Today’s Science Friday post looks at the identification of a potential new biomarker and possible strategies for expanding use of PARP inhibitors in patients most likely to respond to them as a way to validate the the approach prospectively. This has important implications for future clinical trial designs with this class of drugs.
Photo Credit: Ben Sutherland via flickr
Regular readers will be very familiar at my rants against broad catch-all studies and phase III trials with targeted agents that do not have a biomarker or even a logical well defined subset of patients because it’s akin to blindfolding an archer, turning him around 360 degrees and then asking him to hit a bullseye 50 or 100 yards hence.
“RAF inhibitors (vemurafenib and dabrafenib) have profound clinical activity in patients with BRAF-mutant melanoma, but their therapeutic effects are limited by the emergence of drug resistance.”
Solit and Rosen (2014)
For today’s post on Science Fridays, I wanted to take a look at an overview paper, published in Cancer Discovery, from two researchers in the metastatic melanoma field who have been looking at multiple mechanisms of resistance. It’s an important topic because while we have seen incremental improvements in outcomes for this disease, the 5-year survival rate is still rather poor with only 10–20% of metastatic patients still alive by then. This is not to disparage the efforts of scientists, clinicians or companies working in this space, far from it, but there is is clearly a need for new therapies, strategies and combinations, given the high unmet medical need that exists.
At AACR last year, one of the most revealing presentations was on metastatic melanoma, specifically, some elegant research by Meghna Das Thakur (NIBR) demonstrating that intermittent pulsing of vemurafenib (a BRAF V600E inhibitor) led to less resistance than inhibiting the target 24/7.
Many of us wondered whether such a pulsing approach would be useful for other tyrosine kinase inhibitors (TKIs).
Fast forward to this week.
Neal Rosen’s lab at MSKCC has an interesting new paper out looking at the effects of pulse dosing with PI3K and ERK inhibition, since targeting both has long been suspected to be key in overcoming cross-resistance.
This is a preview of Will intermittent dosing transform TKI therapy in cancer research?. Read the full post
For as long as anyone can remember, humanity has wondered, “Why do we do things even when we know we should not?”
James Shelley, Caesura Letters
Akrasia is a rather common affliction in Pharma and Biotech. After all, why do so many companies fall into the deathly trap of running generic catch-all studies in heterogeneous cancers without an oncogenic target or validated biomarker? Or even specific, well defined subsets to improve the homogeneity ratio? Or perhaps they knowingly underpower a randomized trial for overall survival?
The list goes on…
This is a preview of Making a difference in NHL and CLL: an interview with Dr Carol Gallagher. Read the full post
This morning Medivation and Astellas announced the interim results of the PREVAIL trial in the pre-chemotherapy castrate resistant prostate cancer (CRPC) setting.
The independent data monitoring committee (IDMC) recommended stopping the trial early due to significant efficacy and unblinding the data.
Accordingly, the press release headline stated that:
“Study Will Be Stopped Early and Enzalutamide Will Be Offered to All Qualified Study Participants; 30% Reduction in the Risk of Death, Hazard Ratio=0.70 (p < 0.0001); 81% Reduction in the Risk of Radiographic Progression or Death, Hazard Ratio=0.19 (p < 0.0001.”
This is a preview of Medivation announce interim results of PREVAIL in pre-chemotherapy CRPC. Read the full post
There were a number of interesting posters at the AACR-NCI-EORTC Molecular Targets meeting today. Specifically, two on metastatic pancreatic cancer caught my eye. You can read about the other one on Millennium/Takeda’s ADC MLN0264 here.
This is an area of high unmet medical need with the fourth highest number of cancer deaths in the US and a median survival of 10 months or less. Even with improvements in the standard of care, it still remains a miserable cancer to get.
Many of you will be aware that KRAS is mutated in 90% of pancreatic cancer cases. As Dr Barry Nelkin (Johns Hopkins) noted today,
Someone in my Twitter stream kindly shared a link to an article this morning on how removing the PD-1 brake enhances the effect of chimeric antigen receptor (CAR) T cells in solid tumour models.
Whoa! Read that again and digest the implications.
We already know that the current leading immunotherapies, blocking PD-1/PD-L1 and adoptive therapy with CART, are rather effective in some cancers, but I’m willing to bet that few would have expected this effect, even though it makes a lot of sense when you actually sit down and think about it.
Certainly it gave me goosebumps reading the articles.
This is a preview of Removing the PD-1 brake enhances the effect on adoptive CAR T cells. Read the full post
Yesterday evening, Gilead announced that the Data Monitoring Committee (DMC) had recommended early stoppage of the 116 trial, which looks at idelalisib in relapsed/refractory disease in patients who are not eligible for chemotherapy. These patients usually have comorbidities or are elderly and frail, and often receive chlorambucil or rituximab alone. The study compared the combination of idelalisib plus rituximab versus rituximab alone.
Fortunately, the early stoppage was for a good reason – the interim analysis demonstrated a statistically significant improvement in PFS in favour of the combination over rituximab alone. Adverse events were consistent with previous experience of the drug.
A new NEJM article on KRAS and metastatic colorectal cancer (CRC) caught my eye last week. One of the challenges with this disease is the limited effectiveness of EGFR monoclonal antibodies such as cetuximab (Erbitux) and panitumumab (Vectibix).
However, science is very instructive sometimes, as Dr Berlin noted in his NEJM editorial last week:
“After the determination that activating mutations in exon 2 of the gene KRAS predicted the inefficacy of anti-EGFR antibodies, reanalyses of multiple trials suggested that these agents could be more effective when administered to a more limited cohort of patients.”
This is a preview of Update on KRAS and NRAS mutations in colorectal cancer. Read the full post