October 1, 2010 (Vol. 30, No. 17)
George Farmer, Ph.D.
Non-Small-Cell Lung Cancer Standards of Care Challenged by a Cornucopia of New Drugs
Non-small-cell lung cancer (NSCLC), which afflicts about 195,000 patients per year, is the top cancer killer in the U.S. Throughout the 1990s and early part of 2000s, standards of care for inoperable forms of the disease involved platinum-doublet cytotoxic therapies in front-line settings followed by single-agent use of docetaxel (Taxotere, Sanofi Aventis) in second-line settings.
Numerous randomized trials evaluating the addition of other cytotoxic compounds on top of these standards of care have had no meaningful impact on the 10-month overall survival rates typically seen with this disease.
Treating all NSCLC with the same brute-force approach may be part of the reason why progress beyond platinum-doublet chemotherapy has often failed. Comprehensive subgroup analysis of completed trials and subsequent execution of prospectively designed confirmatory trials has revealed that not all NSCLC is the same. Demographic considerations such as tumor histology, patient ethnicity, patient gender, smoking history, and, perhaps most importantly, tumor genotype largely predict treatment response.
While histological analysis of tumor biopsies is the standard to guide treatment regimens, a move to tumor genotype analysis is gaining favor—particularly for nonsquamous cell-core biopsies. The days of formulaic and indiscriminate administration of cytotoxic therapy for progressive and inoperable disease are coming to an end.
Moving the Needle
The first inkling that NSCLC standards of care could be in for major change came in 2002 when single-arm trial data supporting FDA approval of gefitinib (Iressa, AstraZeneca) was released. The data showed a 10% tumor response rate in treatment-experienced patients.
In 2004, treatment with erlotinib (Tarceva, Roche/Astellas), a similar molecule, was shown in the BR.21 trial to provide an overall survival benefit. Like previous precedent-setting Her2+ breast cancer treatment with trastuzumab (Herceptin, Roche) and metastatic colorectal cancer treatment with cetuximab (Erbitux, BMS/Lilly), this data firmly supported the potential of targeted therapies for NSCLC treatment.
Another major advancement in 2004 was approval of the cytotoxic agent pemetrexed (Alimta, Lilly). Sanction was based on results from a randomized trial comparing pemetrexed head-to-head with docetaxel in a second-line setting. Equivalent survival benefits were noted, but pemetrexed proved to be much better tolerated, thus providing second-line patients, particularly those with nonsquamous disease, with a more favorable treatment alternative.
Benefiting from Maintenance
The strategy of continuing patients who respond to front-line therapy on a maintenance drug regimen until disease progression is supported by data from two randomized trials.
A deep analysis of data from the JMEN and SATURN studies evaluating pemetrexed and erlotinib, respectively, showed that pemetrexed provided a distinct benefit in patients with nonsquamous disease while erlotinib did not discriminate.
Importantly, patients with tumor mutations in the epidermal growth factor receptor (EGFR) target demonstrated an astounding 10-fold improvement in progression-free survival in erlotinib- vs. placebo-treated patients.
This data supports the importance of genotypic analysis of NSCLC tumors prior to the initiation of therapy and of offering a small molecule EGFR inhibitor to patients scoring positive as an alternative to chemotherapy.
While any well-designed randomized oncology trial demonstrating improvements in progression-free and overall survival should be heeded seriously, these trials stop short of addressing whether applying these agents in maintenance is better than postponing their use in a true second-line treatment setting.
Many oncologists believe that treatment holidays following front-line therapy are important for maintaining quality of life for these patients with no chance of cure. Indeed, a Fidias trial comparing docetaxel administration in a maintenance or second-line setting showed no difference in overall survival, indicating that keeping patients on continuous chemotherapy regimens may be overkill.
Regardless of treatment regimen, however, the fact that 36% and 33% of placebo-treated patients in the JMEN and SATURN trials, respectively, did not move onto second-line treatment underscores the importance of administering active therapy as early as possible in order to ensure the best possible outcomes.
Results from the IPASS trial, which was prospectively designed to compare treatment with single-agent gefitinib or chemotherapy in patients harboring EGFR-activating tumor mutations, indicated that small molecule EGFR antagonists rather than chemotherapy should be the prescribed front-line standard of care for these patients.
Roche continues to enroll patients in the maturing EURTAC registration trial, which was designed to evaluate erlotinib as front-line treatment similar to how gefitinib was evaluated in IPASS.
In the meantime, data from the randomized Phase II CALGB 30406 trial comparing front-line erlotinib alone or in combination with chemotherapy also supports the importance of EGFR profiling prior to initiation of treatment. While the CALGB trial was designed to compare these two regimens in nonsmokers or light former smokers, 42% of the patients harbored EGFR-activating tumor mutations.
Based on an intent-to-treat analysis, both regimens showed a comparable benefit illustrating that smoking history should also be considered when designing treatment regimens.
Most recently, a discrete cohort of NSCLC patients has been identified that harbors a tumor chromosomal translocation resulting in the formation of an EML4-ALK fusion gene product with constitutive ALK activity.
All patients identified with this translocation so far have wild-type EGFR and, not surprisingly, do not respond particularly well to EGFR inhibitors. Furthermore, these patients exhibit similar response rates to platinum-containing chemotherapy regimens to those who do not carry the translocation.
Presumably due to the hypothesis that upregulation of ALK activity is behind NSCLC progression in these patients, the small molecule ALK inhibitor crizotinib (PF-02341066, Pfizer) has demonstrated notable activity in such patients.
At ASCO earlier this year, data was presented from a Phase I/II trial evaluating crizotinib in 82 treatment-experienced NSCLC patients harboring the EML4-ALK translocation. Interestingly, 96% of patients had adenocarcinoma histology and only one patient was a current smoker.
All but five of these patients exhibited some degree of tumor shrinkage, while 57% of patients obtained confirmed tumor responses. One patient experienced a complete response to crizotinib therapy.
A disease stabilization rate of 87% for at least eight weeks was observed, and median progression-free survival had not been reached after a median follow-up of 6.4 months. As a result of the selectivity of this agent, grade 3/4 serious adverse events were extremely rare. Phase III evaluation of crizotinib in patients with the EML4-ALK translocation is under way.
EGFR-activating and ALK mutations have been observed in only about 15% and 7% of all NSCLC tumors, respectively. Despite these low frequencies, the evidence demonstrating that these mutations are predictive of responses to targeted therapeutics is moving NSCLC treatment in exciting new directions.
The fact that these mutations tend to cluster in nonsmoking patients, those who have a light smoking history, and in those with nonsquamous histology reinforces the importance of screening all such tumors for these genetic markers. Understanding the implications of other genetic markers on patient treatment could lead to the next wave of guided therapy.