2014 Oncology Drugs in the Pipeline

Neratinib

Evolution of HER-2–targeted therapy is one of the most fascinating stories in breast cancer treatment. Introduction of trastuzumab (Herceptin, Genentech) has dramatically changed the survival of patients with HER-2–positive breast cancer. However, a large number of trastuzumab-treated patients will develop resistance. Pertuzumab (Perjeta, Genentech) and ado-trastuzumab emtansine (Kadcyla, Genentech) were found to be effective in this subset of patients. Those patients who progress on multiple HER-2–targeted therapies still continue to have good performance status and will benefit from further treatment options.

Neratinib (PB272, Puma Biotechnology) is an irreversible multikinase inhibitor. In preclinical and clinical studies, it has shown to reverse trastuzumab resistance. Some of the early phase 2 studies have shown very high response rate in patients with trastuzumab-naive metastatic breast cancer.

The NSABP FB-8 trial has shown that neratinib can be safely combined with trastuzumab and paclitaxel in heavily pre-treated patients and still illicit a very good response. Data from recent I-SPY-2 trial (Park JW. Abstract #CT227. Presented at: AACR Annual Meeting; April 5-9, 2014; San Diego) showed that, in hormone receptor negative patients, the pathologic complete response rate is about 55% with neratinib. Based upon these results, the investigators decided to graduate neratinib to the next phase.

The dose-limiting toxicity for neratinib is diarrhea. We learned from our phase 1/phase 2 studies (NSABP FB-8) that if we premedicate patients with anti-diarrheal medicines with the first dose of neratinib, they will be able to tolerate the drug. It is analogous to using anti-nausea pre-medications for highly emetogenic chemotherapy. In that setting, we don’t wait for nausea to occur before we use nausea medicines. In the same manner, in neratinib-containing regimens, we need to pre-treat the patients with anti-diarrheal medicines before the diarrhea happens.

Based upon published studies, neratinib is a very promising drug in trastuzumab-resistant metastatic breast cancer. Results from ongoing and completed trials will be important to understand its role in neoadjuvant and extended adjuvant setting.

Enzalutamide

Enzalutamide (Xtandi; Astellas, Medivation) is a second-generation androgen receptor inhibitor specifically designed for activity in men with castration-resistant prostate cancer (CRPC), where the androgen receptor is commonly amplified. Although the initial FDA approval of enzalutamide in 2013 was in the post-docetaxel metastatic CRPC treatment space, the goal of most patients and providers faced with CRPC progression is to delay the need for systemic chemotherapy and maintain a high level of quality of life without cancer progression.

Based on the results of the phase 3 PREVAIL trial, which compared enzalutamide with placebo, we now have a clear signal that enzalutamide prolongs survival, delays quality-of-life deterioration, delays progression and is well tolerated over long periods of time in men with metastatic CRPC prior to chemotherapy (Beer TM. Abstract #LBA1. Presented at: 2014 Genitourinary Cancers Symposium; Jan. 30-Feb. 1, 2014; San Francisco).

We found an 80% improvement in the risk of progression, a delay in the need for chemotherapy by 16 to 18 months, and a nearly 30% improvement in the risk of death over time, findings that are clearly clinically significant and likely to impact the treatment paradigm for these men.

Enzalutamide joins sipuleucel-T (Provenge, Dendreon) and abiraterone acetate (Zytiga, Janssen) as safe and effective therapies for men prior to chemotherapy, and research efforts are underway to better understand the appropriate sequencing and selection of patients for these therapies based on clinical and biomarker assessments. For example, cross-resistance between abiraterone and enzalutamide exists, and there are emerging data that androgen receptor variants (ie, AR-v7) that do not respond to either of these agents may promote this resistance, as a study by Antonarakis and colleagues scheduled for presentation at the ASCO Annual Meeting will demonstrate.

Enzalutamide is clearly an active agent and provides direct clinical benefit to the majority of men when used early in the disease course, and future trials will help to clarify the optimal setting for its use.

ABT-199

As with many developmentally regulated processes, cancer cells often hijack elements involved in the control of programmed cell death to promote their own survival in a hostile host environment. Bcl-2 was the first protein involved in regulating programmed cell death determined to be an oncogene. Several proteins — including Bcl-XL, Bax or Bak — that share a Bcl-2 homology-3 (BH3) domain have since been described as both positive and negative regulators of apoptosis. Bcl-2–like proteins are countered by a subfamily of distantly related ligands, the BH3-only proteins (Bim, Puma, Noxa, Bid, Bik, Hrk, Bad, and Bmf).

