Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘RCC’ category

There’s been another disturbance in the force – as luck would have it, after mentioning renal cell carcinoma (RCC) in yesterday’s post, BMS subsequently put out a press release on the CheckMate–214 study exploring the combination of nivolumab plus ipilimumab in the previously untreated metastatic setting.

The results to date were mixed, so what does this mean and what’s impacted by the findings?

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Today for the second AACR 2017 Preview, I wanted to switch things up a bit and turn from looking at an important trend to a specific tumour type. One of the reasons for this is that we received questions from readers about recent data presented at medical meetings in this sphere.

It’s also not something that we have covered extensively here on BSB, so looking at something in a different light is often a good idea since insights and intelligence can sometimes jump out afresh.

Given that there are also some important clinical trial results emerging here, this is something we can expect to return to in Washington DC when the data is presented at AACR next month. What can we learn ahead of the event though? It turns out the answer is quite a lot.

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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?

Screenshot 2015-03-23 12.44.32Recently, 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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In her ASCO Gastrointestinal Cancer symposium (ASCO GI) keynote presentation earlier this year, Elizabeth M. Jaffee MD described the future of immunotherapy as being in combinations.

Overcoming or delaying resistance mechanisms or hitting multiple targets to greater effect will be achieved through combinations of drugs rather than single agent therapy. Combination strategies are the accepted future, whether drug companies like it or not.

In her keynote, Dr Jaffee also likened the revolution in immunotherapy to the same excitement the Beatles brought to music or the same magnitude of technology advances made by Apple. We agree completely.

Thought leaders at ASCO expressed similar sentiments. Steven O’Day (UCLA) said,

This is truly a brave new world of immunotherapy. I think the message is that the revolution is here, it’s ongoing, and it’s bursting out of melanoma into solid tumors.”

Interestingly, no immunotherapy data was considered to be of worthy of presentation in the plenary session at ASCO this year for the second year running, a decision that may reflect either an unwillingness to showcase early data, however good it may appear to be, or the influence of politics on the selection committee.

One potential combination is to target more than one checkpoint pathway to see if you can obtain a synergistic response. This is the rational for combining the monoclonal antibody ipilimumab and nivolumab. Ipilimumab (Yervoy) targets the CTLA-4 checkpoint protein that prevents dendritic cells from priming T cells to recognize tumors while nivolumab targets the PD-1 checkpoint protein that prevents T cells from attacking cancer cells. Yervoy is an FDA approved therapy for the treatment of metastatic melanoma.

Data published last year in The New England Journal of Medicine by Wolchok et al, showed that combining ‘ipi’ with ‘nivo’ gave more frequent and deeper responses in melanoma, but at the expense of much greater toxicity. Some 53% of patients receiving concurrent treatment had a grade 3-4 adverse event (see Table S-1B in the article).

Does it make sense to combine two immune pathway modulating agents? Does the enormous potential for synergy outweigh the additional toxicity? 

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We’ve been hearing and writing about a substantial amount of news and information on various immuno-oncology developments over the last year, especially in metastatic melanoma and lung cancer, but despite renal cell cancer (RCC) being a proven immune-sensitive disease with known PD-L1 expression, it seems to be the poor cousin to the other two tumour types given the lag in data and relative media attention.

There’s actually quite a lot going on in this disease though, from biomarker work to phase I to III trials that are either ongoing or just started accruing.

We should be hearing much more about the role of anti-PD–1 and PD-L1 antibodies in RCC over the next couple of years, including data from some large randomised controlled trials, but what’s the current state of play?

With that in mind, I was delighted to catch up with David McDermott’s (DFCI) in-depth presentation at ASCO GU in San Francisco over the weekend.  It’s always unfortunate when an interesting talk is left for the final presentation on the last day of a conference, as only a few diehards will be there to catch it!  It was a well thought out discussion though and he covered a lot of interesting ground in this space.

Agents mentioned:
ipilimumab, nivolumab, MK–3475, MPDL3280A, LAG–3, TIM–3, PD-L2, IL–2, sunitinib, everolimus, bevacizumab

Companies mentioned:
BMS, Roche/Genentech, Merck, GSK, Novartis, Pfizer

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