A review of promising investigational drugs at the annual Hematology/Oncology Pharmacy Association meeting shows the pharmaceutical industry is responding to the call for more targeted agents in oncology. While a few drugs in the pipeline offer little survival advantage over current standards of care, clinical trials suggest their greater selectivity results in less toxicity. Robert T. Dorr, PhD, RPh, a professor of pharmacology at the Arizona Cancer Center in Tucson, expects a handful of new agents to come to market in the United States in the next year.
Prostate Cancer Pipeline
The drug furthest along in the prostate cancer pipeline is abiraterone acetate, which studies show improves overall survival (OS) in men with metastatic castration-resistant prostate cancer (CRPC). Abiraterone is an orally administered, small-molecule, irreversible inhibitor of the CYP17A1 enzyme. Inhibiting CYP17A1 blocks the downstream synthesis of dehydro - epiandrosterone (DHEA) and other androgen precursors into testosterone. Abiraterone is more selective and 10 to 30 times more potent than the commonly used ketoconazole. A pivotal, phase 3, randomized trial (N = 1195) demonstrated that adding abiraterone to prednisone improved OS by 3.9 months in men with CRPC previously treated with docetaxel chemotherapy. Adverse effects were “relatively minimal and easily managed,” said Dorr, with the most common being fluid retention and hypertension. Dorr added that it is not yet clear whether abiraterone exacerbated underlying cardiovascular risk in this elderly patient population or produced it. Dorr expects the US Food and Drug Administration (FDA) to approve abiraterone later this year.
MDV3100 is another emerging therapy for metastatic CRPC, but Dorr said abiraterone’s success has hindered recruitment for the phase 3 trials needed to support the manufacturer’s New Drug Application. Pre liminary study data show that the androgen-receptor antagonist produced fairly high rates of prostate-specific antigen response in chemotherapy-naive and previously treated patients, and he believes it will ultimately receive FDA approval.
Breast Cancer Therapies
TDM-1, a novel agent for HER2-positive breast cancer, suffered a setback when the FDA deferred approving the drug pending stronger evidence of its efficacy. TDM-1 combines trastuzumab and a derivative of the microtubule antibody maytansine, and Dorr considers it superior to trastuzumab. He expects forthcoming trial data to provide the FDA with enough evidence that TDM-1 improves response and OS to warrant approval.
“At the highest dose, you actually get regression with this construct. … In some breast tumors, you can get neartotal suppression,” he said. Although trastu zumab inhibits tumor growth, it does not typically spur tumor regression. Phase 2 studies suggest that TDM-1 is far less toxic than trastuzumab. “This is a big improvement for patients, that you can get the same outcome with markedly reduced toxicity,” he said.
Crizotinib in Lung Cancer
Crizotinib, which Dorr called “a home run,” is another drug he expects to see approved soon. Crizotinib is an oral small-molecule inhibitor, effective for the 5% of patients with non–small cell lung cancer who have chromosomal rearrangements of anaplastic lymphoma kinase. Phase 1/2 trial (N = 82) results published in the New England Journal of Medicine last year by Kwak and colleagues disclosed that 80% of heavily pretreated patients achieved partial response (PR), complete response (CR), or stable disease (SD).
A follow-up analysis slotted for the upcoming annual meeting of the American Society of Clinical Oncology is expected to show responses were fairly durable and is likely to report improvement in OS. Crizotinib appears to be relatively safe, with most toxicities ≤grade 1. “The only grade 3 toxicities we are seeing is AST [alanine aminotransferase] and ALT [aspartate aminotransferase] elevations, and 80% of these patients could go down to 200 mg twice daily,” said Dorr. He added that dose-limiting fatigue was seen at a dose of 300 mg twice daily. Approval could be delayed if the FDA does not approve the companion diagnostic test submitted for consideration at the same time.
