The other week during a conversation with Dr Gordon Mills (MDACC) at the European Multidisciplinary Meeting (EMCC) in Stockholm, he mentioned the conundrum of variable responses to EGFR inhibitors in colorectal cancers and the impact of RAS.  Originally, it was thought that patients who had wild type, but not mutated, KRAS were more likely to respond (see Allegra et al., 2009 in the references below).

The reality, however, is that variable responses to therapy have actually been reported by several groups with cetuximab and panitumumab. De Roock et al., (2010) reported better outcomes with cetuximab in patients with p.G13D-mutated tumours than with other KRAS-mutated tumours, contrary to the US and EU Guidelines, so the situation is clearly more complex than first thought.

Dr Mills speculated that part of the issue may lie in the sensitivity of the assays used at different institutions, since Sanger sequencing requires that 20% of the DNA must have RAS present, whereas the next generation sequencing techniques used at MD Anderson will pick up 1% of the DNA. We don’t know whether that difference will matter or not yet, but it’s an intriquing element that may well be highly relevant going forward.

Meanwhile, at the EMCC meeting there was an update on panitumumab, a monoclonal anti-EGFR in the PICCOLO trial in EGFR mutated colorectal trial that may shed some new light on the matter. This trial, like many UK studies, was highly complex. While the primary endpoint of overall survival was not met, the biomarker analysis revealed some interesting subtleties.1

The trial involved patients (n=1198) randomised to receive either panitumumab or cyclosporin with single-agent irinotecan in advanced colorectal cancer. According to the authors:

“It opened as a 3-arm study in 2007; but from June 08 prospective KRAS testing was introduced and KRAS-wt patients were randomised to Irinotecan / Irinotecan + Panitumumab, KRAS-mut patients to Irinotecan / Irinotecan + Cyclosporin.”

 

What do the latest findings show?

Firstly, the PICCOLO results confirmed some previous findings in that improvement in PFS and response rate were seen in patients with KRAS/BRAF wild-type tumours who received panitumumab, but no benefit from panitumumab in patients with KRAS or BRAF mutated tumours.

Secondly, the biomarker subset analysis revealed some subtle hints of where we can look in further trials. In explaining the lack of overall survival benefit, the subset analysis showed that almost a third (29%) of the wild-type patients were also found to have other mutations, thereby conferring resistance to the drug. The question then is why and what was the cause?  In digging deeper, some interesting nuggets emerged…

Thirdly, it seems that the patients who tended to see a good response had a broad wild type profile for KRAS, NRAS, BRAF and PI3K, whereas those who had a mutation for any of the above kinases did not have as good a response. This suggests that the biomarker testing may need to be extended beyond wild-type and mutant KRAS to avoid resistance to EGFR therapy developing. The results also provide a clear direction in where the adaptive resistance pathways are and thereby where different/new combination strategies may need to evaluated in the clinic.

The future for advanced colorectal cancer is very bright as we learn more about the biology of the disease and how to treat it, but it is also becoming highly complex!

References:

ResearchBlogging.orgAllegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, & Schilsky RL (2009). American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 (12), 2091-6 PMID: 19188670

De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, Van Cutsem E, O’Callaghan CJ, Khambata-Ford S, Zalcberg JR, Simes J, Karapetis CS, Bardelli A, & Tejpar S (2010). Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA : the journal of the American Medical Association, 304 (16), 1812-20 PMID: 20978259

  1. M.T. Seymour, S.R. Brown, S. Richman, G.W. Middleton, T.S. Maughan, N. Maisey, M. Hill, C. Olivier, V. Napp, P. Quirke Panitumumab in Combination With Irinotecan for Chemoresistant Advanced Colorectal Cancer – Results of PICCOLO, a Large Randomised Trial With Prospective Molecular Stratification. ECCO, Stockholm 2011: Abstract #6007  ↩