Updated data are often presented at conferences and therefore the results can differ from the submitted abstracts, which are sometimes submitted as placeholders based on immature data cutoffs. That was certainly the case in several examples at the ASCO GI conference in San Francisco last weekend.
After Monday’s look at new developments in the lower GI tract, we now turn our attention today to the upper GI tract with a focus on oesophageal, gastric (stomach), and gastro-esophageal junction (GEJ) cancers.
Over the last five years we have seen new approvals for targeted therapies such as HER2+ gastric cancer and relapsed refarctory gastric cancers with a VEGF inhibitor. Will that trend continue over the next five years or will we see new approaches such as immunotherapy enter the market and dominate?
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One of the obvious learnings from the American Association of Clinical Research (AACR) meeting earlier this week was that we are coming to the end of the low hanging fruit opportunities for checkpoint inhibitors as monotherapies.
Speaking with numerous company people in this space, there was wide consensus on that point. As one clinical lead put it succinctly, “From here on out, it’s going to get way more complicated – had a low grade headache develop after the very first science session I attended – and it’s still there after two days!”
How many of us know that feeling all too well? AACR always has the heaviest science load of any cancer conference we attend each year. Sure there’s some nice clinical data, but that is like nibbling on the light appetizers before the 20 course banquet. You need much stamina and fortitude to survive the brain fog at AACR. Then there’s the glee at snagging some key poster handouts at the meeting, only to be rapidly diminished when you try to read the 4pt print post hoc and realise your eyes cannot focus easily.
Looking at the long list of topics I want to cover in the in-depth post meeting analysis for a ‘lighter’ post, especially given that it’s Friday after a very long week, that sinking feeling hit home hard – there are no lightweight topics at AACR.
The other day, we posted about the promising data in triple negative breast cancer (TNBC), following on from the Genentech and Merck presentations at the San Antonio Breast Cancer Symposium (SABCS). These data surprised many folks, mostly because they didn’t consider breast cancer to be an immunogenic tumour – nor is lung cancer in the broader scheme of things for that matter – yet we are seeing some nice durable responses in both tumour types with checkpoint inhibitors.
In other words, our definition and perceptions must change as we redefine how we identify and think of possible ‘responsive’ cancers to these agents.
So where are likely heading next?
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Quick Reminder: Today is the last day for the AACR Special – the discount ends at midnight ET tonight. We may not offer this rate again as it’s a limited time only deal!
The metastatic colorectal cancer landscape is slowly changing after decades of multiple chemotherapies followed by the addition of biologics to the base chemo regimen including VEGF (bevacizumab, z-aflibercept, regorafenib) and EGFR inhibitors (cetuximab and panitimumab).
Each of these approvals have led to an incremental improvement in outcomes in different lines of therapy (LOT), but sadly with only one clinically meaningful biomarker identified (KRAS exon 2 mutant vs. wild type for EGFR inhibitors). We still don’t have a more comprehensive way to better select the likely responders from non-responders.
Progress, you might think, has been painfully slow, although the current data suggests that we have now reached a new plateau of around 30 months in overall survival. That’s going to be hard for new entrants to beat without some form of different paradigm shift.
There is only so much that can be achieved with the current strategies. You only have to look at second line VEGF inhibitors to see this incremental effect on survival:
- Bevacizumab – 1.4 months
- z-Aflibercept – 1.5 months
- Ramucirumab – 1.6 months
Overall, we can say that none of them add 2 extra months of life in that setting (never mind the cumulative cost or ‘financial toxicity’ as many attendees referred to it) and you might even consider the benefit to be fairly marginal. No biomarker has yet been identified for any of these therapies, making it impossible to select upfront those who are most likely to respond.
At the ASCO Gastrointestinal Cancers Symposium (ASCO GI) last week, we saw a repeat of the usual studies looking at new VEGF inhibitors (e.g. ramucirumab in the 2L RAISE study) and an update on the TRIBE trial (FOLFOXIRI vs FOLFIRI when either are combined with bevacizumab/Avastin).
Are there other targets that might have a meaningful impact though? If we truly want to see a more precision medicine approach evolve then we have to first find the oncogenic drivers.
With this in mind, one study in particular caught my eye and attention, but you won’t find it written up in the medical lay press and it’s not that obvious unless you know what you’re looking for.
