Areas Where the Effective Integration of Targeted Therapies With Established Therapies Has Been Evolving
Steady progress has been made in the treatment of colorectal and gynecological cancers (as well as in the treatment of other cancers—such as bladder, brain, breast, gastroesophageal, and head and neck cancers) through multimodal strategies that have relied on surgery, radiation, and chemotherapy. In colorectal and ovarian cancers, anti-angiogenic agents have been the first targeted drugs to be successfully added to established combined-modality regimens, while other leads are being pursued based on emerging tumor biology.
This section focuses on the biology of metastatic colorectal cancers, where major strides have recently been made in the incorporation of targeted therapies.
1. What is the underlying tumor biology that is being targeted? Bert Vogelstein et al first articulated the sequential molecular changes that take place in colonic epithelium, starting from dysplasia and progressing through adenoma to carcinoma. After colorectal cancer develops and eventually metastasizes, the tumor cells rely on angiogenesis, as described by Folkman more than 5 decades ago. VEGFs that bind to VEGFRs are involved in new vessel formation via activation of downstream signaling and orchestration of endothelial cellular growth and function, as described by Hanahan and Folkman. The most studied ligand in tumor angiogenesis is VEGF-A—a member of the VEGF family, which includes three other VEGF ligands. In colorectal cancers, VEGF-A is expressed in higher levels in distant metastases than in the primary tumor and is an attractive target—one that is more significant when elevated levels of VEGF-A are accompanied by increased VEGFR expression. In fact, expression of VEGFR-1, the receptor for VEGF-A, increases with tumor grade and lymph node involvement. VEGF-A also binds to VEGFR-2, a receptor that is upregulated in metastases. Several other factors currently being identified, which are involved in the growth and quality of blood vessels (eg, angiopoietins), will likely be the subject of future clinical study.
The EGFR pathway constitutes another well-known target under investigation: 90% of metastatic colorectal cancers have EGFR overexpression, and this is associated with resistance to chemotherapy.[32,33] EGFRs belong to the previously mentioned superfamily of human epithelial receptors (HERs; see Figure 1) Like the VEGF family, the HER family also has multiple ligands, including EGF and transforming growth factor alpha (TGF-alpha). Several ligands can bind to EGFR (HER1), and once bound, EGFR dimerizes with any one of the HER family receptors, leading to downstream signal activation that results in cellular proliferation, metastatic spread, and neo-angiogenesis. Although EGFR inhibition became an early focus of targeted drug development in colorectal cancers as well as in other cancers, antitumor activity showed poor correlation with EGFR expression. The puzzle was partly solved when KRAS, one of the downstream signals of EGFR, was found to be mutated in up to 40% of metastatic colorectal cancers; constitutive activation of downstream RAS signaling was implicated in resistance to EGFR inhibition. The downstream signals of EGFR and RAS include the PI3K and RAF kinase pathways, which are involved in tumor progression and survival. More recently, BRAF signaling (of importance in melanoma) has emerged as playing a role in driving proliferation in certain subsets of colorectal cancer patients even if KRAS is not mutated. Our understanding of these pathways in colorectal cancer is expanding and will undoubtedly lead to new individualized approaches.
2. How “targeted” are the so-called “targeted drugs”? Targeted therapy for colorectal cancer came of age in 2004, when bevacizumab(Drug information on bevacizumab) (Avastin), a monoclonal antibody of VEGF-A, contributed to improvement of overall survival in combination with chemotherapy (fluorouracil [5-FU] and leucovorin) in metastatic colorectal cancer. This landmark study gained FDA approval for bevacizumab and provided the foundation for the use of angiogenesis inhibitors in colorectal cancer. Aflibercept (Zaltrap) is a recombinant fusion protein comprised of VEGFR-1 and VEGFR-2 ligand-binding components fused with the constant region (Fc) of immunoglobulin G1 (IgG1) and inhibiting activation of these receptors (Figure 2). Aflibercept has recently demonstrated an overall survival advantage in patients with metastatic colorectal cancer that has progressed after first-line treatment (which could have included bevacizumab). The impact of these two targeted therapies—bevacizumab and aflibercept—has highlighted the role of angiogenesis in metastatic colorectal cancer and has renewed interest in other angiogenesis inhibitors, such as small molecules (see Table 1). As in other areas, major efforts are ongoing to reduce side effects and identify biomarkers associated with clinical benefit.
