Going Beyond the Label: Targeted Therapies Present New Questions in Clinical Use

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

The long-sought aim of treating malignant disease by targeting particular molecular abnormalities revealed to be present within an individual tumor is becoming a reality in an increasing number of clinical settings.

With the regulatory approval of a number of antineoplastic agents whose biological and clinical activity appears to be strongly related to a particular molecular signature, it is natural to consider whether it is appropriate to treat patients in other settings where the specific individual’s cancer possesses the same, or very similar, genetic abnormalities. It is possible that such a situation may arise at a point in time preceding regulatory approval for that clinical indication, or may occur in a setting where the drug sponsor does not intend to pursue regulatory approval for that specific group of patients.

Further, with the spectacularly rapid advances in whole genomic sequencing, it will become increasingly commonplace for a relatively large or relatively small subpopulation of patients with a particular tumor type to be found to have a unique molecular abnormality that may be favorably impacted by a previously approved antineoplastic specifically directed at that molecular target.

Consider, for example, the recent report of a retrospective examination of more than 1000 patients with non-small cell lung cancer where approximately 5% of the adenocarcinomas in this series were found to have a mutation in the BRAF gene.¹ Perhaps even more provocative, greater than 50% of these mutations were V600E, the specific molecular abnormality targeted by the novel antineoplastic vemurafenib (Zelboraf), recently approved for treatment of metastatic melanoma in the presence of a documented mutation in BRAF.² The lung cancer patients with the V600E abnormality were smokers, had a particularly poor prognosis, and, except in very rare circumstances, this finding was not demonstrated in individuals with a documented activating epidermal growth factor receptor mutation. (Table)

Table. Overall Survival Analysis Using Clinicopathologic and Genomic Factors in 331 Patients With Lung ADC

Variable

Category

Univariate HR

(95% CI)

Multivariate* HR

(95% CI)

Sex

Female/male

1.39 (0.91-2.13)

1.2 (0.63-2.27)

Smoking

Never smoker/smoker

1.1 (0.69-1.76)

1.09 (0.56-2.09)

Stage

III IV/I II

3.26 (2.21-4.80)

2.92 (1.95-4.37)

BRAF V600E

Mutated/wild type

2.97 (1.96-5.81)

2.18 (1.17-4.04)

BRAF Non-V600E

Mutated/wild type

1.56 (0.51-5.04)

1.46 (0.46-4.64)

*Sex, smoking, and non-V600E variables were removed from model at last step of multivariate analysis.

ADC indicates adenocarcinoma; HR, hazard ratio; CI, confidence interval.

Adapted from Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011; 29(26):3574-3579.

Thus, the obvious question is whether it is reasonable to treat patients with metastatic adenocarcinoma of the lung who have a confirmed V600E (or perhaps any BRAF) mutation with vemurafenib. Should a randomized phase III trial be required before such a decision is made, or at least phase II trial data? And, if such therapy is recommended by an individual oncologist based on a demonstrated BRAF mutation, is it fair to conclude that payment for the costs of the drug and any associated medical care should be covered by responsible third-party payers?

It must be emphasized that, at least in the United States, there is no legal requirement for a pharmaceutical company to conduct such a trial for a marketed drug before it is employed by an individual treating physician in routine clinical practice. Further, assuming a decision is actually made to conduct a study, optimistically, a minimum of several years will likely pass before the results are available to inform clinical decision-making. And what happens to patients presenting with this clinical scenario prior to the establishment of these so-called “evidence-based data?”

Molecular analyses of tumors increasingly will yield a relatively large or relatively small subpopulation of patients who may be favorably impacted by a previously approved targeted therapy.

It is virtually certain that these difficult questions will increasingly need to be addressed by a number of interested groups (eg, healthcare plans, governmental authorities). It can only be hoped that the goals of the patient to optimize both the quantity and quality of life are kept at the center of such discussions.

References

1. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol. 2011; 29(26):3574-3579.
2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation [published online ahead of print June 5, 2011]. N Engl J Med. 2011; 364(26):2507-2516.