For what seems the longest time, we have seen the battle in metastatic clear cell renal cell carcinoma (ccRCC) being focused on various anti-VEGF TKIs, whether against interferon, mTOR inhibitors, and even each other.
Lately, anti-PD(L)1 antibodies have also come on the scene – both as monotherapy and in different combinations – so are things set to change?
Will it be plaining sailing or are there hidden dangers ahead for the unwary?
Here, we take a look at the ever evolving landscape in RCC and explore the issues and challenges surrounding some of the novel combination readouts, including a look at the role immuno-oncology might play going forward.
Not surprisingly, there’s a lot to consider, discuss and think about…
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Part 3 of our series on Gems from the Poster Halls at ESMO continues with a look at another four important combination studies that may be of keen interest to readers.
These include both targeted therapies as well as immunotherapies.
Some of the posters I was originally keen to write about turned out a little unexpectedly with some issues to address i.e. lack of efficacy or unwanted toxicities based on the dosing schedule used and may require tweaking of the dosing, schedule or trial design. Others will unfortunately be destined for dog drug heaven unless a new tumour type offers more promise. Such is the R&D roller coaster that is oncology – sometimes we forget that more compounds fail than make it market.
The good news is that there were plenty of promising approaches that are worthy of writing up and discussing. In the third part of our poster mini-series, we take another deeper dive with a careful look at some new data in Copenhagen.
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It’s Day 7 of our 12 day Countdown to AACR 2016 in New Orleans. After exploring GITR and OX40, we’re now looking at another stimulatory target for cancer immunotherapy: CD40.
We’ve been writing about CD40 as a cancer immunotherapy target for some time. See posts: “CD40 as a Cancer Immunotherapy Target” and “Targeting CD40 in Cancer Immunotherapy.”
Anti-CD40 antibodies are agonists that act on stimulatory signalling receptors on T cells and antigen presenting cells (APCs). Targeting CD40 effectively acts to “put the foot on the gas” and may help generate a better immune response. This could be important in cancers that have fewer natural T cells present.
CD40 is an attractive target because it’s expressed in more than 50% of carcinomas and melanomas and almost all hematological B cell malignancies. Of particular interest is the potential to combine a CD40 agonist with a PD-1/PD-L1 checkpoint inhibitor.
Multiple companies have CD40 agonists in clinical development including Roche, Apexigen, Alligator Biosciences and Seattle Genetics. There are others coming too.
In this preview of AACR 2016, we’re looking at the CD40 landscape. New products and companies have entered the scene, so we’re highlighting them and some of the CD40 presentations to look out for at AACR 2016 (and why they matter).
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Oncology R&D is tough and there are many more failures than successes, despite the FDA approving more than they’ve rejected over the last two years. That’s quite unusual in my experience.
As Dr Mario Sznol (Yale) told us at SITC recently, sometimes these things are sometimes more whimsical. He was referring to different types of modalities that can be used in conjunction with cancer immunotherapies, but the sentiment is also highly relevant to the FLT3 AML space.
The critical questions we need to think here about are:
- What’s different about the various approaches?
- What can we learn from the FLT3 experiences to date that give us clues about the changing landscape in AML?
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New developments in renal cell carcinoma
Continuing our focus on genitourinary (GU) cancers this week, today we turn our focus from prostate cancer to renal cell carcinoma (RCC).
There were two important announcments on Monday this week relating to renal carcinoma.
Firstly, Exelixis announced positive top line data from a phase 3 pivotal trial of cabozantinib versus everolimus in relapsed metastatic renal cell carcinoma (METEOR). The study met the primary endpoint (i.e. significantly improved progression free survival) and the company revealed the following data:
- Cabozantinib reduced the risk of disease progression or death by 42%; Hazard Ratio = 0.58, (p < 0.0001) compared to everolimus
- Interim Analysis of OS demonstrated a trend in favour of cabozantinib; Hazard Ratio = 0.67, (p = 0.005) compared to everolimus
- Exelixis to complete US and EU regulatory filings in early 2016
Secondly, a press release from BMS highlighted the phase 3 CHECKMATE–025 trial comparing nivolumab to everolimus, also in relapsed metastatic RCC, where the independent Data Monitoring Committee recommended early stoppage on the basis of the primary endpoint (OS) being met. The company likely be seeking discussions with Health Authorities with a view to filing the data with the FDA and EMA.
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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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