A Pharmacist Reviews Cancer Drugs in the Pipeline

June 2011, Vol 2, No 3 -

Few prolong survival but most offer reduced toxicity

Salt Lake City, UT—A review of promising investigational drugs at the 2011 Hematology/Oncology PharmacyAssociation annual meeting shows that the pharmaceutical industry is responding to the call for more targeted agents in oncology. Although a few drugs moving through the pipeline offer little survival advantage over the current standard of care, clinical trials suggest their greater selectivity is associated with lower rates of serious toxicity.

Robert T. Dorr, PhD, RPh, Professor of Pharmacology at the Arizona Cancer Center in Tucson, said he expects a handful of new therapeutics to be approved and come to market in the United States in the next year.

Prostate Cancer
is an emerging therapy for metastatic castration-resistant pros – tate cancer, but Dr Dorr said abiraterone’s success has hindered trial recruitment for the phase 3 trials needed to support Medivation’s new drug application for MDV3100. Preliminary data from one phase 3 study 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 US Food and Drug Administration (FDA) approval.

Breast Cancer
In discussing breast cancer therapeutics, Dr Dorr said disappointing results from a trial of iniparib delivered a setback to PARP inhibitors in breast cancer. TDM-1, a novel agent for HER2-positive breast cancer, suffered its own setback when the FDA deferred approving the drug pending stronger evidence of its efficacy. TDM- 1 combines trastuzumab (Herceptin) and a derivative of the microtubule antibody maytansine, and Dr Dorr considers it superior to trastuzumab. He expects forthcoming trial data to provide the FDA with enough evidence that TDM-1 improves response and overall survival (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 trastuzumab inhibits tumor growth, it does not typically spur tumor regression. Also, phase 2 studies suggest the newer agent is far less toxic than trastuzumab. “This is a big improvement for patients, that you can get the same outcome with markedly reduced toxicity,” Dr Dorr noted.

Non–Small-Cell Lung Cancer
Crizotinib, which Dr Dorr called “a home run,” is another drug he expects to receive approval in the coming months. Crizotinib is an oral small molecule inhibitor, and its use is restricted to the 5% of patients with non–small-cell lung carcinoma who have chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene.

Results of a phase 1/2 trial (N = 82) showed that 90% of heavily pretreated patients achieved partial response, complete response, or stable disease (Kwak EL, et al. N Engl J Med. 2010; 363:1693-1703). Dr Dorr said a followup analysis slotted for the 2011 American Society of Clinical Oncology meeting is expected to show the responses were fairly durable and is likely to report improvement in OS.

Crizotinib appears to be relatively safe, with most toxicities not surpassing grade 1. “The only grade 3 toxicities we are seeing are AST [aspartateaminotransferase] and ALT [alanine aminotransferase] elevations, and 80% of these patients could go down to 200 mg twice daily,” noted Dr 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.

Chronic Myeloid Leukemia
The pace of drug development in chronic myeloid leukemia (CML) does not appear to be slowing, and Dr Dorr said at its current rate, we would see “a nib a year” for this disease. Of the most promising investigational agents, bosutinib (SKI-606) is probably the furthest along. Like the currently approved tyrosine kinase inhibitors imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna), bosutinib is also ineffective in patients with the 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, showing complete responses and major molecular response in 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, Pfizer filed a new drug application with the FDA in the hopes that it might be approved as a secondor third-line agent, which Dr Dorr believes is likely.

Renal-Cell Carcinoma
Patients with renal-cell carcinoma refractory to sorafenib (Nexavar) could have a new option soon. A 2007 phase 2 trial of the oral drug axitinib, which Dr Dorr described as a “pure” inhibitor of vascular endothelial growth factor (VEGF) 1, 2, and 3, demonstrated a 44% overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, time to progression of 15.7 months, and median OS of 29.9 months.

A total of 62 heavily pretreated patients with refractory metastatic renal-cell carcinoma were enrolled in a single-arm trial of axitinib and found that the majority experienced partial response or standard deviation (Rini BI, et al. J Clin Oncol. 2009;27:4462- 4468).

“I think [renal-cell carcinoma] 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 Dr Dorr. Grade 3/4 adverse events included hand-foot syndrome, which he noted is a class effect of VEGF inhibitors.

Thyroid Cancer
A number of novel and marketed multikinase inhibitors that target RET signaling are being investigated in thyroid cancer, including motesanib, sorafenib, and XL-184. Dr Dorr said RETmutations appear to be a driver of medullary thyroid cancer.

At the meeting, vandetanib was introduced as furthest along in development and was correctly predicted to receive FDA approval soon after the meeting, which it did on April 6, 2011 (see page 4), for nonresectable and/or metastatic medullary thyroid cancer.

This agent inhibits VEGF receptor and epidermal growth factor receptor and has been the subject of approximately 23 clinical trials, including 10 unsuccessful studies in non–small-cell lung cancer. The partial response rate for patients with medullary thyroid cancer has been low, but submitted trial data showed a median progression- free survival (PFS) of 22.6 months for patients treated with vandetanib, compared with 16.4 months for patients taking placebo. Dose-limiting toxicities consist primarily of rash and diarrhea, which Dr Dorr said have been manageable with minor dose reductions.

BRAF Mutations
Drug developers have become increasingly interested in BRAF pathway mutations. Constitutively active BRAFV600E mutations are found in 60% of patients with melanoma, 40% with papillary thyroid cancer, 30% with serous ovarian cancer, 10% with colorectal cancer, and 10% with prostate cancer. “BRAF is not believed to be an initiating mutation. It’s believed to be a propagating mutation, which makes it a much better target for therapy,” Dr Dorr explained.

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 partial or complete response and that 81% of patients had 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.

In a January 2011 press release, the manufacturer of 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,” Dr Dorr noted.

Another BRAF inhibitor under investigation for advanced melanoma is GSK2118436, which shrank tumors anywhere from 20% to 100% in 9 of 10 patients, according to data presented at the 2010 annual meeting of the European Society of Medical Oncology. Multiple metastatic sites also demonstrated response, including metastases of the central nervous system. Adverse effects were modest, consisting primarily of fatigue, pyrexia, and dehydration.

Multiple Myeloma
Dr Dorr discussed some agents progressing down the multiple myeloma drug pipeline. Carfilzomib is a new 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 last year at the American Society of Hematology indicated that it was highly active in patients with heavily pretreated disease.

They reported an overall response rate of 62%, and Dr Dorr said 24% of partial responses fell into the “very good” category. One third of patients experienced neutropenia ≥grade 3, which might be something to watch for in future analyses.

Pancreatic Cancer
Dr Dorr briefly reviewed a handful of additional investigational agents at earlier stages of development. Ganitumumab (AMG479) was given with gemcitabine in a phase 2 trial of patients with metastatic pancreatic cancer. The 1-year OS rate was 40% compared with 20% for gemcitabine plus conatumumab and 23% for gem – citabine monotherapy, and the drug was “very well tolerated.”

Advanced Solid Tumors
BMK120 is an oral pan-class 1 PI3K inhibitor in trials for patients with advanced solid tumors. An early phase study that accrued 15 patients found a 50% to 80% rate of down regulation of pS6 and an 80% response rate (8 of 10 patients evaluable).

Going back to PARP inhibitors, Dr Dorr said although they have not done well in breast cancer in the past year, some are optimistic about preliminary data last year that showed activity with oliparib in serous ovarian cancer.

Dr 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,” Dr Dorr said, but with more than 500 protein kinases identified in humans, a tremendous amount of room remains for future discovery.