Cetuximab and panitumumab (Vectibix) are monoclonal antibodies that target EFGR. Much clinical experience has accumulated since the initial demonstration in colorectal cancer metastases of cetuximab(Drug information on cetuximab)’s reversal of clinical resistance to the topoisomerase I inhibitor irinotecan(Drug information on irinotecan). (Curiously, small molecules that narrowly target EGFR have not resulted in clinical benefit.) Both cetuximab and panitumumab were initially approved by the FDA for EGFR-overexpressing metastatic colorectal cancer, but such a basis for patient selection was questionable from the outset. A breakthrough in personalizing the clinical application of these drugs would not occur until the demonstration that the agents were ineffective in and possibly detrimental to patients whose tumors harbored KRAS mutations. Although no prospective studies to date have shown overall survival advantages, both agents extend progression-free survival in patients with KRAS wild-type tumors when combined with chemotherapy. Finally, regorafenib (Stivarga), an orally available small molecule inhibitor of VEGF-2 and -3, RAF kinases, and platelet-derived growth factor receptor (PDGFR), has demonstrated an impressive overall survival and progression-free survival advantage as a single agent (vs placebo) in patients who have progressed through standard therapies. These findings provide further impetus for the continued study of these pathways in metastatic colorectal cancer.
3. Is the targeted therapy also suitable for immunomodulation and/or immunoconjugation? Efforts to develop vaccine therapies for metastatic colorectal cancer have been disappointing. A phase I study of autologous tumor cells modified to express interleukin-2 (IL-2) in colorectal cancer patients showed an increase of five times the normal level in the frequency of tumor cytotoxic T-cell precursors in a small number of patients following immunization. Ipilimumab did not elicit responses in a phase I study that included three colorectal cancer patients, and it is questionable whether CTLA-4 is an exploitable immune target in colorectal cancer.
4. In what way does the targeted therapy constitute a meaningful improvement over chemotherapy? Bevacizumab has helped redefine the concept of “synergy” of therapeutic interventions (already established in colorectal cancer after 5-FU + oxaliplatin(Drug information on oxaliplatin) was compared to merely additive 5-FU + irinotecan combinations). When added to FOLFOX (5-FU + folinic acid [leucovorin] + oxaliplatin [Eloxatin]), bevacizumab led to a significant prolongation in overall survival, suggesting that it made chemotherapy more effective. A similar improvement in survival has been achieved with aflibercept in the second-line setting. The other remarkable achievement of the application of targeted therapy concepts in colorectal cancer has been the definition of the role of KRAS pathways in the personalization of treatment: data mining in clinical trials demonstrated that molecular profiling that could identify when a tumor was KRAS wild-type predicted the usefulness of the EGFR antibodies, cetuximab and panitumumab. Thus, optimal treatment selection by oncologists is contributing not only to greater patient benefit but also to enhanced cost-effectiveness—a key element in the practice of medicine today.
1.What is the underlying tumor biology that is being targeted? Here we will discuss primarily high-grade serous cancers of extra-uterine Müllerian epithelial origin (the majority of ovarian, tubal, and primary peritoneal cancers). Endometrial cancers have been classified as type 1 (which result from atypical hyperplasia, and are generally ER-positive and well differentiated) and type 2 (which have a poorer prognosis and share many features with extra-uterine tumors). While type 1 tumors may be responsive to endocrine therapies, systemic treatment of type 2 tumors, especially uterine papillary serous cancers (UPSCs), consists of chemotherapy similar to that used in extra-uterine high-grade serous cancers.
