Therapeutic focus - Phase III lung cancer pipeline loses Nexavar as novel agents approach

Analysis

A miss for Nexavar in a late-stage lung cancer study, after having previously failed to have an impact in earlier stages of the disease, does not come as a huge surprise. However, it seems likely that development of this agent in this tumour type will now end, removing another treatment option from the lung cancer pipeline.

Aside from the notable success with Pfizer’s Xalkori, a genetically targeted therapy that treats a very small subset of patients, few breakthroughs have been achieved in phase III in lung cancer in the last few years. The approaching Asco conference should contain some interesting data – the results from Boehringer Ingelheim’s pivotal trial of Tomtovok, an irreversible ErbB inhibitor, have been held back for the conference and are keenly awaited. A number of other novel agents are approaching read outs in the coming years and it is hoped after a series of set backs, more success stories will emerge (see table).

Hard to treat

Because the lung has no pain fibres, patients have few signs early on and tend to present with symptoms due to metastatic spread to other regions such as the brain, bone and liver. By this stage the tumour in the lung is frequently too large to operate on, meaning drug therapy is the only option for many patients.

Lung cancer patients tend to be elderly with other illnesses in addition to having late-stage disease, making them very hard to treat. Long term cancer survival remains low, although it has edged higher in recent years, mainly due to improved screening designed to catch it earlier.

The development of agents targeted at specific genetic mutations probably holds much hope for further advances. Pfizer's Xalkori, which targets an abnormality in the ALK gene that occurs in about 4% of lung cancers and is particularly common in non-smokers, was the first example of this. It was approved last year.

Failed impact

Nexavar, a multi-kinase inhibitor approved to treat liver and kidney cancers, had previously failed to show an impact as a first-line treatment in phase III studies. As such, although the agent appears to have some activity in the disease, hopes were low for success in this later-stage trial.

The Mission study recruited 703 patients with advanced relapsed or refractory non-squamous NSCLC whose disease progressed after two or three previous treatments. Patients received either Nexavar as single agent or placebo, on top of best supportive care. While the drug failed to extend overall survival, the primary endpoint of the trial, an improvement in progression-free survival was seen, the companies said.

It seems unlikely that developers Bayer and Onyx will chose to push on with lung cancer now, despite the unmet need - analysts at Leerink Swann reckoned success in this setting could have opened up a sales opportunity worth $300m-$400m.

Nexavar joins a long list of drugs that have failed to make an impact in lung cancer, both experimental agents and those that have shown effectiveness in other tumour types. Vectibix, Velcade and Caprelsa all made it as far as phase III, while figitumumab, NOV-002 and ASA404, being developed by Pfizer, Novelos and Novartis respectively, failed to live up to promise in late stage trials in the last few years.

The table below highlights some candidates that should report data in the coming years.

Selected late-stage NSCLC pipeline Indication sales ($m)
Product Generic name Pharmacological Class Company 2011 2018 Clinical Trial ID
Filed Abraxane paclitaxel (albumin-bound) Taxane Celgene/Otsuka Holdings 8 526  -
Erbitux (EU only) cetuximab Anti-EGFr MAb Merck KGaA 1 5 -
Phase III ARQ 197 tivantinib c-Met tyrosine kinase inhibitor Daiichi Sankyo/Kyowa Hakko Kirin/ArQule - 1,046 NCT01377376,
NCT01244191
Ganetespib Ganetespib Heat shock protein 90 (Hsp90) inhibitor Synta Pharmaceuticals - 845 NCT01348126
Stimuvax emepepimut-S Anti-MUC1 vaccine Merck KGaA/Oncothyreon - 345 NCT00409188
IMC-11F8 necitumumab Anti-EGFr MAb Bristol-Myers Squibb/Eli Lilly - 165 NCT00981058
PF-00299804 dacomitinib Pan-HER tyrosine kinase inhibitor Pfizer - 134 NCT01360554
SAR2405550/ BSI-201 iniparib Poly (ADP-ribose) polymerase (PARP) inhibitor Sanofi - 119 NCT01082549
Nexavar sorafenib Multi-kinase inhibitor Bayer/Onyx Pharmaceuticals - 114 NCT00863746
MAGE-A3 astuprotimut-R Anti-MAGE-A3 vaccine GlaxoSmithKline - - NCT00480025
MetMAb onartuzumab Anti-cMet MAb Roche - - NCT01456325
Ramucirumab ramucirumab Anti-VEGFr MAb Eli Lilly - - NCT01168973
Tomtovok afatinib EGFr & HER2 (ErbB-2) dual kinase inhibitor Boehringer Ingelheim  -  - NCT00949650
Yervoy ipilimumab Anti-CTLA4 MAb Bristol-Myers Squibb - - NCT01285609

In terms of agents close to reaching the market, theoretically at least, Erbitux’s developers have been struggling to win regulatory backing in both Europe and the US for the drug’s use as a first line treatment for some time; applications have been knocked back in both territories. In the US Lilly and Bristol-Myers recently confirmed they would not be pursuing another review by the FDA. However, Merck KGaA in March 2011 applied for approval again, this time specifically in patients with high EGFR expression, and news is awaited. The drug is used off-label in the US in lung cancer already.

