In my last post on The Haystack, we discussed the phase III data from the Abraxane MPACT trial in advanced pancreatic cancer that was presented at the recent ASCO GI meeting in San Francisco. Two other late-stage studies in pancreatic cancer caught my eye—fresh data for AB Science’s kinase inhibitor masitinib and Sanofi’s multidrug pill S1.
Masitinib is an oral tyrosine kinase inhibitor from AB Science that targets KIT, PDGFR, FGFR3 and has shown activity in gastrointestinal stromal tumours (GIST). A different version of the drug (Masivet, Kinavet) is also approved in France and the US for the treatment of a dog mast cell (skin) cancers, which are also known to be KIT-driven.
S1 is multidrug pill from Sanofi and Taiho that consists of tegafur (a prodrug of 5FU), gimeracil (5-chloro-2,4 dihydropyridine, CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) enzyme, and oteracil (potassium oxonate, Oxo), which reduces gastrointestinal toxicity. Previous Japanese studies have demonstrated effectiveness of this agent in gastric and colorectal cancers, so a big unaswered question is whether it is effective in pancreatic cancer.
So what was interesting about the latest data at this meeting?
At the ASCO GI conference in 2009, French oncologist Emmanuel Mitry presented data from a small Phase II study of the effect of combining masitinib and Eli Lilly’s Gemzar in advanced pancreatic cancer. The study had just 22 patients, but the median overall survival of 7.1 months in was not a large improvement over what is often seen with the standard of care, Gemzar given alone, or with a combination of Gemzar and Genentech’s Tarceva. Over the years, many combination therapies based on Gemzar have failed to show superiority over single agent therapy. It’s both a high unmet medical need and a high barrier to beat. Thus, the phase III data for the combination of masitnib and Gemzar was highly anticipated at this year’s ASCO GI meeting.
Gael Deplanque and colleagues compared masitinib plus Gemzar to Gemzar plus placebo. Although the overall trial results for median overall survival were slightly higher than in the phase II study, they were not significant (7.7 versus 7.0 months, P=0.74; HR=0.90).
Some promising data was observed, however, in a subset of the population identified by a profile of biomarkers that the authors vaguely described as, “a specific deleterious genomic biomarker (GBM) consisting of a limited number of genes.” No other details on the actual genes or biomarkers were was provided, but the subset was described as having an improved MOS to 11.0 months compared to the Gemzar and placebo arm.
They also noted that patients with high pain, who usually do poorly on standard chemotherapy, also saw improvement with the masitinib combination. AB Science might have found a particularly aggressive subset that respond to masitinib, in which case, a biomarker would be useful in selecting those patients most likely to respond, as opposed to a catch-all approach where everyone is treated regardless of the predictive value.
AB Science has asked European regulatory authorities for approval, but the Phase III data will not be sufficient for US approval. The company will need to validate the biomarker panel in a large-scale randomized study, and a new phase III trial is now recruiting patients. The outcome of that study won’t be known for awhile, but the hope is for more insight into how to choose the right patients to respond to masitinib in combination with Gemzar.
The other compound featuring late-stage results in pancreatic cancer was Sanofi’s S1. The compound is interesting, but so far its development has been limited to Asian patients, particularly people of Japanese origin. Studies in caucasians have not seen any benefit over standard 5FU therapy.
Katsuhiko Uesaka, medical deputy director at Shizuoka Cancer Center Hospital in Japan, presented encouraging data for the use of S1 as adjuvant therapy in combination with Gemzar after surgical resection (relevant in stage I-III pancreatic cancer). They compared S1 and Gemzar in a head to head non-inferiority trial (with 385 patients. In the interim analysis reported at this year’s ASCO GI meeting, the hazard ratio for S-1 to Gemzar was 0.56, while the 2-year survival rates were 53% for Gemzar and 70% for S-1. The percentage of serious side effects were similar to previously reported studies with Gemzar and S-1, including fatigue (4.7/5.4), anorexia (5.8/8.0), leukopenia (38.7/8.6), thrombocytopenia (9.4/4.3), anemia (17.3/13.4), and elevated AST (5.2/1.1).
Overall, the authors concluded that S-1 adjuvant chemotherapy was shown to be as good as, perhaps even better than Gemzar, even suggesting that S-1 could be considered the new standard treatment for resected pancreatic cancer. It should be noted, however, that this data is only applicable to patients of Japanese origin since no caucasian data was included in this analysis.
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