Interested readers can sign up or sign in to learn more about this novel concept in advanced colorectal cancer below. This could be the start of a new era of research for this disease.
Adenocarcinoma associated with gastric (stomach) cancer is more common in Asian than North America people and tends to occur in men over 40. Risk factors include smoking, H. pylori, and diet. Asian countries also tend to have larger amounts of smoked foods, salted fish and meat, and pickled vegetables in their diet. Nitrates and nitrites are substances commonly found in cured meats and can be converted by bacteria, such as H. pylori, into compounds that have been shown to cause stomach cancer in animals.
According to the NIH cancer statistics, it was estimated that there would be approximately 22,000 new cases in the US in 2014 and 11,000 deaths.
Treatment of advanced gastric cancer typically involves chemotherapy, or in cases where the patient is HER2+, with the monoclonal antibody, trastuzumab (Herceptin).
Numerous trials with EGFR inhibitors and also multi-kinase blockers have unfortunately proven fruitless and largely negative, with the exception of ramucirumab (Cyramza), a VEGF antibody, which was approved earlier this year for the treatment of both gastric and gastroesophageal junction adenocarcinoma by the FDA.
At the recent ESMO conference in Madrid, initial results from several early studies were presented on gastric cancer, with vastly different results. In this post, we take a deeper look at the new data, including the novel checkpoint inhibitors, and where R&D might be heading in this dynamic space.
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One of the interesting new developments at AACR was the return of FGFR inhibitors with more enthusiasm and encouraging data compared to the past. Recall that previous small molecule inhibitors such as brivanib (BMS) and dovitinib (Novartis) didn’t fare particularly well, despite a multitude of clinical trials in different tumour types where FGFR was thought to matter.
This begs several key questions:
- Does the target matter to the tumour?
- Do we have enough therapeutic index to shut down the pathway?
- Is it better to be a specific or a pan-FGFR inhibitor?
- Does having multi-kinase effects offer off-target adverse events to the detriment of efficacy?
- Do we need an antibody or an ADC rather than a small molecule to improve potency?
And many other questions that cannot be addressed or answered on the basis of two chemical entities.
Interestingly, and perhaps even surprisingly, new data emerged in San Diego that might help us answer some of these questions.
In this review, a number of anti-FGFR compounds are mentioned including brivanib (BMS), dovitinib (Novartis), lenvatinib (Eisai), ponatinib (Ariad), BGJ398 (Novartis) and BAY 1179470 (Bayer).
Here, we take a particular focus on promising new FGFR compounds with new data at AACR from Novartis (BGJ398) and Bayer (BAY 1179470, BAY 1163877, FGFR2-ADC).
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Cancer immunotherapy was described in the December 20, 2013 issue of Science magazine as their Breakthrough of the Year, but really, we are just scratching the surface of what can be achieved.
“We are at beginning of a REVOLUTION in immunotherapy,” said Elizabeth M. Jaffee, MD at the start of American Society of Clinical Oncology GastroIntestinal (ASCO GI) symposium keynote lecture on Immunologic Treatments for GI Cancers.
Elizabeth M Jaffee, MD
Jaffee likened the revolution in immunotherapy to the same excitement the Beatles brought to music, or the same magnitude of technology advances made by Apple.
Dr Jaffee is the Dana and Albert “Cubby” Broccoli Professor of Oncology at Johns Hopkins, and has developed a number of vaccines including GVAX, which is currently licensed to Aduro Biotech.
Subscribers to Premium Content can login to read more about Dr Jaffee’s keynote lecture at ASCO GI.
The 2014 ASCO Gastrointestinal (GI) Cancer Symposium takes place in San Francisco from Jan 16-18 and is the second meeting in this year’s oncology conference calendar. GI cancers include oesophageal, gastric, colorectal and pancreatic cancers, as well as hepatocarcinoma or HCC (liver).
You can follow any tweets from ASCO GI using the hashtag #GI14.
This year, the topics that most caught my eye in the program were pancreatic and gastric cancers.
This post provides insights on the key studies that looked interesting to me at this event, based on the schedule available. The abstracts will be available on January 14th and can be accessed here.
Companies mentioned: Celgene, Lilly, Roche/Genentech, Aduro Biotech
Drugs mentioned: Abraxane, Gemzar, ramucirumab, Avastin, Herceptin, GVAX