Abraxane, bought by Celgene in 2010, is due to hear on Japanese approval imminently, and from the FDA by October. The paclitaxel-based drug combined with carboplatin substantially improved response rates in patients with advanced NSCLC with a notable impact in older patients – those 70 years and older achieved overall survival of 19.9 months versus 10.4 months in comparator arm. However on other read outs the data were mixed and it remains to be seen what regulators make of the application. Approval with a progression free survival claim on the label will mean a big pay day for the drug’s former owners - Celgene committed to paying a further $250m to shareholder of Abraxis if that happens.

Next up for phase III data are pivotal results from Boehringer Ingelheim’s Tomtovok, generically called afatinib. The drug irreversibly inhibits both Her2 and EGFR receptors, a novel mechanism of action that many expect to generate positive results. The Lux-Lung 3 trial pitted the drug against chemotherapy agents Alimta and cisplatin, and results are eagerly awaited.

Asco will also provide a peek at phase II data on Pfizer’s PF-00299804, or dacomitinib, another irreversible kinase inhibitor that targets the HER receptors. A phase III trial is ongoing comparing the drug to erlotinib for advanced NSCLC, with data likely next year.

Pipeline

In May, Daiichi Sankyo and ArQule announced they had completed patient recruitment into a phase III trial of ARQ197, or tivantinib, testing the drug in combination with Tarceva in previously treated patients with locally advanced or metastatic NSCLC. An interim analysis is anticipated later this year, with the final read out due in 2013.

The c-Met inhibitor showed strong and consistent efficacy in combination with Tarceva in its phase II trial (Therapeutic focus – Pfizer and ArQule hope to see needs met in NSCLC, January 13, 2011). C-Met inhibitors are emerging as an important new class of targeted anti-cancer agents and with tivantinib the most advanced agent, its progress will be watched with interest.

Targeting C-met with an antibody is Roche’s MetMab. In phase II the drug improved overall survival in patients with high expression of c-Met, which is about 20-50% of the NSCLC market; however, it had decreased efficacy in patients expressing low c-Met. A phase III study started earlier this year.

Interim data is also likely for Synta Pharmaceutical’s Hsp90 inhibitor, ganetespib, later this year. The trial is testing the drug in combination with docetaxel versus docetaxel alone in late stage patients. At last year’s Asco the company released data on its phase II trial, which showed significant tumour shrinking ability in patients with advanced NSCLC (Asco EventAnalyzer - 2011's winners and losers, June 8, 2011).

Next year should also see data on Sanofi’s PARP inhibitor iniparib, which generated disappointing results in breast cancer last year. The lung cancer trial in patients with previously untreated late stage 4 squamous NSCLC, pitting iniparib with and without chemotherapy.

Earlier this year news that the pivotal trial of Merck KGaA's lung cancer vaccine Stimuvax would continue to conclusion, rather than stop early due to efficacy, caused partner Oncothyreon to a 40% share price plunge (Oncothyreon falls back as Stimuvax results wait another year, March 7, 2012). The drug has a chequered history that includes a clinical hold in multiple myeloma, and few are holding out hope for success – final results are expected next year.

Another vaccine approach, Glaxo's MAGE-A3, is also some way from reporting phase III lung cancer data.

Antibody approach

Next year should also see results from the second phase III trials of IMC-11F8, or necitumumab, an IgG1 monoclonal antibody.  In February last year Lilly and BMS announced the stop of a phase III trial called Inspire because of safety concerns related to blood clots in the experimental arm of the study.  In this trial necitumumab was added to a combination of Alimta and cisplatin, as a first line treatment for patients with advanced nonsquamous NSCLC, compared to a regimen of the two drugs alone.

It is currently in another phase III trial, called Squire, in combination with Gemzar and cisplatin as a first-line treatment for squamous cell NSCLC. The trial is looking to enrol a total of 1,100 patients with results expected mid-2013 according to the company.

Lilly is also still recruiting patients for a large 1,242 patient study with ramucirumab, another IgG1 monoclonal antibody, which targets VEGF receptor-2. The product is undergoing a huge pivotal programme in a variety of cancer types; lung data is not expected until late next year later.

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