- What was done and what was found?
Cetuximab, an anti-epidermal growth factor receptor (EGFR) agent, has recently been added to
the therapeutic armamentarium. Two important CRTs examined its impact in patients with mCRC
(metastatic-stage Colorectal cancer). In the first one, 56 centers in 11 European countries
investigated the outcomes associated with cetuximab therapy in 329 mCRC patients who experienced
disease progression either on irinotecan therapy or within 3 months thereafter.
The study reported that the group on a combination of irinotecan and cetuximab had a
significantly higher rate of overall response to treatment (primary endpoint) than the
group on cetuximab alone: 22.9% (95% CI, 17.5-29.1%) vs. 10.8% (95% CI, 5.7-18.1%) (P=0.007),
respectively. Similarly, the median time to progression was significantly longer in the
combination therapy group (4.1 vs. 1.5 months, P<0.001). As these patients had already
progressed on irinotecan prior to the study, any response was viewed as positive.
Safety between the two treatment arms was similar: approximately 80% of patients in each arm
experienced a rash. Grade 3 or 4 (the more severe) toxic effects on the skin were slightly
more frequent in the combination-therapy group compared to cetuximab monotherapy, observed
in 9.4% and 5.2% of participants, respectively. Other side effects such as diarrhea and
neutropenia observed in the combination-therapy arm were considered to be in the range
expected for irinotecan alone. Data from this study demonstrated the efficacy and safety
of cetuximab and were instrumental in the FDA’s 2004 approval.
A second CRT (2007) examined 572 patients and suggested efficacy of cetuximab in the treatment
of mCRC. This study was a randomized, non-blinded, controlled trial that examined cetuximab
monotherapy plus best supportive care compared to best supportive care alone in patients
who had received and failed prior chemotherapy regimens. It reported that median overall
survival (the primary endpoint) was significantly higher in patients receiving cetuximab
plus best supportive care compared to best supportive care alone (6.1 vs. 4.6 months,
respectively) (hazard ratio for death=0.77; 95% CI: 0.64- 0.92, P=0.005). This RCT
described a greater incidence of adverse events in the cetuximab plus best supportive
care group compared to best supportive care alone including (most significantly) rash,
as well as edema, fatigue, nausea and vomiting.
- Was this the right answer?
These RCTs had fairly broad enrollment criteria and the cetuximab benefits were modest.
Emerging scientific theories raised the possibility that genetically defined population
subsets might experience a greater-than-average treatment benefit. One such area of
inquiry entailed examining “biomarkers,” or genetic indicators of a patient’s greater
response to therapy. Even as the above RCTs were being conducted, data emerged showing
the importance of the KRAS gene.
- Emerging Data
Based on the emerging biochemical evidence that the epidermal growth factor receptor
(EGFR) treatment mechanism (Cetuximab,) was even more finely detailed than previously
understood, the study authors of the 2007 RCT undertook a retrospective subgroup analysis
using tumor tissue samples preserved from their initial study. Following laboratory
analysis, all viable tissue samples were classified as having a wild-type (non-mutated)
or a mutated KRAS gene. Instead of the previous two study arms (cetuximab plus best
supportive care vs. best supportive care alone), there were 4 for this new analysis:
each of the two original study arms was further divided by wild-type vs. mutated
KRAS status. Laboratory evaluation determined that 40.9% and 42.3% of all patients
in the RCT had a KRAS mutation in the cetuximab plus best supportive care group compared
to the best supportive care group alone, respectively. The efficacy of cetuximab was
found to be significantly correlated with KRAS status: in patients with wild-type (non-mutated).
KRAS genes, cetuximab plus best supportive care compared to best supportive care alone
improved overall survival (median 9.5 vs. 4.8 months, respectively; hazard ratio for
death=0.55; 95% CI, 0.41-0.74, P<0.001), and progression-free survival (median 3.7
vs. 1.9 months, respectively; hazard ratio for progression or death=0.40; 95% CI,
0.30-0.54, P<0.001). Meanwhile, in patients with mutated KRAS tumors, the authors
found no significant difference in outcome between cetuximab plus best supportive
care vs. best supportive care alone.
- What next?
Based on these and similar results from other studies, the FDA narrowed its product
labeling in July 2009 to indicate that cetuximab is not recommended for mCRC patients
with mutated KRAS tumors. This distinction reduces the relevant population by approximately
40%. Similarly, the American society of Clinical oncology released a provisional clinical
recommendation that all mCRC patients have their tumors tested for KRAS status before
receiving anti-EGFR therapy. The benefits of targeted treatment are many. Patients who
previously underwent cetuximab therapy without knowing their genetic predisposition
would no longer have to be exposed to the drug’s toxic effects if unnecessary, as the
efficacy of cetuximab is markedly higher in the genetically defined appropriate patients.
In a less-uncertain environment, clinicians can be more confident in advocating a course
of action in their care of patients. And finally, knowledge that targeted therapy is
possible suggests the potential for further innovation in treatment options. In fact,
research continues to demonstrate options for targeted cetuximab treatment of mCRC at
an even finer scale than seen with KRAS; and similar genetic targeting is being investigated,
and advocated, in other cancer types.
- Lessons Learned From this case Study
Although RCTs are generally viewed as the gold standard, results of one or even a series of
trials may not accurately reflect the benefits experienced by an individual patient.
This case-study suggests that cetuximab initially appeared to have rather modest clinical
benefits. Albeit, new information that became available and subsequent genetic subgroup
assessments led to very different conclusions. Clinicians should be aware that the current
knowledge is likely to evolve and any decisions about patient care should be carefully
considered with that sense of uncertainty in mind. As in this case study, subgroup analyses
(e.g., genetic subtypes) need a theoretical rationale. Ideally, the analyses should be
determined at the time of original RCT design and should not just occur as explorations
of the subsequent data. When improperly employed, post hoc analyses may lead to incorrect
patient care conclusions.
- RCTs Tips for the CER Practitioners
- RCTs can determine whether an intervention can provide benefit in a very controlled
environment.
- The controlled nature of an RCT may limit its generalizability to a broader population.
- No results are permanent; advances in scientific knowledge and understanding can
influence how we view the effectiveness (or safety) of a therapeutic intervention.
- Targeted therapy illuminated by carefully thought out subgroup analyses can improve
the efficacious and safe use of an intervention.
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