ASCO Preview - Melanoma set to hog limelight as Parps given a boost

As always, the swathe of data released last night by the American Society of Clinical Oncology ahead of its huge cancer confab in June has already prompted almost as many headlines as numbers. Attracting attention this year will be AstraZeneca with its Parp inhibitor, olaparib, with positive data that could well cause hopes to rise again for this class after recent disappointments; meanwhile high hopes look likely to be confirmed for Exelixis’s multi-kinase inhibitor, cabozantinib, and Incyte’s ruxolitinib, a Jak1/2 inhibitor.

For the second year running, eye catching data in melanoma looks set to hog the limelight, although a number of the more significant findings have been kept back to announce at the conference. Taking plenary spots this year include phase III data on two melanoma drugs - Bristol-Myers Squibb’s ipilimumab with first line data and Roche’s vemurafenib tested in patients with a specific gene mutation. In the meantime, cancer specialists have the next few weeks to chew over the more than 4,000 abstracts now available; a selection of those already prompting interest are discussed below.

Plenary Session

Given recent successes with both ipilimumab and vemurafenib, formerly called RG7024, both these plenary spots have been granted on the back of positive data. These will be announced on the Sunday of the conference, June 5, at a session that is always widely attended.

Now branded Yervoy, BMS won approval for ipilimumab in the US and Europe earlier this year, for inoperable or metastatic melanoma who had failed on other therapies, a broader label than expected (Week of good Yervoy news boosts BMS fortunes, March 28, 2011).

A study called 024 will be presented at ASCO, testing Yervoy in combination with dacarbazine in first-line treatment of metastatic melanoma. BMS has already announced the combination extended survival over dacarbazine alone and the finer details are eagerly awaited. Analysts believe a survival improvement of four months would be considered clinically meaningful.

Meanwhile, Roche has already filed for approval for vemurafenib on the back of the trial, called BRIM3, which will be presented. Again, all that has been announced is that patients given the drug lived longer overall, while progression free survival (PFS) was also improved. The study compared the drug, a B-RAF inhibitor, to dacarbazine in patients with previously untreated BRAF V600 mutation-positive, unresected or locally advanced metastatic melanoma.

Approval is widely anticipated for the drug next year; analysts are already pencilling in sales of $523m by 2016, according to EvaluatePharma.

Late breakers

Among the late breakers, details of which are also being held back, is the Oceans study of Avastin in ovarian cancer, in patients with platinum sensitive disease but who have failed one prior line of therapy. Roche has already announced the trial significantly extended PFS, so the magnitude of benefit is awaited – four to six months beyond chemotherapy alone would be considered meaningful.

Given a muted response to the first line data announced at ASCO last year a strong read out could help build hopes for the antibody in this cancer type, for which it is not yet officially approved. Data will be released on Saturday, June 4.

Overall survival from a first-line trial, called Icon 7, will also be presented, again in the late breakers – this will also help determine Avastin’s chances of winning approval in this setting, which analysts believe represent a $1bn opportunity.

Roche, which remains a dominant force in oncology research, says it will be presenting data in approximately 300 abstracts across more than 30 cancer types at the conference. As well as Avastin and vemurafenib, phase II data from a novel lung cancer agent, MetMab, looks set to attract attention. Abstracts reveal that in combination with Tarceva the drug had a large impact on overall and progression free survival.

In the spotlight

Phase II data from Exelixis’ cabozantinib (XL184) are being touted by the conference organisers as among the most interesting, although much has already been pre-announced. The drug’s ability, beyond anything seen before, to shrink bone metastases in prostate cancer is causing a lot of excitement – 86% of patients in a phase II study had complete or partial resolution of metastases detected on bone scans, often accompanied by pain relief, researchers confirmed on a conference call yesterday.

Across trials in a variety of solid tumours, shrinkage was observed in the majority of patients, ranging from 40% in non-small cell lung cancer and 76% of hepatocellular patients. Four abstracts will be presented on cabozantinib, a kinase inhibitor that targets both VEGF and MET signalling pathways, keeping the drug in the spotlight as the release of the first set of pivotal data approaches.

Results from a phase III trial in medullary thyroid cancer are due in the next couple of months, with Exelixis planning to file for approval before the end of the year (Event - Exelixis needs to deliver late-stage validation, March 7, 2011).