It has been postulated that tissue homeostasis is regulated largely by the balance between BH3-only proteins and Bcl-2 pro-survival family members. Upon cell damage (eg, exposure to chemotherapy agents), BH3-only proteins are activated and inactivate Bcl-2 anti-apoptotic proteins by inserting their BH3 domain into a hydrophobic groove on the surface of Bcl-2 pro-survival proteins. The neutralization of Bcl-2 pro-survival proteins by BH3-only proteins favors the activation and oligomerization of Bax/Bak that leads to changes in mitochondrial potential and apoptosis.

ABT-199 (AbbVie) is a novel and selective BH3 mimetic that inhibits several of the anti-apoptotic Bcl-2 family-members proteins that promote programed cell death. Previous BH3 mimetics had been studied extensively in preclinical models and in early clinical trials. Although significant anti-tumor activity was observed in preclinical models, first-generation of BH3 mimetics exhibited serious adverse events that hindered their further clinical development, such as central nervous system toxicity with obatoclax (Cephalon), or grade 3 or grade 4 thrombocytopenia with ABT-263 (Genentech/AbbVie).

BH3 inhibition-associated thrombocytopenia is mediated by the inhibition of Bcl-XL in platelets and its precursors. ABT-199 was modified from ABT-263 to maintain its binding affinity for Bcl-2 and BCL-W, but it lacks affinity for Bcl-XL, resulting in minimal impact in platelet counts. Seymour and colleagues presented the results of the first phase 1 clinical study designed to determine the maximum tolerated dose of ABT-199 in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (Seymour JF. Abstract #872. Presented at ASH Annual Meeting; Dec. 7-10, 2013; New Orleans). Thirty-eight percent of patients in the study had high-risk cytogenetics.

Patients were divided in several dose cohorts (range, 150 mg to 1,200 mg). ABT-199 was administered orally; on the first week of treatment. Patients received a single dose on either day -3 or -7 and daily thereafter until disease progression or unacceptable toxicity. ABT-199 was well tolerated and acceptable toxicities were observed. On the other hand, significant anti-tumor activity was observed in 84% of the patients, including complete response (21%). Perhaps related to its anti-tumor activity, early tumor lysis syndrome (TLS) was observed in 11% of patients. Moreover, one patient in the 1,200 mg-dose cohort died as a result of severe TLS.

The study continues to enroll patients, but the agent has been administered at a reduced dose and dose-escalation schedule in order to better identify, prevent or control TLS. The clinical results observed, including the high rate of complete response among treatment-resistant CLL/SLL, are encouraging and suggest that ABT-199 potentially can be tested in other patients with relapsed/refractory lymphoid malignancies.

Sorafenib (Nexavar; Bayer, Onyx), a multikinase inhibitor, remains the only standard systemic therapy for advanced hepatocellular carcinoma (HCC). However, the survival benefit is modest and no second-line therapy currently exists. Therefore, systemic therapy for advanced HCC is an evolving field.

A novel potential target for HCC is phosphatidylserine (PS), a potent immunosuppressive agent located in the inner aspect of the plasma membrane. Exposure of the PS to the outer plasma membrane leaflet and its subsequent interaction with PS receptors on immune cells leads to immunosuppression and tumor progression. External PS is abundant in the tumor environment and is markedly enhanced by therapy (eg, radiation/chemotherapy).

Several pre-clinical trials have demonstrated that antibody-mediated PS blockade leads to increased cytotoxic T-cell immunity and decreased immunosuppression. This has led to the use of bavituximab (Peregrine Pharmaceuticals), a chimeric PS targeting antibody, in several phase 2 clinical trials.

The drug is being studied in HCC by Adam Yopp, MD, assistant professor of surgery at UT Southwestern in Dallas. The combination of bavituximab with sorafenib could be a promising option for patients with advanced HCC as it targets immune checkpoints at different levels, potentially leading to a robust antitumor immunity that is a very exciting field currently. This has the potential to significantly impact clinical outcomes for these patients, while demonstrating a very favorable adverse-effect profile. Accrual is proceeding on target and results are expected in 2015.

AMG 386, Ipilimumab

There are four major classes of drugs that comprise the majority of drugs in phase 2 and 3 trials:

1) antiangiogenic drugs, which inhibit blood vessel formation and, therefore, limit tumor growth;

2) cell cycle regulators, or molecules that target certain growth pathways or pathways that prevent cell death;

3) epi-drugs, a newer class of drugs that reverse epigenetic inactivation of key genes needed for correct cell growth and allow cancer cells to reprogram themselves; and

4) cancer immunotherapy, which is a really exciting area that taps the power of the body’s own immune system to inhibit growth of cancer cells and shrink tumors.

