#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma
Jun29

#ASCO12 Data Digest: Overcoming Resistance in Metastatic Melanoma

The following is a guest post from Sally Church (known to many in the twittersphere as @MaverickNY), from the Pharma Strategy Blog. Not long ago, metastatic melanoma was considered a graveyard for clinical research. But last year brought a major breakthrough in treating skin cancer: the approval of Roche’s Zelboraf (vemurafenib), a small molecule that has proven highly effective at treating the roughly 50% of the patient population that carry the BRAFV600E mutation. However, Zelboraf has limitations. Patients’ disease eventually becomes resistant to the drug and the lesions caused by the skin cancer tend to return after 6 to 9 months. At the American Society of Clinical Oncology (ASCO) meeting earlier this month, the big two questions on cancer specialists’ minds were: what are the mechanisms of resistance and how can we develop strategies to overcome them? An amazing thing about current melanoma research is that several physician-scientists involved in the clinical trials are also actively involved in translational research--this is sadly the exception rather than the rule, in oncology. But the connection between basic science and bedside has meant new targets are being identified and quickly tested in the clinic. One potential target recently discovered was MEK, a kinase that sits along the same signaling pathway as BRAF. When BRAF activity is turned off by Zelboraf, cancer finds a way to compensate for the loss by exploiting other kinases in the pathway. Researchers think that by combining a BRAF inhibitor with a MEK inhibitor, the pathway might be more comprehensively shut down than by either alone. Consequently, there was a tremendous amount of buzz around a melanoma trial that looked at combining a BRAF inhibitor, GSK2118436 (dabrafenib), and a MEK 1/2 inhibitor, GSK1120212 (trametinib). Previous studies have shown that given alone, dabrafenib could result in solid response rates of 59%; trametinib, meanwhile, produced a 25% response rate when given as a single agent. Jeffrey Weber from Moffitt Cancer Center in Tampa presented the results of the complex phase I/II study, which included melanoma patients with either the BRAFV600 E or K mutation who had not undergone treatment of any kind. The hope was that by suppressing the MAP kinase-dependent resistance mechanisms, patients would enjoy three kinds of improvements over current treatment: 1) Improved progression-free survival (PFS), response rate, and survival 2) Prolonged duration of response 3) Decreased incidence of BRAFi-induced proliferative skin lesions An impressive waterfall plot of tumor shrinkage for patients (n=77) with the BRAFV600K mutation drew gasps from the audience - only four patients failed to respond to the combination, while the majority had a response of 30% or better. This isn't something you see every...

Read More
Genentech Says Experimental Cancer Combo is Safe
Apr05

Genentech Says Experimental Cancer Combo is Safe

Genentech this week unveiled promising results from a Phase I study suggesting it is possible to safely combine two cancer drug candidates, its MEK inhibitor GDC0973 and its PI3K inhibitor GDC0941. In addition to a relatively clean safety profile, there were also early signs that the combination is combating cancer. Genentech is one of several companies running a trial to test the safety of combining inhibitors of the lipid kinase PI3K, part of the PI3K/AKT/mTor pathway, and drugs blocking the protein kinase MEK, part of the KRas/MAP signalling pathway. As we discuss in our upcoming April 11th cover story on PI3K inhibitors, the rationale for knocking down both pathways  is compelling: both are considered to be crucial in cancer cells’ survival, and blocking only one pathway has more often than not proven ineffective. As Robert Abraham, CSO of Pfizer’s oncology research unit, explains in Monday’s story: “KRas mutations are associated with many of the deadliest cancers,” including colorectal and pancreatic, Pfizer’s Abraham says. Yet they are incredibly resistant to conventional chemotherapy, and based on preclinical studies of the mutations, are expected to be resistant to the new batch of mTor/PI3K inhibitors as well, he adds. The working hypothesis is that knocking out two of the major drivers of cancer—the KRas and PI3K pathways—could have a significant effect on the most recalcitrant tumors. To date, there are at least six Phase I trials planned or ongoing that combine MEK inhibitors with compounds that block some aspect of the mTor/PI3K pathway. Merck and AstraZeneca made headlines in 2009 when they said they would partner to test Merck’s AKT inhibitor with AstraZeneca’s MEK inhibitor. Sanofi-Aventis has meanwhile teamed with Merck Serono to explore the potential of combining two of its PI3K inhibitors in combination with Merck Serono’s MEK inhibitor. GlaxoSmithKline has two of its own drugs in a combination trial, and its MEK inhibitor GSK1120212 is also being tested in combination with Novartis’ PI3K inhibitor BKM120. And while Pfizer has yet to initiate such a study, Abraham said the company is “keeping two eyes on that combination.” We go into much more detail in Monday’s cover story about the efforts to match PI3K inhibitors with other drugs, and the rationale behind different flavors of compounds (mTor/PI3K inhibitors vs. pan-PI3K inhibitors vs. single-isoform inhibitors). Stay...

Read More