SUMMARY
Data presented ASCO has cast doubt on the use of IGF-R and TRAIL pathway nteractors for the treatment of NSCLC.  However, new data investigating inhibition of the c-Met pathway has been met with physician optimism and suggested c-Met inhibition in combination with EGFR therapy may be an efficacious treatment option.  In particular, data on Arqule / Daiichi-Sankyo's Phase II pipeline candidate, ARQ 197, demonstrated a pronounced effect on progression-free survival and overall survival.  If these results are substantiated by the planned Phase III trials, we believe ARQ 197 may have blockbuster potential.  Pfizer's c-Met / ALK inhibitor, crizotinib, also holds tremendous potential for the 4% of NSCLC harbouring EML4-ALK translocations.  The drug's response rate and safety profile presented at ASCO is impressive, although we note that the limited target population will prevent crizotinib obtaining blockbuster status.

ANALYSIS

  • Full results of Pfizer's recently discontinued IGF-R1 inhibitor trial were presented today, Saturday, at ASCO.  In the Phase III trial, figitumumab was added to a chemotherapy backbone for the treatment of first-line NSCLC. The results demonstrated severe adverse events including dehydration, hyperglycemia, and hemoptysis.  Grade V events, including infection and cardiovascular, led to an imbalance of deaths and a subsequent discontinuation of the trial.  There was no evidence the drug exerted efficacious properties.
  • A more favourable safety profile and suggestion of efficacy was demonstrated in a subset analysis of individuals with high levels of serum IGF-1.  Although investigators suggested further research was warranted in those individuals, Decision Resources regards the observed side-effect profile as being inappropriate to warrant further development.
  • In addition, the class-associated side-effects of hyperglycemia, asthenia and dehydration are likely to cause problems in the development of other IGF-R inhibitors. This was highlighted by Phase II data of Amgen's AMG 479 for the treatment of advanced pancreatic cancer which showed 18% of AMG 479-treated patients experienced hyperglycemia compared with just 3% of patients receiving placebo.
  • Negative results of Human Genome Sciences TRAIL agonist, mapatumumab were also presented: Although no adverse events were observed, there was no evidence of efficacy either.
  • This may have negative ramifications for the probability of success of other TRAIL agonists including Amgen's conatumumab, Daiichi Sankyo's CS-1008 and Roche's dulanermin.
  • However, all is not negative within the NSCLC landscape.  Positive data from a Phase II trial of Arqule / Daiichi-Sankyo's ARQ 197 were presented as a late-breaking abstract.  In the trial, the addition of ARQ 197 to Tarceva in previously treated EGFR inhibitor-naïve patients with NSCLC produced promising results.
  • Data from the 167 patient study demonstrated a statistically significant adjusted progression-free survival hazard ratio of 0.68, from 9.7 weeks in the control to 16.1 weeks in the test arm.  Overall survival (OS), a secondary endpoint, also improved from 29.4 weeks to 36.6 weeks, although this didn't reach statistical significance.  Subset analysis showed a particularly strong effect in individuals with non-squamous NSCLC (in this population OS improved significantly from 29.4 weeks to 43.1 weeks), K-Ras mutant and EGFR wildtype subsets.  Data involving these subsets are to be presented at ESMO in September 2010.
  • Many other companies have c-Met inhibitors in development (including Amgen, Incyte, BMS, J&J and Roche) but ARQ 197 is the most advanced in development.  Phase III trials of ARQ 197 in NSCLC and soft-tissue sarcoma are in planning.  Success in these indications could lead to ARQ 197 obtaining blockbuster status.
  • However, Arqule and Daiichi-Sankyo's inexperience of marketing of oncology treatments in ex-Japanese regions may restrict uptake and prevent the drug reaching its full sales potential.
  • Data on Pfizer's crizotinib (PF-2341066) was presented in the plenary session at ASCO: the overall response rate to date (from 50 evaluable patients) is 64% and the disease-control rate an impressive 90%.  Progression-free survival data is not yet mature.
  • Although PF-2341066 use will be limited to patients with the specific ALK gene translocation, restricting the market to 4% of all NSCLC cases, the response rate surpasses any other response rate we have seen to-date in any NSCLC trial and if the Phase III interim data is substantiated by the mature data, use in this niche population will be compelling.  Decision Resources estimates crizotinib has the potential to launch in 2013 and garner $334m of sales in 2016.

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