In Part I, we covered selected solid tumors in which targeted therapies have had a major impact, transforming and often substituting for the therapeutic options available prior to the identification of suitable targets; these tumors included renal cell carcinoma, hepatocellular carcinoma, malignant melanoma, and a wide range of sarcomas. Our review was focused on answering four fundamental questions about the use of targeted therapy for each of these tumors:
1. What is the underlying tumor biology that is being targeted?
2. How “targeted” are the so-called “targeted drugs”?
3. Is the targeted therapy also suitable for immunomodulation and/or immunoconjugation?
4. In what way does the targeted therapy constitute a meaningful improvement over chemotherapy?
Here, in Part II, we continue this approach for disease areas in which 1) targeted therapies have had a major impact on special patient subsets (eg, in breast cancer and lung cancer) or 2) some degree of usefulness has been demonstrated for targeted therapies as their integration with established treatments has evolved (eg, in gynecologic and gastrointestinal malignancies). We do not specifically address prostate cancer therapeutics, an area in which major strides have led to improved survival and resulted in US Food and Drug Administration (FDA) approval of four new drugs in the past 2 years. These advances have come about through efforts to strengthen the inhibition of androgens and/or androgen receptor signaling—long-established targets[1,2]—by harnessing immunity against prostate-specific antigens, and by introducing a taxane that overcomes resistance to docetaxel. Advances resulting from improved targeting will undoubtedly be reflected in better outcomes for patients diagnosed with this disease in 2012, thereby rendering prostate cancer another “high-impact area.” We chose not to cover the remarkable changes that are taking place in prostate cancer therapeutics because several of the new drugs have only recently received FDA approval and are just entering the clinical arena—as well as for the sake of brevity. Another area of impact not covered in this review is thyroid cancer. The landscape of thyroid cancer treatment is changing: once a patient’s disease has become refractory or not amenable to treatment with I131, clinical benefit has been established for certain drugs that inhibit receptor tyrosine kinases (RTKs) relevant to oncogenesis and/or angiogenic pathways in specific cellular subtypes, leading to FDA approval (Table 1). Thyroid cancer may soon be recognized as still another area on which the impact of targeted therapies is becoming sizable and is resulting in the modification of pathologic classifications according to oncogenetic changes.
Areas Where Targeted Therapies Have Had an Impact on Special Tumor Subsets
The discovery of key molecular targets in some patients with cancers of the breast and lung opened up therapeutic opportunities in identifiable subsets in these diseases, eventually leading to the routine embracing of molecular profiling for treatment selection upon diagnosis. Demonstration that trastuzumab (Herceptin) added to chemotherapy in gastric cancer yielded benefits in patients with human epidermal growth factor receptor 2 (HER2) overexpression has stimulated interest in routine testing for HER2 overexpression in this disease, and the discovery may herald a trend for use of such a strategy in settings beyond these common cancers.
1. What is the underlying tumor biology that is being targeted? Decades after the discovery by Jensen et al of estrogen receptors (ERs) in rodent endometrium, Perou et al introduced a molecular classification—now widely embraced by clinicians—in which breast cancer biology was defined primarily by the presence or absence of hormone receptors. This took place after amplification of the oncogene HER2 joined the estrogen receptor as recognized powerful tumorigenetic mechanisms in breast cancer, providing further stimulus for the adoption of a classification based on genomics. Successful targeting led to robust drug development and galvanized efforts to better define remaining subsets (usually identified within the “triple-negative” subset). The biology of this last broadly defined category is characterized by marked genetic instability, BRCA1 mutations, and activation of other angiogenic and epithelial growth factor receptor (EGFR) pathways.
Adjuvant and advanced-disease clinical trials are proceeding separately in these three categories: hormone receptor–positive, HER2-positive, and triple-negative. Trials do not yet separate luminal A and luminal B subtypes but are focusing on hormone resistance and concomitant blockade of downstream pathways that may account for the frequent failure of hormonal agents in patients with luminal B tumors. These hormone-dependent subsets are also characterized by delayed recurrences; this finding has stimulated research into the dormancy of stem cells, and into immune eradication of these tumor cells. Clinical successes achieved by targeting HER2 have led to further insight into signaling pathways within this family of receptors and to the testing of small-molecule drugs as well as antibodies. Immunotherapy and immunoconjugates already play a major role in the treatment of HER2-overexpressed tumors. On the other hand, strategies against triple-negative tumors have included chemotherapy in combination with RTK inhibitors that are either highly selective or “promiscuous” (targeting a range of vascular endothelial growth factor receptors [VEGFRs] and EGFRs). Thus, although much remains to be defined in the tumor biology of breast cancer, the road map for integrating targeted therapies into our clinical trials is well on its way.
