Therapeutic focus - Vectibix failure leaves few new options for head and neck cancer

Analysis

The failure of Amgen’s Vectibix to significantly prolong survival of patients with metastatic head and neck cancer, as reported last week, casts a light on a somewhat sparse phase III landscape for this indication (Amgenwill be disappointed with Vectibix failure, August 12, 2010).

Erbitux is the only targeted agent approved for use in this cancer in Europe and the US, and only six others are in late stage development, none of which are due to release pivotal results anytime soon. The next phase III data in this setting is likely to come from Eli Lilly’s chemotherapy agent Alimta. As such, researchers might have to wait for earlier stage candidates to progress, where more novel mechanisms of action are being tested (see tables).

Rare and hard to treat

Head and neck is a broad term for a number of cancers; these include eye, nose, mouth, larynx and oesophageal tumours. It is not particularly common and mainly occurs in men over 50, with a strong association to smoking and alcohol. The National Cancer Institute (NCI) estimates that head and neck tumours constitute roughly 3-5% of all cancers in the US, with just under 40,000 new cases last year.

The UK's Institute of Cancer Research (ICR) explained to EP Vantage the significant challenges faced with treating quite a diverse set of diseases. Unique factors come into play, like the complex anatomy of that region of the body gives rise to unpredictable invasion by metastatic cells. Unlike most metastatic cancers, the primary cause of death in head and neck is from local recurrence of the disease. From 35-55% of patients tend to suffer local recurrence of the disease within two years, and two thirds of these patients die within a year. A major need for therapy, therefore, is in the prevention of this recurrence.

Current standard of care (SOC) is a combination of surgery, radiotherapy, and chemotherapy, although surgery is generally only an option for earlier-stage disease, and can leave the individual disfigured. In the case of oropharyngeal cancer, for example, sections of the mouth or tongue may be removed, impairing speech or swallowing ability.

Whilst locally-advanced cases, when caught early, can be curable around half of cases are not diagnosed until the disease has already spread. As such, life expectancy can range widely.

Platinum-based chemotherapies and the taxanes are mainly used to treat the disease, as well as radiotherapy.

EGFR approach

Erbitux, sold by Bristol-Myers Squibb and Merck KgaA is the US and Europe, was approved in 2006 to treat second-line metastatic disease and first-line locally-advanced tumours. The cancer accounted for a quarter of the drug’s total revenues of $1.65bn last year, or $458m, according to indication data from EvaluatePharma. Analysts are not expecting huge growth over the next few years, $652m is forecast by 2016.

These forecasts could rise if the drug wins approval in a first-line metastatic setting in the US; European approval was granted in 2008 and sales are thought to be higher in this region. Bristol-Myers Squibb received a complete response letter last year on its filing, and confirmed to EP Vantagetoday that it expects to re-file in mid-2011.

As a first-line treatment in combination with chemotherapy the drug extended survival to 10.1 months versus 7.4 for chemo alone, highlighting the short life expectancy.

Like Erbitux, Vectibix is an anti-EGFR antibody. In the first-line trial that failed last week adding the drug to chemotherapy meant patients lived a bit longer, 11.1 months versus 9 months for chemo alone, but missing statistical significance.

Another anti-EGFR antibody that failed to extend overall survival in this cancer was Genmab’s zalutumumab. The drug was tested in a slightly different setting, as a monotherapy in non-curable head and neck cancer patients who had failed standard platinum-based therapy. Patients were given the antibody in combination with best supportive care (BSC) or BSC alone and although overall survival improved slightly in the drug arm, to 6.7 months versus 5.2 months, again the difference was not significant.

A significant improvement in progression free survival was seen, however. New Genmab CEO Jan van de Winkel told EP Vantage recently that he was optimistic about the future for the antibody-based therapeutic, although admitted that the large costs of onward development would be hard to meet for the company, and a partner would be need to be sought (EP Vantage Interview – New Genmab CEO aiming to turn tide in its favour, July 13, 2010).  Once full phase III data are available, the chances of a collaboration will become clearer.

Still, with both zalutumumab and Vectibix seemingly failing to demonstrate much potency in this setting, Erbitux could well end up the only anti-EGFR therapy available in this cancer.

