Mutated ras as a Predictor of Response: Is It Ready for the Clinic?

May 15, 2008

Preliminary results from two trials presented at the 44th Annual Meeting of ASCO in Chicago have consolidated the role of K-ras as a biomarker of nonresponse to cetuximab and panitumumab in metastatic colorectal cancer (mCRC). The phase III CRYSTAL and OPUS trials presented unplanned subgroup analyses of the correlation of K-ras status with response to therapy with first-line FOLFIRI or FOLFOX, respectively, with or without cetuximab in patients with mCRC. Both studies demonstrated a clear benefit with the addition of cetuximab in K-ras WT patients.

Updates from the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) 2008

Preliminary results from two trials presented at the 44th Annual Meeting of ASCO in Chicago have consolidated the role of K-ras as a biomarker of nonresponse to cetuximab and panitumumab in metastatic colorectal cancer (mCRC). The phase III CRYSTAL and OPUS trials presented unplanned subgroup analyses of the correlation of K-ras status with response to therapy with first-line FOLFIRI or FOLFOX, respectively, with or without cetuximab in patients with mCRC. Both studies demonstrated a clear benefit with the addition of cetuximab in K-ras WT patients. In contrast, the phase III CAIRO2 study offered conflicting results. This study evaluated response and progression-free survival to capecitabine, oxaliplatin, and bevacizumab with or without cetuximab, with subgroup analysis of results in K-ras WT and mutant patients. Unlike CRYSTAL and OPUS, however, CAIRO2 showed no significant benefit and possibly worse outcomes with the addition of cetuximab independent of K-ras mutational status.

The phase III CRYSTAL trial randomized 1198 patients with mCRC to first-line treatment with cetuximab plus FOLFIRI (n=599) versus FOLFIRI alone (n=599) and showed a significant improvement in PFS with cetuximab in the intent-to-treat (ITT) population with HR 0.85 (p=.048).[6] Subgroup analysis investigated the impact of K-ras mutational status on the endpoints of PFS and response rate.[5] Of the 540 patients (45% of study subjects) whose tumors were evaluated for K-ras status, 35.6% were K-ras mutant. Among the K-ras WT patients, addition of cetuximab significantly improved PFS over FOLFIRI alone, with median PFS 9.9 months versus 8.7 months and HR 0.68 (P = .017). The secondary endpoint, response rate, was similarly improved with RR 59% with cetuximab versus 43% without in the K-ras WT patients (P = .0025). In contrast, there was no significant benefit with the addition of cetuximab to FOLFIRI in K-ras mutant patients, with a nonsignificant trend towards shorter PFS in the cetuximab-treated group (HR 1.07, P = .47). Comparing outcomes with cetuximab in combination with FOLFIRI in both groups, the median PFS in K-ras WT patients was 9.9 months as compared to 7.6 months in mutant patients (P = .007) (Table 1). Among the 176 K-ras WT and 87 K-ras mutant patients treated with FOLFIRI alone, there was no significant difference in PFS with HR 0.97 (P = .87). This finding suggests that K-ras mutation is not an independent prognostic factor.

Table 1. Summary of efficacy data.

The OPUS trial evaluated the addition of cetuximab to first-line fluorouracil, leucovorin, and oxaliplatin therapy (FOLFOX).[1] This study showed no significant benefit in PFS with addition of cetuximab to FOLFOX-4 (HR 0.93, P = .62). The authors presented a retrospective subgroup analysis of the role of K-ras mutational status in this study.[2] 42% of patients were found to have K-ras mutation. In the K-ras WT subgroup, addition of cetuximab produced significant improvement in the primary endpoint, response rate, with RR 37% with FOLFOX alone and 61% with addition of cetuximab (P = .011). Similar improvement was seen in PFS for K-ras WT patients with HR 0.57 (P = .016). This benefit was not observed in the K-ras mutant population, with response rate 49% with FOLFOX alone and 33% with addition of cetuximab (P = 1.06). As was observed in the CRYSTAL trial with FOLFIRI, the K-ras WT and mutant subgroups in the OPUS trial showed no significant differences in response to FOLFOX alone, again suggesting that K-ras mutation is not an independent prognostic factor.