The Cancer Genome Atlas (TCGA) has identified a vast number of genetic alterations among nearly 500 ovarian cancer specimens beyond stage I that displayed papillary serous histology at diagnosis. Among the changes noted, somatic mutations in p53 were the most consistent findings, while somatic mutations in BRCA1, BRCA2, PI3Kinase, and PTEN were found in a small percentage (less than 10%) of the samples, with the occurrence of a mutation in any one of these genes excluding mutations in the others—a finding that tends to underscore the relevance of these mutations to oncogenesis. Amplification of c-MYC was found in more than 60% of the tumors included in TCGA, with KRAS showing a lesser extent of activation. The most common deletions involved PTEN, RB1, and NF1—and also PIK3R1. With regard to genomic and somatic mutations in BRCA1 and BRCA2 specifically, these were found in 20% of the high-grade serous ovarian cancers—and in another 8% one may find epigenetic silencing of BRCA1 via hypermethylation. The TCGA analysis has identified at least four gene expression subtypes, but the importance of these subtypes for personalizing treatment has not yet been determined. By contrast, platinum sensitivity is reflected by antitumor responses of as high as 80% on first exposure to these agents in stage III and IV tumors. Women treated with platinum-based regimens experience benefit that is sustained for a median of 18 months (and longer for those with minimal residual disease after surgical cytoreduction). This somewhat unique sensitivity of ovarian cancer to cisplatin(Drug information on cisplatin)—which is exceeded only by the sensitivity of germ cell tumors—is now mostly attributed to alterations in homologous recombination (HR) DNA repair arising from defective BRCA function. This platinum sensitivity has been reproduced in genetically engineered mouse models of ovarian cancer and is retained in the majority of cancer recurrences that occur 6 months or longer after treatment has been stopped (the definition of “platinum-sensitive disease”)—although retreatment with any number of platinum-containing doublets generally results in lower response rates and duration of response than were obtained on first remission. Defects in HR also confer increased sensitivity to other DNA-damaging drugs, such as pegylated liposomal doxorubicin(Drug information on doxorubicin) (PLD); furthermore, these defects have been implicated in both in vitro[44,45] and clinical responsiveness to inhibitors of base-excision DNA repair (poly[ADP-ribose] polymerase, or PARP)—ie, they lead to dual blockade and ensuing synthetic lethality). However, the platinum lesion on DNA, as shown in murine models, cannot be repaired without HR,[47,48] and the backbone of treatment of ovarian cancer remains platinum-based chemotherapy. Although carboplatin(Drug information on carboplatin) achieves clinical results similar to those seen with cisplatin, on intraperitoneal (IP) administration, cisplatin may be more effective—consistent with a hypothesis that recurrences arise from less–cisplatin-sensitive cancer stem cells, while these cells’ progeny are still responsive to carboplatin or lower cisplatin doses.
Genomic changes in other histologic subtypes of ovarian cancer, such as endometrioid, clear-cell, and mucinous, are emerging but are not yet generally applied in clinical trials. Similarly, knowledge that folate receptor alpha is expressed in these epithelial tumors while being restricted to specialized normal tissues (such as the apical membrane of tubular cells, retinal pigment epithelium, and choroid plexus) has also been utilized in targeting.
2. How “targeted” are the so-called “targeted drugs” In addition to PARP inhibitors (which remain experimental because of the paucity of phase III data on any one of the compounds under study), agents to which both ovarian and endometrial cancer have been responsive include the anti–VEGF-A antibody bevacizumab. Unlike its use in breast, colon, and lung cancers, in ovarian cancer bevacizumab appears to be useful as a single agent; in randomized trials it has contributed to prolongation of progression-free survival in first- and second-line platinum-sensitive relapses. In addition, the AURELIA trial, which tested PLD, paclitaxel(Drug information on paclitaxel), or topotecan(Drug information on topotecan) alone vs with bevacizumab, demonstrated a significant contribution of this targeted agent to response rates and progression-free survival in the challenging treatment of platinum-resistant disease (the trial reported too few events to evaluate overall survival). Other anti-angiogenic targets have received less testing, but responsiveness to agents that target Tie-1 and Tie-2 (receptors for angiopoietins) or responsiveness to RTK inhibitors (eg, sorafenib(Drug information on sorafenib) [Nexavar]) has been noted; studies are ongoing with these drugs in combinations,[51,52] although toxicities are a concern. Screening for HER2 overexpression as a target for trastuzumab(Drug information on trastuzumab) proved futile in a Gynecologic Oncology Group study, but this concept needs to be revisited in UPSC, since HER2 overexpression is more common in UPSC than in ovarian cancer.