Head & neck cancer - phase III pipeline
Product Pharmacological Class Company
Vectibix Anti-EGFr MAb Amgen / Takeda
Alimta Thymidylate synthase inhibitor Eli Lilly
Avastin Anti-VEGF MAb Roche
Multikine Cytokine CEL-SCI / Teva Pharmaceutical Industries
Tykerb EGFr & HER2 (ErbB-2) dual kinase inhibitor GlaxoSmithKline
Reolysin Therapeutic virus - Ras activated Oncolytics Biotech
Zalutumumab Anti-EGFr MAb Genmab

Other options

Eli Lilly has a well-advanced pipeline candidate with Alimta, already a blockbuster in non-small cell lung cancer (NSCLC). The company told EP Vantagethat it will be reporting data from a phase III head and neck trial at a medical conference this autumn. The study, in combination with cisplatin, was completed in March 2010 in patients with recurrent or metastatic disease.

Roche’s Avastin is being trialed in 400 primary site recurrent or metastatic head and neck cancer patients, also in combination with chemotherapy. The trial is expected to be complete in August 2013.

A separate phase II trial of a combination of Avastin and Alimta in head and neck cancer was completed by both Roche and Lilly in September last year.

Other more experimental therapies in development includes CEL-SCI’s Multikine; Teva Pharmaceutical Industries has already bought rights to this agent in Israel and Turkey and is involved in its development. Phase III trials of the immunostimulatory cytokine in 800 advanced primary head and neck cancer patients will begin enrolling in the third quarter, designed as a prior therapy to standard of care.

Reolysin, Oncolytics Biotech’s therapeutic virus-based candidate, is being studied – in combination with paclitaxel and carboplatin – in a randomised phase III study in 280 metastatic or recurrent head and neck cancer patients who have progressed on or following prior platinum-based chemotherapy. The study, started a couple of months ago, will run until December 2012. Due to its mechanism of action, targeting the Ras pathway, the company hopes that the drug will be available to patients that do not respond to Erbitux.

Finally, in an alternative disease setting, GlaxoSmithKline’s Tykerb, an EGFr and HER2 (ErbB-2) dual kinase inhibitor, is being studied as an adjuvant to post-operative therapy, in a phase III combination trial with chemotherapy, to reduce disease recurrence in high-risk patients. The 680-patient study is expected to be complete in June 2012.

Later stage

A review of the phase II pipeline shows a more diverse range of mechanisms of action, most designed as second-line treatments. Boehringer Ingelheim’s Tovok, like Tykerb a dual inhibitor of EGFr and HER2 (ErbB-2), reported promising first-line data recently, demonstrating tumour shrinkage in 22% of patients, compared to 13% in the comparative group receiving Erbitux.

GenVec’s gene therapy TNFerade is being studied in several ongoing trials, including as a pretreatment to surgery to locally-advanced oesophageal tumours, in a safety/tolerability trial for recurrent head and neck cancer, and in combination with radiotherapy and Erbitux in locally-advanced tumours in elderly or frail patients.

Idera Pharmaceuticals and Merck KGaA began a phase II trial of its TLR9 agonist, IMO-2055, in December, in recurrent or metastatic carcinoma sufferers. Finally, Novartis’ mTOR inhibitor Afinitor began a phase II trial at the start of this year as a second-line therapy in recurrent disease.

If some of these new avenues of therapy can progress to phase III, hopefully the void of novel late-stage candidates can be filled somewhat, and eventually open up more options for patients.

Head & neck cancer - selected phase II pipeline
Product Pharmacological Class Company
ARQ 501 (R1668) E2F modulator ArQule / Roche
1363089 VEGFr2 & Met tyrosine kinase inhibitor Exelixis
TNFerade TNFa gene therapy GenVec/Asahi Kasei
IMO-2055 TLR9 agonist Idera Pharmaceuticals/Merck KGaA
Tovok EGFr & HER2 (ErbB-2) dual kinase inhibitor Boehringer Ingelheim
IMC-A12 Anti-IGF-1R MAb Eli Lilly
Cilengitide Integrin inhibitor Merck KGaA
Afinitor Rapamycin analogue (mTOR inhibitor) Novartis
Tarceva EGFr tyrosine kinase inhibitor Roche / Aetellas Pharma

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