Drugs in Hematologic Malignancies
The pace of drug development in chronic myeloid leukemia (CML) does not appear to be slowing. Of the most promising investigational agents, bosutinib (SKI-606) is probably the furthest along. Like the currently approved tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib, bosutinib is not effective in patients with a T315I mutation. Bosutinib’s primary targets are ABL, SRC, and CAMK26, and it has a maximum tolerated dose of 500 mg once daily. Bosutinib has demonstrated activity in phase 2 trials, which have reported CRs and major molecular response in nearly three-quarters (74%) of patients resistant to or unable to tolerate imatinib and in patients resistant to dasatinib or nilotinib. Trials report low rates of grade 3/4 toxicities, with diarrhea, neutropenia, and hypomagnesemia among the most common.
“The problem that happened with bosutinib is that the so-called pivotal 3000 trial that was supposed to show a superior cytogenetic response rate [over imatinib] at 1 year did not reach its primary end point,” he said. Despite this, the manufacturer filed a New Drug Application with the FDA in the hopes that it might be approved as a second- or third-line agent, which Dorr believes is likely.
Dorr discussed 2 agents progressing down the multiple myeloma pipeline. Carfilzomib is a proteasome inhibitor undergoing investigation in a large, closely watched, phase 3 trial enrolling patients refractory to bortezomib. He expressed skepticism as to whether it would prove superior to existing agents in terms of efficacy but praised its lower toxicity profile. An added benefit of carfilzomib is that patients do not need steroid treatment while taking it.
Pomalidomide is another promising drug for refractory multiple myeloma. It is an oral immunomodulatory agent, and preliminary phase 1/2 trial data presented by Lacy and associates at the American Society of Hematology meeting in December 2010 indicated that it was highly active in patients with heavily pretreated disease. They reported an overall response rate (ORR) of 62%, and Dorr said 24% of PR fell into the “very good” category. One-third of patients experienced neutropenia ≥grade 3, which might be something to watch for in future analyses.
Is Axitinib Next in Kidney Cancer?
Patients with renal cell carcinoma (RCC) refractory to sorafenib could have a new option soon. A 2007 phase 2 trial of the oral drug axitinib, which Dorr described as a “pure” inhibitor of vascular endothelial growth factor (VEGF) 1, 2, and 3, demonstrated a 44% ORR using RECIST criteria, time to progression of 15.7 months, and median OS of 29.9 months. Rini and colleagues enrolled 62 heavily pretreated patients with refractory me tastatic RCC in a single-arm trial of axitinib and found that most patients experienced PR or SD. Grade 3/4 adverse events included hand-foot syndrome, which he noted is a class effect of VEGF inhibitors.
“I think RCC is turning out to be a little like CML. You’ll start on a drug and ultimately fail on it, move to another one and then another one, and there’s a possibility you can later go back to an original drug and get response,” said Dorr.
BRAF a Target in Melanoma
Constitutively active BRAFV600E mutations are found in 60% of patients with melanoma.
PLX4032 (also known as RG7204), a powerful inhibitor of BRAFV600E, is the furthest along in development. Early trial results in advanced melanoma showed that most patients with a BRAFV600E mutation achieved PR or CR and that 81% of patients saw their tumors shrink by at least 30%, which prompted numerous headlines touting PLX4032 as a possible cure. Many patients ultimately become refractory to the drug, however, and some researchers are looking at whether combining it with a MET inhibitor might provide more durable responses. A January 2011 press release by the companies making PLX4032 announced that upcoming preliminary data would show improved OS and PFS for patients taking PLX4032 as part of a phase 3 trial. “I think the molecular drug will probably be approved sometime next year,” Dorr said.
Dorr predicted that in the coming year, we would likely see many more novel targeted agents making their way out of the crowded oncology pipeline. He expects a number of RET and MET inhibitors and drugs that affect RAS signaling to start generating interest. We have “maybe 15 or 16 kinase inhibitors in the armamentarium now,” he said, but with more than 500 protein kinases identified in humans, a tremendous amount of room remains for future discovery.
Robert T. Dorr receives a salary from AmpliMed Corporation, for which he is chief executive officer; owns interest in stock in AmpliMed; and has received royalties from Clinovel