Until recently, we followed the race to market in EGFR T790M lung cancer with Clovis’s rociletinib and AstraZeneca’s osimertinib (Tagrisso). In phase 2, AstraZeneca caused quite a stir when they came from behind and leapfrogged their biotech rival with a large global randomized controlled trial seemingly out of nowhere. They never looked back.
Can they do the same thing with durvalumab (Imfinzi), one of their IO therapies that targets PD-L1?
If there’s one thing that many astute observers of the IO space have learned this week it’s that irrational exuberance and the hopeful sentiment that ‘everything’ will just tweak the immune system and work positively no matter what has thankfully come to an end.
We’ve seen several highs and lows already with Merck’s pembrolizumab gaining accelerated approval in 1L NSCLC in allcomers when combined with chemotherapy and AstraZeneca reporting positive phase 3 data for durvalumab in unresectable (stage 3) NSCLC based on meeting the study endpoint (PFS).
There is much to be learned because the nivolumab disaster in 1L NSCLC last year was not a singular aberration given that durvalumab has seen some missteps in the past and even atezolizumab had some unexpected news with urothelial cancer this week (Check out our insights), as compared to chemo in the second line setting. Just like mutations, there will be many more to come, perhaps even some additional ones before the year is out.
What about today’s news from AstraZeneca in unresectable NSCLC?
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On Friday last week, AstraZeneca confirmed that their combination trial for osimertinib, as it’s expected to be called or AZD9291, as it’s more commonly known (anti-EGFR mutant, T790M inhibitor) plus durvalumab (MEDI–4736, anti-PD-L1) in non-small cell lung cancer (NSCLC) is on clinical hold following an increase in ‘interstitial lung disease-like reports.’
As companies with checkpoint inhibitors and other immunotherapy agents expand beyond monotherapy into logical combinations, is the risk of increased ILD from combining an EGFR inhibitor with a checkpoint something other companies need to watch out for?
By the way, we strongly disagree with the reported conclusion of Goldman Sachs on this issue – and here’s why…
Today’s article explores this controversial issue in more depth.
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Last month’s Biotech Strategy mailbag – where we answer questions from subscribers – turned out to be rather controversial with strong feelings running in several camps on Puma Biotech’s neratinib in breast cancer.
This time around we have a bunch of questions on completely different topics and compounds to cover:
- BRAF plus MEK and/or immunotherapy in BRAFV600 metastatic melanoma
- Immunogen’s IMGN853 – now known as mirvetuximab soravtansine – in platinum resistant ovarian cancer
- AbbVie/Genentech’s ABT–199/GDC–0199 venetoclax
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There can be no doubt that immuno-oncology is a hot topic in cancer research of late with checkpoint inhibitors, immune agonists, immunocytokines, CAR T cells, TILs, TCRs, not forgetting innate immunotherapies. We’ve written extensively about many of these topics, but what about the companies behind them and their strategies?
One thing subscribers tell us they love reading about here on BSB is not only fireside chats with thought leaders, but also interviews behind the scenes with company personnel, be scientists, clinicians or CSOs.
Recently, we’ve posted some interviews with Roche and Genentech scientists/physicians about their IO platform that were well received. Today, it’s the turn of AstraZeneca and MedImmune, who are also developing checkpoint inhibitors and immune agonists against various cancers.
With the anti-PD1 antibodies i.e. Merck’s pembrlizumab (Keytruda) and BMS’s nivolumab (Opdivo) already approved by the FDA, and Roche/Genentech’s atezolizmuab well on the way to filing in advanced urothelial bladder cancer with the announcement this week that the IMvigor 210 trial in relapsed/refractory disease met its primary endpoint, the big question now remains is what’s happening with the fourth element of the quartet? How well is progress coming along there and what is the main focus we can expect in the near future?
Like most Brits, when AstraZeneca noted back in 2013 that they expect to establish their global R&D hub in Cambridge, I assumed they meant in the Golden Triangle and not Massachusetts. This is a burgeoning area for European biotech research, which is somewhat ironic after the KuDos scientists working on olaparib (Lynparza) moved to Alderley Park in Cheshire with the acquisition and will likely face moving back again!
At ASCO, we had the pleasure of a chat with Dr Rob Iannone, the head of the AstraZeneca Immuno-oncology development program. The company also published a number of interesting abstracts and posters that were on show in Chicago, as well as a burgeoning pipeline in this area beyond their lead compounds, the anti-PDL1 inhibitor, durvalumab (MEDI4736) and tremelimumab (anti-CTLA4).
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We’ve heard a lot about agents that target the PD–1/PD-L1 pathway over the last two years, in particular, from:
- Nivolumab (BMS)
- Pembrolizumab (Merck)
- Atezolizumab (Roche/Genentech)
- MEDI–4736 (AstraZeneca/MedImmune)
What about other agents against this pathway that are in earlier development? It really doesn’t take long for a new space to become quickly crowded and very competitive, as the Pharma R&D machines start cranking out results from clinical trials.
A critical question that will to be considered is how will the third, fourth or even 19th agent to market differentiate themselves from those already approved and established? Is it realistic to expect a blue ocean strategy approach or will the pieces of the pie become ever smaller?
At the annual meeting of the American Society of Clinical Oncology (ASCO) earlier this month, there was new data presented from other companies on checkpoint inhibition. We took at look at some of the emerging data in more detail.
To learn more about the increasingly competitive anti-PD1/PDL1 pathway market, check out our insights in the mini report below.
We know from preclinical research that immunosuppressive tumour microenvironments can restrain anti-tumour immunity, thereby making subsequent therapeutic interventions less effective than expected. CD40 activation has been shown to reverse immune suppression and drive antitumor T cell responses, which in turn could lead to potentially better outcomes.
What happens when patients with advanced melanoma are given a checkpoint inhibitor plus an immune agonist such as anti-CD40?
Can we help the non-responding patients to checkpoint blockade improve their outcomes and shift the long tail in survival curves up using this approach?
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At the last count, the renal cell carcinoma (RCC) space is quite competitive with five VEGF inhibitors (sunitinib, sorafenib, axitinib, pazopanib and bevacizumab), two mTOR blockers (temsirolimus and everolimus) and not forgetting IL–2, all approved by the FDA for the treatment of advanced disease.
Much of the recent focus has been on sequencing, exploring combinations (generally too toxic with little added benefit), and evaluating the potential for novel immunotherapies in development such as checkpoint inhibitors. Biomarkers are few and far between, making it hard to rationally decide which therapy each patient should get and in which sequence.
The key question is, why is this tumour type so challenging from a clinical and scientific perspective?
Recently, new data has begun to emerge that may help inform or enable us to switch to new approaches. While the urologists are eagerly watching the live surgery on the EAU cam, we highlight research data presented at the European Association of Urology (EAU) in Madrid and take a look at how the underlying biology of RCC can elevate our knowledge about where the potential future strategies and blueprint might lie, if we want to facilitate exciting new developments in this field.
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