Therapeutic focus – Pfizer and ArQule hope to see needs met in NSCLC

Analysis

A novel anticancer approach, yet to win any regulatory approvals, is in the spotlight this week for the notoriously difficult treatment of non-small-cell lung cancer (NSCLC). Two inhibitors of c-Met kinase have made positive strides, with a US filing for Pfizer’s crizotinib (PF-2341066), and the start of phase III for ArQule and Daiichi Sankyo’s ARQ 197.

The candidates are indicated for different subsets of NSCLC patients, and as such will not be in competition. They do, however, stem from similar schools of thought. Activation of the c-Met receptor, which stimulates proliferative signalling, is implicated in all manner of oncogenic, angiogenic and metastatic processes. Blocking this, therefore, appears a logical approach, but so far no drugs have been commercialised. Pfizer and ArQule’s candidates have shown promise in shrinking tumours and improving overall survival, and a first approval would provide important validation for a class of drug with several pipeline candidates across multiple tumour types (see table below).

Logical target

The MET gene is expressed by epithelial progenitor and stem cells, giving rise to tyrosine-kinase-based c-Met (mesenchymal endothelial transition factor) kinase receptors, otherwise known as the hepatocyte growth factor receptor (HGFR).

Activation of the c-Met pathway by its only known ligand, hepatocyte growth factor (HGF), is crucial for tissue generation in a developing embryo, and regeneration, such as the liver, in adult tissues.

Mutations of MET can cause unregulated c-Met activity, whereby oncologic stem cells are able to proliferate and grow, promoting tumour growth and angiogenesis.

Interestingly, c-Met initiates numerous downstream and therapeutically-validated pathways, such as JAK/STAT and Wnt signalling, the PI3K pathway, and RAS activation. As such, the approach holds broad potential and candidates tackling these pathways are among the industry's most promising pipeline products.

Rolling basis

Pfizer has filed crizotinib on a rolling basis – available for fast track-designated filings – whereby results are submitted for review by the FDA as they are revealed. The company expects to complete the submission by mid-year.

Crizotinib was studied specifically for anaplastic lymphoma kinase (ALK)-positive NSCLC. ALK gene mutations are thought to be the cause of 3-5% of NSCLC cases, in 40,000 patients worldwide that tend to be young non-smokers, unresponsive to chemotherapy. While this seems a niche market, incidence is comparable to ovarian cancer. Two phase III trials are ongoing: one pitting the drug against pemetrexed or docetaxel, due to report mid-2012, and another in 2013. The strength of earlier-stage results revealed at the Asco meeting last year suggested an accelerated approval process was possible (Asco – Pfizer basks in glow of crizotinib applause, June 8, 2010).

Final phase I results reported last October showed significant tumour-shrinkage in 57% of cases, with an 87% disease control rate, and median progression-free survival of 9.2 months. Side effects, such as nausea, were manageable.

Global sales consensus for 2016, that stood at $79m prior to the results, are now nearly $400m. With such confidence, both scientifically and commercially, it seems an approval is odds-on, feasibly even by year-end.

Scoring with overall survival

ArQule’s ARQ 197, partnered with Daiichi Sankyo, has started phase III, in combination with Tarceva, in nearly 1,000 non-squamous NSCLC patients that have received one or two prior treatments. Needham analysts reckon this represents a target market of 70% of NSCLC cases, or over 100,000 people in the US alone. ArQule’s stock gained 6% over the course of Wednesday to close at $6.73 – equalling the two-year high of April 2010, following the release of final phase II data; Needham has set a $12 price target.

The phase II results demonstrated a 66% increase in progression-free survival, overall survival of 8.4 months for the combination versus 6.8 months for Tarceva alone in the intent-to-treat population, and 9.9 months versus 6.8 months for Tarceva alone in the non-squamous population. ARQ 197 also showed promising efficacy in blocking tumour metastases, was well-tolerated, and also elicited manageable side effects that were on a par with Tarceva alone.

The results supported using overall survival as a primary pivotal endpoint, an increasingly important outcome measure for the FDA to approve cancer drugs. The study should release data in mid-2013.

ARQ 197 is also being studied as a monotherapy for liver cancer, due to report phase II results in the third quarter, and in germ cell tumours, to report late this year. The candidate is also undergoing earlier-stage combination trials with other chemotherapeutics, including a phase I/II colorectal cancer trial with irinotecan and cetuximab.

As such, strong pivotal data showing broad anticancer activity, with equal potential as both monotherapy and combination, could add substantial value to the candidate.

ARQ 197 was forecast to sell $100m in 2016 prior to the start of phase III, a risk-adjusted figure likely to increase substantially through the phase III programme should the data continue to be successful.

All facets of oncology

ARQ 197’s immediate competitor is Roche’s MetMab, although ArQule appears to have the commercial edge. MetMab improves overall survival in patients with high c-Met expression – representing 20-50% of the NSCLC market. However in patients expressing low c-Met, decreased efficacy was observed in combination with Tarceva, versus Tarceva alone. Roche recently announced plans to take MetMab into phase III and trials should start this year.

A look at the development of other pipeline c-Met inhibitors, including Exelixis and GlaxoSmithKline’s partnership on phase III thyroid cancer candidate XL-184 and GSK1363089 in phase II for renal cell carcinoma, and Incyte and Novartis’ broadly-indicated INCB28060, demonstrates the level of effort to spot efficacy in all facets of oncology.

Given c-Met’s high expression in progenitor cells, its inhibition has broad remit, and seems a logical upstream approach from targeting validated oncogenic pathways. With approval of crizotinib on the cards, and ARQ 197 at a pivotal point, the lung cancer community has waited some time to see the potential strides ahead. Furthermore, approvals could open the doors on a variety of anticancer drugs with broad efficacy that can still accommodate specific targeting.

Mid- to late-stage c-Met inhibitor pipeline
WW Annual Sales ($m)
Product Generic Name Pharmacological Class Indication Summary Company Originator 2012 2014 2016
Filed PF-2341066 crizotinib c-Met tyrosine kinase & ALK inhibitor Non-small cell lung cancer (NSCLC) [Phase III] Pfizer Pfizer 54 250 423
Phase III ARQ 197 Met tyrosine kinase inhibitor Non-small cell lung cancer (NSCLC) [Phase III] ArQule / Daiichi Sankyo / Kyowa Hakko Kirin ArQule - 26 123
XL-184 VEGFr2, RET & Met tyrosine kinase inhibitor Thyroid cancer [Phase III] Exelixis / GlaxoSmithKline Exelixis - - -
Phase II GSK1363089 foretinib VEGFr2 & Met tyrosine kinase inhibitor Renal cell carcinoma (RCC) [Phase II]; Stomach cancer [Phase II]; Head & neck cancers [Phase II] Exelixis / GlaxoSmithKline Exelixis - 13 40
MetMab (RG3638) onartuzumab Anti-cMet MAb Non-small cell lung cancer (NSCLC) [Phase II] Roche Genentech - - 8
INCB28060 Met tyrosine kinase inhibitor General cancer indications [Phase II] Incyte / Novartis Incyte - - -
Total 54 289 595
Product Trial IDs Status
Crizotinib  NCT00932893 / NCT01154140 Phase III
ARQ 197 NCT01244191 Phase III
ARQ 197 NCT01055067 / NCT00802555 / NCT01075048 Phase II

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