Many ongoing trials are targeting the PI3K/AKT/mTOR pathway, but much remains to be learned about patient selection, molecular signatures that can predict for response, and whether pathway activation and mutations require different strategies for inhibition. Trials are also ongoing in endometrial cancer, where researchers hope to establish a link between resistance to endocrine therapy and activation of this pathway (perhaps analogous to what is seen in breast cancer). Striking preliminary results in ovarian cancer were reported in a study of cabozantinib, a potent MET inhibitor. However, targeting individual pathways may not be appropriate for most ovarian cancers. In fact, given that the hallmark of serous ovarian cancers in The Cancer Genome Atlas is great variability in the genome from patient to patient, the discussant at the American Society of Clinical Oncology (ASCO) 2012 oral gynecologic cancer session that covered three targeted therapy trials made the suggestion that no phase III study of a targeted drug should be started without a full genome display as a criterion for entry.
3. Is the targeted therapy also suitable for immunomodulation and/or immunoconjugation? The IP route of administrastion has some appeal for testing of immunomodulatory strategies. In fact, studies with IP IL-2 and lymphokine-activated killer (LAK) cells yielded some long-term survivors. In addition, reversal of platinum resistance has been postulated to occur with agents such as cyclosporine or the proteasome inhibitor bortezomib(Drug information on bortezomib) (Velcade). Attempts at delivering an adenovirus vector conferring wild-type p53 have been made in the past, but studies beyond phase I have not been completed. A sustained response to ipilimumab in one patient sparked interest in trials in ovarian cancer, but activity has not been reproduced.
Over the past decade, drug targeting has, justifiably, frequently taken center stage in cancer therapeutics. This overview, limited to selected areas in the treatment of solid tumors, provides already ample evidence of the major impact of targeting on outcomes in certain cancers and in specific subsets of other cancers. These gains have led to the expectation that whole-genome studies will eventually result in the identification of key “druggable” targets for all cancers. However, in at least two of the most common solid tumors—those arising in the colon and in the gynecologic tract—major strides took place against a backdrop of chemotherapy, and the picture is now one of somewhat empirical “evolving integration” of new targeted drugs with established therapeutic modalities. In fact, in high-grade serous ovarian cancers, genetic abnormalities are so numerous and varied that replacing current treatments with targeted approaches is unlikely. Hence, in these areas, therapeutic advances in the near future are not expected to come from characterizing the genome and selecting from a menu of targeted drugs. Rather, improved selectivity in the treatment of ovarian cancer, with its innumerable somatic mutations, will likely emerge from understanding repair of chemotherapy-induced DNA damage, from consequences of modulating neo-angiogenesis, or from harnessing the immune system after major tumor cytoreduction. The challenge in the future is not only one of target identification—what years ago we dubbed “reaching for the magic bullet summit” (ie, rational therapeutics in drug development). In addition, empiricism emanating from the study of biological systems (including clinical trials) is needed to explore which of a vast number of emerging drug products should be integrated into current therapies, and how this should be done. These cautionary comments should not preclude continuing efforts to couple tumor biology with a search for molecular targets as the key to future advances. Hopefully, in the midst of the development of targeted therapies, this brief overview provides a perspective on how therapeutic progress against a range of solid tumors is being achieved.
Financial Disclosure: Dr. Muggia has served on safety data monitoring committees for Bayer, Lilly, Pfizer, and Roche. Dr. Joseph and Dr. Wu have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.