The Retreatment Strategy: Would It Work With the Same Molecularly Targeted Therapy?

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

A well-recognized feature of cytotoxic chemotherapy for malignant disease is the observation that patients who initially exhibit a response to a particular strategy may achieve substantial clinical benefit if the same or very similar agents are delivered after variably defined (eg, 6 months, 1 year, 2 years) treatment-free intervals.

While the utility of such strategies was first documented in the realm of hematologic malignances, such as Hodgkin disease, this approach currently represents an important component in the management of many solid tumors, notably ovarian cancer.

With the introduction during the past several years of an increasing number of rationally designed and targeted antineoplastic agents, it remains an open question as to whether this property of cytotoxic drugs in cancer management will be an equally prominent characteristic associated with novel molecularly designed approaches to therapy.

For example, if such an antineoplastic drug is administered in the adjuvant setting, is then subsequently discontinued as part of the management plan (not due to excessive toxicity), and the cancer recurs sometime later, will the agent be clinically inactive as a result of the theoretically predicted development of resistance following previous exposure to the cancer? Or, will a clinically relevant degree of sensitivity remain?

Erlotinib, an EGFR inhibitor that Genentech markets as Tarceva, is under investigation for its potential benefits in retreating patients whose cancer recurs after prior anti-EGFR therapy.

It is apparent that this is more than a mere academic question, since it is likely that many novel targeted antineoplastic agents will be examined for their utility in the adjuvant setting following documentation of their benefits in patients with metastatic disease. Further, evidence of the potential continued sensitivity of cancers that have previously been exposed to a targeted antineoplastic will permit exploration of a variety of novel options with less fear that a patient has only a single opportunity to experience benefit from a particular drug in this category.

The results of a quite provocative retrospective examination of the residual sensitivity of recurrent non-small cell lung cancer to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) following their prior use in the adjuvant setting provides important support for the general concept that secondary responses in this setting may realistically occur. In this report, a group of 22 patients with a documented sensitizing EGFR mutation received adjuvant treatment with an anti-EGFR tyrosine kinase inhibitor.1 Eleven patients from this limited population had adjuvant treatment discontinued and had evaluable disease present when treatment with this class of drugs was reinitiated for disease progression. Of these, 8 (73%) attained radiographic evidence of an objective response.

While the results of this small retrospective analysis will require confirmation, these data provide solid support for the general hypothesis that retreatment with molecularly targeted therapeutic agents, after some “to be determined” time interval may be a rational treatment strategy in a number of clinical settings.

As novel targeted antineoplastic agents are examined for their utility in the adjuvant setting, questions about the value of treatment-free intervals with these agents will follow.

It is also relevant to note that in this reported experience there was a strong rationale to administer the particular targeted agent in both the adjuvant and metastatic settings. Hopefully, future explorations of this concept will continue to focus on the appropriateness of specific treatment based on the documentation of a valid molecular target within the cancers of individual patients.

Reference

1. Oxnard GR, Janjigian YY, Acrila ME, et al. Maintained sensitivity to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer recurring after adjuvant erlotinib or gefitinib. Clin Cancer Res. 2011; 17(19):6322-6328.