The Retreatment Question: Research Suggests Benefits to Continuing Molecularly Targeted Therapy Beyond Progression

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 readministration of a cytotoxic antineoplastic agent is a well-established management paradigm in a number of malignancies, yet it is generally believed such a strategy may not prove beneficial if the patient experiences disease progression while receiving the therapy. For novel biological and molecularly targeted agents, however, emerging evidence suggests that some patients may, in fact, derive benefit from continuing therapy after and even amid disease progression.

As a starting point for this discussion, let us consider this scenario from the realm of cytotoxic therapies: It is the standard of care to deliver second-line platinum-based therapy to women with ovarian cancer who have previously received a platinum-based agent in the primary management setting.¹

This strategy assumes that there has been a sufficient time interval between the discontinuation of front-line therapy and evidence of disease progression. Moreover, the reason for drug discontinuation in the earlier setting in this example should be an indication other than evidence of disease progression, such as demonstrated clinically or surgically defined complete response followed by observation in the absence of continued therapy.

In general, documented disease progression at some point in the natural history of a cancer in an individual patient while receiving an agent has been considered a strong relative, if not an absolute, contraindication for additional treatment with this specific class of drugs (eg, carboplatin, cisplatin).

Patients typically are not candidates for treatment with an antineoplastic drug beyond evidence of progression; likewise, patients who previously progressed while receiving the drug in the past are not candidates for retreatment with that agent.

These concepts have been challenged in recent years in reports about two important antineoplastics, bevacizumab and trastuzumab.^2,3 A large European study found a survival advantage for patients with metastatic colorectal cancer who continued bevacizumab plus chemotherapy beyond first progression after they had been treated with a standard first-line bevacizumab-containing regimen.² Similarly, a randomized phase III trial demonstrated that patients with HER2-positive breast cancer whose disease progressed during treatment with trastuzumab experienced longer times to progression if they continued with a trastuzumab plus capecitabine regimen than they did if they received capecitabine alone (median 8.2 months vs 5.6 months).³

The hypotheses supporting this approach may vary based on the individual agent, but the basic concept is that, even in the presence of progression, favorable biological and clinical effects may continue to be observed. This may occur if the agent in question is combined with a different, second antineoplastic (eg, bevacizumab plus a new cytotoxic) or if drug-sensitive clones persist even in the presence of the resistant cells that resulted in evidence of clinical progression (eg, continued trastuzumab).

A recent report⁴ regarding the delivery of imatinib to patients with advanced gastrointestinal stromal tumors who had previously received and subsequently failed this agent (as well as sunitinib) provides strong support for the potential clinical utility of the retreatment approach. In this double-blind trial, 81 patients in this specific clinical setting were randomized to receive imatinib or placebo. Unsurprisingly, there were no complete or partial responses to imatinib, yet the median progression-free survival was 1.8 months for active treatment versus 0.9 months for placebo (HR = 0.46; P = .005). The overall survival (OS) was not statistically significant between the two groups, with a median OS of 8.2 months and 7.5 months, respectively, for imatinib and placebo. However, 93% of the patients receiving placebo crossed over to receive imatinib following progression.

These data suggest sensitive clinically relevant clones persist despite documented disease progression during treatment with two active antineoplastics in this clinical setting. Further, while the overall duration of response in this population may be limited, it is possible for patients to achieve quite meaningful short-term clinical benefit, despite prior failure on the agent.

It is important to note that the intent of discussing the results of the imatinib trial is not to suggest this approach is necessarily the best option in this particular setting. In fact, another study previously revealed the clinical utility of a different antineoplastic agent (regorafenib) in this patient population.⁵

Rather, the point to be made is that a previous history of disease progression should not be considered an absolute—or perhaps even a relative—contraindication to the readministration of an antineoplastic agent, assuming a sufficient time interval has passed to permit the reemergence of previously sensitive malignant cell clones whose growth had been suppressed during the previous delivery of the drug. This decision also assumes there is not a superior available therapeutic option, and the anticipated toxicity profile associated with the drug in question is believed to be acceptable.

As more data concerning novel agents are compiled, it is likely that there will be an increasing number of reports in the future demonstrating the utility of this basic approach to cancer management.

Maurie Markman, MD, editor-in-chief, is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America. maurie.markman@ctca-hope.com

References

1. Hennessy BT, Coleman RL, Markman M. Ovarian cancer [published online September 28, 2009]. Lancet. 2009;374(9698):1371-1382.
2. Kubicka S, Greil R, Andre T, et al. Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings [published online July 12, 2013]. Ann Oncol. 2013;24(9):2342-2349.
3. Von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 Study [published online March 16, 2009]. J Clin Oncol. 2009;27(12):1999-2006.
4. Kang Y-K, Ryu M-H, Yoo C, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial [published online October 18, 2013]. Lancet Oncol. 2013;14(12):1175-1182.
5. Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial [published online November 22, 2012]. Lancet. 2013;381(9863):295-302.