2. How “targeted” are the so-called “targeted drugs”? ER targeting has been ongoing since the discovery of ERs, starting with the early use of pharmacologic doses of hormones and ablative surgeries and the introduction of selective estrogen receptor modulators (SERMs) in the 1970s. The past two decades have witnessed the superior benefits conferred by third-generation aromatase inhibitors and ER down-regulators. The focus has now shifted to understanding downstream pathways and the reasons that ER inhibition proves to be inadequate. The double-blind randomized BOLERO-2 trial examined the role of the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) (vs placebo) added to second-line treatment with an aromatase inhibitor in advanced breast cancer: it provided persuasive evidence of “cross-talk” with other key targets when targeting the ER alone has limited benefit. However, it is HER2 that continues to be the quintessential target to be exploited for clear benefit, since as many as 25% of breast cancer patients have amplification of this growth factor receptor. Trastuzumab, an antibody to the extracellular domain of HER2, has dominated the treatment of patients with HER2-amplified tumors since it led conclusively to improved outcomes in combination with chemotherapy for advanced disease, and most strikingly as adjuvant therapy. The RTK inhibitor lapatinib (Tykerb), which targets the catalytic domain of HER2, also attained an established role in the treatment of advanced breast cancer patients who had failed trastuzumab. Additional breakthroughs include the recent approval of pertuzumab (Perjeta) by the FDA; pertuzumab, an antibody that binds to a different extracellular domain of HER2, appears to act in tandem with trastuzumab to further inhibit proliferation or the development of resistance to pathway inhibition. This encouraging area of research (discussed further below) represents an important example of the way in which key targets have the potential to bring about dramatic advances, including in areas beyond breast cancer.
3. Is the targeted therapy also suitable for immunomodulation and/or immunoconjugation? As noted, a second monoclonal antibody (pertuzumab) potentiates the action of trastuzumab (as seen, for example, in the CLEOPATRA trial); it is possible that this effect is due in part to immune mechanisms. Also, the conjugation of a derivative of the potent mitotic inhibitor maytansine with trastuzumab—to form trastuzumab-DM1—has resulted in improved outcomes and clear advantages in the therapeutic index compared with a combination of docetaxel with trastuzumab. This is the first example of a successful immunoconjugate in an epithelial tumor (although the concept is well established in leukemias and lymphomas). Immunoliposomes with trastuzumab projecting on the surface of a liposome containing pegylated liposomal doxorubicin represent another type of immunoconjugation—one that can potentially enhance the actions of chemotherapy on tumor cells with the target of interest.
4. In what way does the targeted therapy constitute a meaningful improvement over chemotherapy? Breast and prostate cancers were the first examples of tumors in which the exploitation of molecular targets (ie, hormone receptors) was used to control the cancer. The adjuvant treatment of breast cancer with chemotherapy was the crown jewel of chemotherapy-related advances, but the successes seen with this approach have now paled in comparison to the effects of adjuvant trastuzumab (in combination with chemotherapy) when given to patients in whom HER2-overexpressing cancers have been diagnosed. This development has shifted the focus of research to “target-selected” clinical trials and a more extensive understanding of molecular pathways, including those mediated by hormone receptors.
1. What is the underlying tumor biology that is being targeted? The study of the histological subtypes of lung cancer and their relationship to smoking coincided with the birth of chemotherapy and with awareness of this disease as a public health menace. By the 1970s, the National Cancer Institute had become involved in therapeutic research through its extramural and intramural programs.[14,15] Recognition of the biological features that help distinguish between small-cell carcinomas, squamous cell carcinomas, adenocarcinomas, and large-cell anaplastic carcinomas, as well as the less common neuroendocrine lung cancer subtypes, increased steadily over the next three decades. Currently, these distinctions are becoming reinvigorated through molecular profiling that has identified specific activating mutations in adenocarcinomas that are increasingly recognized and effectively targeted, although such studies are less developed in the other major subtypes. Lung cancer varies with ethnicity and smoking history, pointing to major genetic and environmental etiologic factors.
