies for completely resected stage IB-IIIA disease. In 2015, a total of seven and four phase III trials were initiated in NSCLC for atezolizumab and durvalumab. However, enrolment into the phase III CAURAL trial of durvalumab plus osimertinib was suspended in October 2015 because of safety concerns. Avelumab entered phase III development for NSCLC in 2015, and two phase III trials are ongoing in the metastatic setting.

Rociletinib, a third-generation EGFR TKI, is under regulatory review for NSCLC positive for EGFR-T790M mutation in the United States and Europe. Like osimertinib, rociletinib was granted FDA breakthrough therapy designation (BTD) and regulatory submissions were based on promising early phase clinical data. The phase III TIGER-3 trial is ongoing in patients with EGFR activating mutations (excluding exon 20) but does not require patient to harbour EGFR-T790M. The phase II/III TIGER-1 trial explores rociletinib as a first-line therapy for EGFR mutation positive NSCLC. Another third-generation EGFR TKI, ASP8273, is also in a phase III trial as a first-line therapy for NSCLC with EGFR activating mutations.

Dacomitinib, an irreversible pan-HER2 inhibitor, is being evaluated as a first-line treatment for metastatic NSCLC; however, two separate phase III trials in previously treated patients failed to meet their primary endpoint.

The anti-HER3 monoclonal antibody patritumab is also in phase III development for NSCLC.

Other drug classes in late phase development include inhibitors of BRAF/MEK, CDK4 and CDK6, as well as PARP inhibitors. The BRAF inhibitor, dabrafenib was granted FDA BTD for BRAF V600E-positive patients as a single agent in 2014 and in combination with trametinib, a MEK inhibitor, in 2015. The MEK inhibitor selumetinib is being evaluated in the phase III SELECT-1 trial in KRAS mutation positive NSCLC.

A diverse array of therapeutic vaccines is also in late phase development for NSCLC (BV-NSCLC-001, EGF antigen vaccine; TG-4010, viral vector vaccine; tergenpumatucel-L, whole-cell tumour vaccine, OSE-2101, multi-antigen vaccine). However, the field of therapeutic vaccines has been marred by high profile failures.    


Nawaz K, Webster RM. The non-small-cell lung cancer drug market. Nature Reviews Drug Discovery 2016;15(4):229-230.