Amgen Inc. is absorbing another late-stage oncology failure as the phase III GAMMA study of the monoclonal antibody ganitumab, also known as AMG 479, comes to a close in pancreatic cancer.
On the recommendation of a data safety and monitoring committee assessing a preplanned interim analysis, the trial will be terminated for lack of efficacy, Amgen said Aug. 8.
The GAMMA study tested ganitumab against placebo, with a gemcitabine (Gemzar) backbone, as a first-line treatment for metastatic adenocarcinoma of the pancreas. According to the committee, the drug was unlikely to demonstrate a statistically significant improvement in the primary end point of overall survival, compared with gemcitabine alone. No safety concerns were raised in the review.
The company says it is reviewing all ongoing clinical studies of the monoclonal antibody ganitumab – a member of the troubled class of insulinlike growth factor-I receptor (IGF-IR) inhibitors – and "determining next steps."
IGF-IR is important for cell proliferation and survival and is overexpressed in many tumor types. The IGF-IR pathway also is related to resistance to a range of treatments, including chemotherapy and targeted therapies. But it has proven to be a tough target.
One of Amgen’s very few phase III oncology programs left standing, ganitumab has been among the pipeline candidates representing the company’s goal of addressing unmet medical needs.
Ganitumab has been positioned for a number of diseases including pancreatic cancer, the indication that was in the most advanced stage of development. In addition to the GAMMA study, a phase II study in locally advanced pancreatic cancer will be halted, Amgen said. Ganitumab also had already shown no benefit and a trend toward harm in a second-line breast cancer trial.
Research continues in extensive stage small-cell lung cancer and KRAS wild-type metastatic colorectal cancer, Amgen confirmed. However, the company said that in light of the results, it is "taking the time to evaluate all of our clinical programs with 479."
IGF-IR Drug Trials Stack Up Failures
Drugs targeting IGF-IR were all the rage in 2009 but a number of trials have not panned out, so ganitumab was viewed as a long-shot, wild-card candidate, Dr. Karen Andersen of Morningstar Research noted in an interview.
Perhaps the most notorious failure was Pfizer’s monoclonal antibody figitumumab, which in late 2009 blew up in phase III for non–small cell lung cancer (NSCLC); one pivotal study was terminated early by a data safety monitoring committee because there were more deaths in the treatment arm vs. control. Roche’s R1507 failed to show a benefit when paired with erlotinib (Tarceva) in NSCLC, compared with erlotinib alone.
Eli Lilly’s monoclonal antibody cixutumumab (IMC-A12), one of three key mid-stage candidates picked up in the ImClone Systems acquisition, has had mixed results in phase II and has not progressed to phase III. The drug is still being evaluated in an "extensive list" of phase I and phase II trials in adult and pediatric settings by ImClone itself and in collaboration with the National Cancer Institute, Lilly says. Citing concerns about the "competitive landscape," Lilly declined to confirm its priorities in terms of lead indications or timing of development.
Others in the class that have been discontinued include Sanofi’s AVE1642, Schering’s Sch717454, and Biogen Idec’s BIIB-022.
In an Aug. 9 note after the ganitumab news, analyst Dr. Alex To of Cross Current Research pointed out that IGF-IR drugs, including the molecules from Pfizer and Lilly, have failed in randomized studies despite initially promising results. "This class of drug may be increasing production of growth hormone and the tumor cells’ expressing more receptors for insulin and growth hormone. Consequently, the tumor grows faster," Dr. To wrote. "In some cases, the drug may even promote cancer growth after longer-term exposure."
Reported clinical trials have "raised serious concerns" about IGF-IR inhibition as an effective cancer treatment, but in some ways, the concerns are "not completely fair," Dr. Douglas Yee of the University of Minnesota and director of the Masonic Cancer Center, both in Minneapolis, wrote in a commentary in the Journal of the National Cancer Institute (2012;104:975-81 [doi: 10.1093/jnci/djs258]). Meaningful single-agent, long-term responses have been documented in patient subsets.
Predictive biomarker analysis is "desperately needed" to improve patient selection and different approaches to IGF-IR inhibition, such as with tyrosine kinase inhibitors as opposed to monoclonal antibodies, might avoid some of the problems seen in trials, he said.
Late-Stage Cancer Pipeline Looks Sparse
Following the IGF-IR/pancreatic trial failure, Amgen’s late-stage oncology pipeline is now looking even sparser. Motesanib, partnered with Takeda, failed to meet the overall survival end point in the pivotal MONET1 study of advanced nonsquamous NSCLC, the companies announced in March 2011. Amgen’s annual report for 2011 notes that "the parties continue to further analyze data to explore potential opportunities for additional development in first-line NSCLC."