The main focus of targeted therapy in lung cancer has been EGFR. EGFR is an RTK that forms part of an RTK family that includes HER2 (the human epithelial receptor [HER] superfamily; Figure 1)—which, as described earlier, is a powerful target in breast cancer. Once activated, these tyrosine kinases drive both the RAS and the phosphatidylinositol 3 (PI3) kinase pathways, resulting in proliferation and suppression of apoptosis. Both overexpression of EGFR and activating mutations in the kinase domain of the intracellular portion of the RTK have been demonstrated in responding lung adenocarcinomas; however, initial patient selection for clinical trials of EGFR-targeted drugs—as with trials of other systemic agents—did not discriminate among subtypes of non−small-cell lung cancer (NSCLC). Once activating mutations were correlated with response, an intensive search for other changes in the kynome began. EML4-ALK is a fusion protein that is the result of an inversion in chromosome 2p that leads to the fusion of the echinoderm microtubule−associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene. The function of the fusion protein is under study; however, ALK itself is a target of interest in other malignancies, and it partners with other genes to create novel proteins implicated in tumorgenesis. Approximately 4% to 5% of NSCLC may be driven by ALK fusion products.
2. How “targeted” are the so-called “targeted drugs”? More than a decade ago, erlotinib (Tarceva) and gefitinib (Iressa) were the first small molecule tyrosine kinase inhibitors introduced clinically to selectively block EGFR signaling, and they showed some antitumor activity (Table 2). As noted earlier, their benefit was later related to the presence of activating mutations of EGFR. In fact, the Iressa Pan Asia Study (IPASS), which examined the efficacy of gefitinib vs carboplatin and paclitaxel in patients with metastatic pulmonary adenocarcinoma, demonstrated that gefitinib was significantly more effective than chemotherapy given as first-line therapy in patients with EGFR mutations; on the other hand, in patients without EGFR mutations, chemotherapy was superior to gefitinib. The OPTIMAL study compared erlotinib to gemcitabine (Gemzar)/carboplatin in Chinese patients (with untreated EGFR-mutated NSCLC); it found a considerable progression-free survival advantage for erlotinib compared with chemotherapy. Patients with KRAS mutations tend not to respond to such EGFR inhibition, presumably because KRAS is downstream of EGFR signaling.
Crizotinib (Xalkori) is a small-molecule inhibitor of ALK and c-MET tyrosine kinases that binds to the adenosine triphosphate (ATP) binding site of the ALK enzyme, thus preventing its ATP-mediated autophosphorylation. Crizotinib is highly selective for this family of tyrosine kinases and has been shown to be effective in the treatment of NSCLC patients with EML4-ALK fusion genes.[18,22]
3. Is the targeted therapy also suitable for immunomodulation and/or immunoconjugation? EGFR targeting has also been achieved with cetuximab (Erbitux), an antibody to EGFR, which has been shown to be of benefit in tumors that overexpress EGFR on the cell surface. Immunoconjugation with cytotoxic elements has not yet been studied. Interestingly, ipilimumab (Yervoy; discussed in Part I of this review), the antibody to CTLA-4, has shown some promise in treating NSCLC. While the study of this unique antibody is still in early stages, preliminary data on this and other antibodies that target endogenous modulators of the immune system, such as Programmed Death (PD)-1 and its ligand PD-L1, suggest that we will soon need to consider immunomodulation in treatment plans for NSCLC.
4. In what way does the targeted therapy constitute a meaningful improvement over chemotherapy? Mutational analysis of NSCLCs is becoming nearly essential for patient management because of its prognostic and predictive value. As new mutations are discovered and subsequently targeted for treatment, growth in our armamentarium is foreseen against all cell types. Targeted therapy has not yet shown a meaningful benefit in the adjuvant setting, but it is likely that future therapeutic designs will incorporate these agents. Hopefully, the currently grave prognosis for most patients with advanced lung cancer and the high incidence of relapse in early-stage disease[24-26] will be altered by the results of targeted therapy trials. Alternatives that delay initiation of platinum doublet chemotherapy also carry with them a quality-of-life benefit for patients. Thus, targeted therapies are an impressive step forward in the treatment of NSCLC, and provide the basis for future meaningful steps.
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