Antiangiogenesis is an area that is fairly mature. We have bevacizumab (Avastin, Genentech) in the market, which is now FDA approved for ovarian cancer. A drug in the pipeline, AMG 386 (Amgen), is a first-in-class investigational peptibody designed to block angiogenesis by inhibiting angiopoietin-1 and angiopoietin-2, which play a key role in blood vessel formation. It not only prevents angiogenesis but also prevents the maturation of vessels, which are harder to target with chemotherapy. The drug was also noted to have a tolerable side-effect profile.

AMG 386 has been studied in a phase 3 trial for women with recurrent epithelial ovarian, peritoneal or fallopian tube cancer in combination with weekly paclitaxel vs. paclitaxel alone. The combination showed a 34% reduction in risk of disease progression or death. The Gynecologic Oncology Group (GOG) is currently studying AMG 386 in a randomized phase 3 multicenter trial as a front-line agent for patients with ovarian cancer in combination with chemotherapy.

The immune system, headed by activated T cells, is a powerful natural agent against cancer. Cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T-cell response, can restrict this antitumor immune response. Another drug in the pipeline, ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human monoclonal antibody that inhibits CTLA-4–mediated T-cell suppression to enhance the body’s own immune response against tumors. In metastatic melanoma, ipilimumab induced a significant positive response and improved survival, and the agent is FDA approved for these patients. Currently, there is a phase 1 GOG trial evaluating sequential ipilimumab given after chemoradiation in patients with locally advanced cervical cancer.

Nearly all cervical cancers are attributable to HPV and, therefore, immunotherapy against cervical cancer cells that express HPV antigens is especially attractive. The hope is that, by modulating the immune system, we may be able to improve the efficacy and durability of response to radiotherapy. This novel treatment strategy would be particularly relevant for those women who are at high risk for recurrence despite standard chemoradiation.

CA-18C3/MABp1

CA-18C3/MABp1 (Xilonix, XBiotech) is an inhibitory human monoclonal antibody against interleukin-1 alpha (IL-1 alpha). As we look for innovative ways to treat cancer, IL-1 alpha is an interesting target because this cytokine is associated with inflammatory responses and immune regulation, both important areas of active research for novel approaches for treating tumors.

IL-1 alpha also is associated with growth of tumors and angiogenesis. Therefore, blockade of IL-1 alpha by Xilonix may have both direct and indirect effects on tumors. Xilonix was well tolerated in a recently completed phase 1 trial, with no significant toxicities when given every 2 weeks. Based upon a survival benefit in a phase 2 trial, it is currently being studied as a single agent in a phase 3 trial in patients with previously treated metastatic colorectal cancer. The FDA has granted fast track status for the development of Xilonix.

Cachexia is a significant problem that decreases the quality of life for patients with advanced cancer and often limits their ability to continue chemotherapy. The benefits of good palliative care have been shown numerous times. IL-1 alpha is important for development of cachexia, and the early phase clinical trials with Xilonix show a reduction in cachexia in patients treated with this antibody. The phase 3 trial in patients with advanced colorectal cancer will enroll patients with cachexia and will have OS as the primary endpoint. An antitumor effect and reduction in cachexia due to Xilonix may lead to a tremendous benefit in patients with many types of cancer.

Genitourinary cancer drugs

The accompanying chart listing drugs in the pipeline for hematology–oncology indications provokes a few thoughts, at least from the perspective of a genitourinary medical oncologist.

1) There are a lot of drugs in the works. Some, to be sure, are not paradigm shifters (eg, a new taxane, new GnRH analogues); however, of 35 agents in development for prostate cancer, 14 (40%) are immunologic agents. That is a shift in the past 5 years! Twenty percent continue work aimed at the androgen receptor signaling axis — an approach that is bearing fruit. This, despite GU medical oncologists of my generation being brought up on the concept of "androgen-independent prostate cancer." That concept has proven to be quite limiting and often, frankly, wrong.

2) A second observation: We need more work and more ideas in bladder/transitional cell and renal cell carcinomas (see Table).

Prostate cancer is a common disease and a leading cause of death, but these data continue to emphasize the need for more work in bladder cancer, a disease for which there has not been a new drug in 20 years and a disease in which immunotherapy works well (eg, bacillus Calmette-Guérin [BCG] in superficial disease).

Progress and opportunity have never been greater, but there is much to do.