The phase III CAIRO2 study evaluated the combination of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in the first-line setting for advanced colorectal cancer.[4] There was no difference in PFS, RR, or OS between the treatment arms with and without cetuximab. K-ras mutation was identified in 39% of the 501 evaluable patients on study. Unlike the results in CRYSTAL and OPUS, however, addition of cetuximab amongst the K-ras WT patients in CAIRO2 did not appear to confer any benefit with PFS 10.7 months without cetuximab versus 10.5 months with cetuximab (P = .10). Likewise, there was no significant difference in PFS or OS between WT and mutant patients treated with cetuximab, with PFS 10.5 versus 8.6 months, and OS 22.2 months versus 19.1 months, respectively (P = .47 and P = .52, respectively). It is also noteworthy that, in the K-ras mutant patients, cetuximab appeared to confer an adverse effect, with PFS 12.5 months without cetuximab versus 8.6 months with cetuximab (P = .043). It may prove relevant to compare these results with the results of cetuximab-induced skin toxicity in this study. Consistent with prior results, patients with grade 3 skin rash on cetixumab demonstrated superior PFS in comparison to patients with lesser or no skin rash in response to cetuximab therapy. Contrary to prior results, however, even in this optimal group with grade 3 skin rash, PFS remained essentially equivalent to PFS in patients without cetuximab therapy, and patients without cetuximab had longer PFS than those who did not develop rash on cetuximab (P < .0001). These findings could be explained in a number of ways. One possibility would be that there is a negative interaction between bevacizumab and cetuximab. Another explanation could be an imbalance in patient randomization to cetuximab and no cetuximab treatment arms in this study, although the reported baseline characteristics of patients in each arm of the study were similar. The inferior results with cetuximab could also be due to differences in duration of therapy, with median number of 12.0 cycles received in the treatment arm without cetuximab, versus 10.6 cycles with cetuximab (P = .02). The risk of grade 3-4 toxicities was significantly increased at 82% in the cetuximab arm, compared with 72% without cetuximab (P = .0013). The reasons for treatment discontinuation, however, were similar in both arms, with no excessive discontinuation for toxicity in the cetuximab arm (P = .22). Finally, these endpoints were evaluated by investigators so there could be unintended bias, as well.

In concert with the data presented in the body of this manuscript, the results of the CRYSTAL and OPUS phase III, randomized studies firmly establish K-ras mutational status as a biomarker for response to EGFR-directed therapy. Though unplanned, retrospective subgroup analyses can be problematic, both the CRYSTAL and OPUS trials demonstrated clinical equivalence between the K-ras evaluable subgroups and the overall intent-to-treat populations, lending credence to their robust data suggesting a differential response to cetuximab between K-ras WT and mutant patients. Conflicting results from the CAIRO2 study may reflect the effect of treatment discontinuation due to toxicity, or a negative interaction between cetuximab and bevacizumab. Further study is required to explain these findings. Results from the ongoing CALGB 80405 trial – which will be amended to treat only K-ras WT patients – will further clarify the question of interaction between cetuximab and bevacizumab.

Taken together, the data above provide further support for the initiation of routine testing for tumor K-ras status in patients with mCRC prior to initiating therapy with cetuximab or panitumumab. Patients with K-ras mutation should not be offered therapy with cetuximab or panitumumab for mCRC. High concordance has been reported between K-ras status in primary tumor and metastatic sites, suggesting that any available tumor tissue is appropriate for testing.[3] Commercially-available PCR-based assays are available to test for the common K-ras mutations in codons 12, 13, and 61. Additional studies are required to evaluate for other relevant mutations and to validate the assays used in their detection.

In conclusion, K-ras mutational status is a biomarker for nonresponse to EGFR-targeted therapy in colorectal cancer and should be incorporated into routine tumor testing and treatment decision-making. Based upon these findings and the rationale that downstream activating K-ras mutation may render any upstream EGFR-targeted therapy futile, further study is warranted to clearly define the role of K-ras mutation in all malignancies treated with EGFR-targeted therapy. Results from the CAIRO2 trial also emphasize the need for better understanding of interactions between different targeted therapies, noting the possibility of a negative interaction between VEGF-targeted and EGFR-targeted therapies in this trial. Ultimately, K-ras mutational status is a biomarker for nonresponse that represents a first step towards personalized therapy for cancer. This finding will guide a new generation of research in targeted therapies.

REFERENCES
1. Bokemeyer C, Bondarenko I, Makhson A, et al: Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study (abstract 4035). J Clin Oncol 25(suppl 18S): abstract 4035, 2007.
2. Bokemeyer C, Bondarenko I, Hartmann J, et al: KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFOX with or without cetuximab: The OPUS experience. ASCO Annual Meeting 2008.
3. Etienne-Grimaldi 2008, Francoual M, Formento J, et al: K-ras mutations and treatment outcome in colorectal cancer patients receiving fluoropyrimidine (FU) therapy (abstract 427). ASCO Gastrointestinal Cancers Symposium 2008.
4. Punt C, Tol J, Rodenburg C, et al: Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer: CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). ASCO Annual Meeting 2008.
5. van Cutsem E, Lang I, D'Haens G, et al: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. ASCO Annual Meeting 2008.
6. van Cutsem E, Nowacki I, Lang S, et al: Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial (abstract 4000). J Clin Oncol 25(suppl 18S):164s, 2007.

Click here for full text of original e-Update by Drs. Kelley and Venook