A new NEJM article on KRAS and metastatic colorectal cancer (CRC) caught my eye last week. One of the challenges with this disease is the limited effectiveness of EGFR monoclonal antibodies such as cetuximab (Erbitux) and panitumumab (Vectibix).
However, science is very instructive sometimes, as Dr Berlin noted in his NEJM editorial last week:
“After the determination that activating mutations in exon 2 of the gene KRAS predicted the inefficacy of anti-EGFR antibodies, reanalyses of multiple trials suggested that these agents could be more effective when administered to a more limited cohort of patients.”
The KRAS exon 2 finding essentially became the first biomarker of response for these drugs, although it should be noted that it is not perfect because even after screening for it, not all patients respond, so other factors are also involved.
The big question is what are they?
The new analysis by Douillard et al., (2013) attempted to address this issue further. They delved deeper by doing a pre-planned retrospective analysis of the phase III Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) study. Specifically, they looked at rarer KRAS mutations and also NRAS mutations to see if they had any impact.
RAS mutation status was determined for 90% of the patients who were randomised in the trial, giving a solid body of data from which to draw some meaningful conclusions.
What does the data show?
The PRIME study results demonstrated that in patients without RAS mutations (n=512), progression-free survival (PFS) was 10.1 months with panitumumab–FOLFOX4 versus 7.9 months with FOLFOX4 alone. Overall survival (OS) was 26.0 months in the panitumumab–FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group.
These results showed a clear benefit in favor of adding panitumumab to standard chemotherapy in patients without RAS mutations.
What was interesting, however, was that not all patients in this subset responded well. In total, there were 108 patients (17%) who had nonmutated KRAS exon 2, but had other RAS mutations instead. These mutations were associated with inferior PFS and OS with panitumumab–FOLFOX4 treatment. In other words, it was more consistent with the findings in patients with KRAS mutations in exon 2. Additionally, BRAF mutations were a negative prognostic factor.
What does the data mean?
This was the key question I asked Dr Douillard, since understanding the impact of the findings is usually important to how oncologists will select and treat patients when considering panitumumab therapy:
“The data mean that we need to better select patients in 1st line treatment of metastatic colorectal cancer to be treated by FOLFOX-panitumumab to improve the risk/benefit ratio. This analysis extended to other exons of Kras and the 3 exons of Nras, identified the proper targeted population to deliver appropriate personalized medicine and avoid using this combination in any RAS mutant patients who will not benefit from it and potentially experience a detrimental effect.”
Where are we going next?
Science never stands still and our learnings are necessarily incremental. This data, while important, isn’t the final answer, as Dr Douillard observed:
“First, the full mutational status analysis of Kras exons 2, 3 and 4 as well as Nras exons 2, 3 and 4 should be rapidly implemented. However this does not fulfill all the unmet needs, and further research is needed to understand the mechanism(s) of resistance that will develop later under treatment.”
In other words, we still need to continue to understand the science of resistance better, so that we can develop new improved therapeutic strategies to overcome it.
ECCO 2013 trial updates
A couple of trial updates in the ECCO program for next week caught my eye and if there’s anything of interest, then a fresh update will follow:
Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. Speaker: V. Heinemann (Germany)
ASPECCT: a randomized, multicenter, open-label, phase 3 study of panitumumab (pmab) vs cetuximab (cmab) for previously treated wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Speaker: T. Price (Australia)
In Europe, where people with cancer are diagnosed and treated in Academic cancer centers, doing routine detailed mutation analysis as part of the work-up in order to make definitive therapy decisions isn’t an issue. In the US, though, not all patients are seen in Academic or tertiary hospital centres, so I’m not sure how many oncologists in the Community setting will consider this in advanced colorectal cancer patients.
The good news is that research such as this will help us not only better select select patients for targeted therapy but also avoid harm, as Berlin noted in his editorial:
“Although the benefit of excluding patients with RAS mutations from receiving anti-EGFR antibody therapy is logical and expected, it was not anticipated that anti-EGFR antibodies might harm patients who have tumors expressing nonmutated KRAS in exon 2 and other RAS mutations.”
This speaks eloquently to the first rule of medicine – first do no harm. Selecting out patients with KRAS and NRAS exon mutations will clearly lead to better outcomes on EGFR therapy such as panitumumab in colorectal cancer.
I look forward to seeing KRAS research evolve further as we continue to improve our knowledge and understanding going forwards. One thing that may be of interest is where we are with MEK inhibitors and KRAS mutations in CRC in different mutational subsets.
Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, & Patterson SD (2013). Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. The New England journal of medicine, 369 (11), 1023-34 PMID: 24024839
Berlin J (2013). Beyond exon 2–the developing story of RAS mutations in colorectal cancer. The New England journal of medicine, 369 (11), 1059-60 PMID: 24024844