Improving Harmonious Precision

Eleven years have passed since the US Food and Drug Administration (FDA) approval of imatinib (Gleevec) for Philadelphia chromosome–positive chronic myeloid leukemia. Since the advent of imatinib, the landscape of drug development research in solid tumors has changed drastically, with numerous novel molecular targets identified that have the potential to drive tumor growth. The identification of these targets is coupled with the development of targeted monoclonal antibodies and/or small molecular inhibitors, each with varying degrees of specificity and potency. Carefully chosen agents enter into clinical testing, but very few succeed in phase III tests and obtain FDA approval. The success rate of new agents and the clinical benefit of those that do “succeed” remain well below expectations.

In this issue, Wu and colleagues provide a focused review of the evolution of targeted therapies in selected solid tumors in which these therapies are believed to have major clinical impacts: renal cancer, hepatocellular carcinoma, melanoma, and sarcomas. These tumors are notorious for being chemotherapy-resistant. Without question, the molecularly targeted therapies have expanded treatment options and patient outcomes in these diseases. Nonetheless, we have not even come close to the success we saw with imatinib. The impact of these targeted therapies has yet to rival the dramatic effects of imatinib.

Why have these agents not been more successful? In part it is because hitting the target does not equate to clinical efficacy. Our reference standard, imatinib mesylate, failed to demonstrate clinical benefit as a maintenance therapy in c-kit–positive small-cell lung cancer patients.[1] Additionally, imatinib in combination with docetaxel was of no benefit to patients with metastatic non–small-cell lung cancer or to those with head and neck cancer.[2] Also, not all targets are created equal. Epidermal growth factor receptor (EGFR) in colon cancer is a perfect example of a target that has a highly variable predictive and prognostic impact. To date, we have yet to identify molecular targets that, when hit, have curative potential.

How do we take the field of targeted therapeutics to the so-called “era of precision medicine?” Unlike 10 years ago, we now have tools to explore the cancer genome and identify the potential driver mutations for each individual tumor, offering high impact not only on molecular diagnosis and prognosis, but also on the prediction of response to treatment regimens.[3] Just as important is the rational and effective rendering of clinical trial designs that will accelerate the drug development process. One of the agents that Wu et al reviewed, and that is most promising, is vemurafenib (Zelboraf). Vemurafenib is a potent, specific BRAF kinase inhibitor that was approved by the FDA for treatment of unresectable or metastatic melanoma with BRAF V600E mutations. The clinical development leading to the FDA approval was targeted to the patients who harbor the BRAF V600E mutation as detected by the real-time polymerase chain reaction assay (Cobas 4800 BRAF V600 Mutation Test, Roche Molecular Systems). The companion diagnostic assay was approved by the FDA at the same time as vemurafenib. Vemurafenib’s approval is an example of the future of drug development: right target, right drug, and right patient.

However, our patients expect us to cure them, and we are unlikely to succeed with single-agent therapy. Therefore, we must address drug development using a combinatorial approach. As Wu et al noted regarding the underlying biology of cancers, the more we learn, the clearer it seems that targeting a single pathway, or a single driver mutation, is unlikely to reverse a tumor’s neoplastic growth. What adds to the challenge is the intratumoral heterogeneity that is underestimated by a single tumor biopsy, and that may account for resistance to (or ineffective) monotherapy.[4,5] The complex heterogeneity of the tumor biology requires rationally designed combination regimens. The rationale for combining everolimus (Afinitor) with exemestane (Aromasin) heralds high potential for this approach. Aberrant activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway has been shown to be associated with resistance to endocrine therapy. Co-inhibition of aromatase and the mTOR signaling pathway prolonged freedom from disease progression in patients with hormone receptor–positive advanced breast cancer.[6]

Another important consideration in a combinatorial approach, as Wu et al discuss, is the immunomodulatory effects of these targeted therapies. Although they may be off-target effects, we must understand these effects in order to optimize the future development of these agents, particularly when they are used in combination with an immune-based therapy. Given that many of the tumors discussed by Wu et al are known to be influenced by immunomodulatory agents, it will be important to understand whether targeted agents have favorable or negative immunomodulatory effects when used together with cytokine-based therapy, immune check-point inhibitors, or therapeutic cancer vaccines. For instance, some of the mTOR inhibitors have demonstrated negative effects on immune suppressive cells, such as myeloid-derived suppressor cells. An mTOR inhibitor is currently being tested in combination with a therapeutic cancer vaccine in ovarian cancer (NCT01536054). As immunotherapies become more mainstream, we will need to understand the impact of the dose and schedule of targeted agents on the immune response.

During the past decade, targeted therapeutics have changed the landscape of cancer therapy with bold brush strokes, but the resulting images are still unclear. As we enter into the second decade of targeted therapy, our increased understanding of tumor biology together with cancer genomic sequencing tools will clearly show the way forward. It is imperative that we use these fine brushes, not only to improve precision, but in the end to realize the art of medicine.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES

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2. Tsao AS, Liu S, Fujimoto J, et al. Phase II trials of imatinib mesylate and docetaxel in patients with metastatic non-small cell lung cancer and head and neck squamous cell carcinoma. J Thorac Oncol. 2011;6:2104-11.

3. Tran B, Dancey JE, Kamel-Reid S, et al. Cancer genomics: technology, discovery, and translation. J Clin Oncol. 2012;30:647-60.

4. Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer. 2012;12:323-34.

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6. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520-9.