Pump up the Parps

Encouraging results from AstraZeneca’s olaparib in ovarian cancer could help revive optimism around Parp inhibitors, which suffered a setback in breast cancer earlier this year (Therapeutic focus - High hopes around Parp inhibitors punctured, January 28, 2011)

A large phase II study testing the drug in a maintenance setting in patients with platinum-sensitive relapsed serous ovarian cancer found the drug significantly extended PFS, to 8.4 months compared with 4.8 months for those given a placebo pill. This is the first time a maintenance therapy has proven effective in this patient group; 60-80% of ovarian cancer cases are the serous subtype, the most aggressive form of the disease, the majority of which are detected at a late stage.

Sanofi is also due to present reams of data on its Parp inhibitor, iniparib, including more detail from the failed phase III study in triple negative breast cancer; top line data emerged in January (Pivotal failure shows Sanofi's BiPar acquisition as a questionable gamble, January 28, 2011).

Exactly why this trial failed is still unclear, and some believe further analyses may have revealed a subgroup in which the drug worked. With earlier stage data from other drugs in this class, including Abbott Laboratories' veliparib, Pfizer’s PF-01367338 and Merck’s MK-4827, the Parp inhibitors are likely to attract a lot of attention at the conference.

Other agents

Further information from a phase III trial in sarcoma of Merck & Co’s ridaforolimus, an mTOR inhibitor licensed from Ariad Pharmaceuticals, will be of interest in the wake of encouraging top line data released in January (Ariad soars on sarcoma success, January 19, 2011).

The abstract revealed a first look at interim overall survival data; survival was extended to 88 weeks with the drug compared to 78.7 weeks in the control arm; previously announced PFS data should an improvement of 3.1 weeks. Given the aggressive nature of this cancer many believe these data should lead to approval, although Ariad shares were trading 6% down $8.64 at the open today - perhaps some investors had been hoping for a more unequivocal signal of efficacy, although some profit-taking is also possible with the shares trading at seven-year highs.

ASCO is also set to be big event for Incyte, which will present fresh data from the ongoing pivotal programme for ruxolitinib, a JAK1/2 inhibitor, in myelofibrosis. Top line data have already been released, and encouraging new results revealed in the abstract means hopes for approval are likely to build (Incyte passes first test with myelofibrosis trial, December 21, 2010).

Incyte shares were largely unchanged this morning, at $19.29.

The table below lists other studies that are likely to be attracting attention this year.

Other interesting clinical trial data to be presented at ASCO 2011 WW annual sales ($m) - indication specific
Company Product Pharmacological class Technology Asco trial data Current Indication Status Indication launch 2012 2013 2014 2015 2016
Bayer Nexavar Multi-kinase inhibitor Small molecule PIIb in breast cancer Phase III 2014 - - 57 194 282
Celgene Abraxane Taxane Plant extract PIII in NSCLC Phase III 2011 59 130 208 291 373
Pomalidomide (Actimid) Immunomodulator Small molecule PII in multiple myeloma Phase III 2013 - 11 31 55 79
Amrubicin (Calsed) Anthracycline Small molecule PIII in SCLC Phase III 2012 - - - - -
Eli Lilly Alimta Thymidylate synthase inhibitor Small molecule PIII in NSCLC (maintenance) Marketed 2004 2,832 3,035 3,206 3,356 2,919
Enzastaurin Serine/Threonine kinase inhibitor Small molecule PII in B cell lymphoma  Phase III 2014 - - 36 94 151
Tabalumab (BAFF Ab) B-cell activating factor (BAFF) inhibitor Monoclonal antibody PI in multiple myeloma Phase III 2014 - - 16 58 103
Cixutumumab Anti-IGF-1R MAb Monoclonal antibody PII in soft tissue sarcomas Phase II 2013 - 8 23 42 67
Pfizer Crizotinib c-Met tyrosine kinase & ALK inhibitor Small molecule PI + PII in NSCLC Phase III 2012 45 173 265 370 475
Axitinib VEGF tyrosine kinase inhibitor Small molecule PIII in RCC Phase III 2012 85 160 238 309 383
Bosutinib Src & BCR-ABL kinase inhibitor Small molecule PIII in CML Phase III 2012 26 76 139 195 252
Roche Tarceva EGFr tyrosine kinase inhibitor Small molecule PIII in 1st line NSCLC Marketed 2004 1,264 1,351 1,422 1,495 1,545

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