Biotech Strategy Blog

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

Posts tagged ‘MPDL3280A’

Philadelphia – at the 2015 annual meeting of the American Association for Cancer Research (AACR), new data was presented that showed checkpoint inhibitors have a greater effect when they work in combination, they may also offer a new effective treatment option in Triple Negative Breast Cancer (TNBC).

Are two checkpoints are better than one?

At AACR 2015, F. Stephen Hodi MD (Dana-Farber Cancer Institute) presented results, published simultaneously in the New England Journal of Medicine, that showed in advanced melanoma, combining two checkpoint inhibitors (nivolumab and ipilimumab) showed better results than with one alone (ipilumumab). The authors in their NEJM paper conclude:

The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile.

What is the potential for checkpoint inhibition in TNBC?

Yesterday at AACR, Leisha S. Emens MD, PhD (Johns Hopkins) presented the results in TNBC from a phase 1 trial of MPDL3280A (Roche/Genentech), a checkpoint inhibitor that targets the PD-L1/PD-1 signaling pathway.

Dr Emens (right) is shown in the picture below presenting at an AACR media briefing moderated by Louis M. Weiner MD, Dr Hodi is pictured left.

AACR 2015 Press Briefing

The only currently available treatment for TNBC is chemotherapy, but sadly patients often do not live long, and rapidly progress. Progression-free survival (PFS) is estimated to be around 4 months in TNBC. This means there is a real unmet medical need for effective new treatments. The fact that cancer immunotherapy, and in particularly checkpoint inhibitors targeting the PD-L1/PD-1 signaling pathway may have potential in this disease is huge.

Cancer immunotherapy and in particular checkpoint inhibitors are a hot topic at AACR. In this post we look in more detail at the data presented.

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Today I’m answering recent questions from readers, in this case on checkpoint inhibition and where this field is going in the near future.

No doubt we can expect to hear a lot of new data and research being presented at the upcoming AACR and ASCO conferences, so this is a timely point to reflect on a few topics of relevance.

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It’s time to answer some more subscriber questions. Several readers wrote in and asked about the anti-PD1 checkpoint data that was presented at the recent American Society of Hematology (ASH) meeting in classic Hodgkin’s lymphoma (cHL):

What did we think of it?

Well, for starters it was one of our highlights of the ASH 2014 conference (see quick write-up, open access), with an impressive 87% response rate for nivolumab in refractory cHL. Many of these patients had failed both autologous stem cell transplant and brentuximab (Adcetris), for which FDA granted breakthrough therapy designation.

ASH14 CHECKPOINTSOverall, I agreed with Ron Levy (Stanford) when he noted in the packed Special Session on Checkpoint inhibitors in Hematology that there were only 4 or 5 abstracts to actually discuss (he didn’t spend much time on the preliminary data) and that the results are still very early without seeing how good the durability will be.

As he observed in the session, which was standing room only, figuring out how best to integrate these new agents into clinical practice with other successful approaches will be most interesting.

That said, there are some new data that have emerged since ASH that are worthy of discussion in terms of potential future directions and how they could impact the checkpoint landscape in both hematologic malignancies and even solid tumours.

This is part of our ongoing immuno-oncology series on how we can manipulate T cells in creative ways to kill the cancer cells.  The findings discussed in this article are completely new and have not been discussed here before.

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It’s now time to turn our attention to genitourinary oncology and, in particular, prostate, renal and urothelial bladder cancers. This week brings this ASCO GU meeting (#GU15), which is being held in Orlando this year and began this morning.

There are quite a few interesting topics being covered here, particularly in the poster sessions over the next three days. Hopefully, 2015 will also bring more good news in this space as 2014 was a rather dismal one on several fronts!

We decided to highlight some of the most interesting abstracts on castrate resistant prostate cancer and urothelial bladder cancer in our latest conference preview.

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Our latest European Society of Medical Oncology (ESMO) 2014 conference preview takes a look at some of the key immunotherapy sessions and presentations that look interesting in Madrid.

Based on a detailed look at the online program, some abstracts are clearly a re-hash of the ASCO data for a European audience, yet there are clearly some new topics and data being presented too.

As companies begin to ramp up development with data emerging from phase I to III trials across a gamut of different tumour types, things start to get very interesting indeed.  Let’s not also forget the importance of science and translational work, particularly in understanding the tumour microenvironment and how the immune system can impact that in many ways.

Companies mentioned: BMS, Merck, Roche/Genentech, Biothera
Drugs mentioned: ipilimumab, nivolumab, pembrolizumab, MPDL3280A, Imprime PGG

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Over the last few days, we’ve covered data from the leading checkpoint inhibitors from BMS, Merck and Roche, but what about other agents in development in immuno-oncology? One of the companies that burst on the scene in Chicago at ASCO 2014 with solid data was AstraZeneca with their anti-PD-L1, MEDI4736.

To put progress in context, last year Merck had one single abstract for MK–3475 (pembrolizumab), whereas this year MEDI4736 debuted with 7 abstracts, including several Trials in Progress posters in combination with their anti-CTLA4, tremelimumab, plus some important oral presentations too.

The last morning of the final day of the ASCO conference has not exactly been well attended in past years, especially in Developmental Therapeutics. This year was different – the large hall was jam packed and it was standing room only. I was lucky to get one of the last seats in the front row a good 15–20 mins early!

As we were waiting for the proceedings to start, the Japanese doctor sitting next to me turned and said:

“What do you think of this compound? I’m not expecting much, and they are behind the others already!”

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One of the most exciting presentations that I heard at ASCO 2014 – the sort that give you goosebumps and elicit a wow from people sitting next to you – was not in the plenary or even a tumour type oral session, but a clinical science symposium.

The subject? Bladder cancer.

The situation? Phase I clinical trial.

The therapy? Anti-PD-L1 therapy with MPDL3280A.

Prof Thomas Powles, Barts Cancer Institute, London

Prof Thomas Powles, Barts Cancer Institute, London

As the presenter, Prof Thomas Powles (Barts), dryly observed to the packed auditorium, it made a welcome change from the ten people who usually show up for bladder cancer sessions! After all, there have been no new approved therapies for this disease for some thirty years.

It wouldn’t have been out of place in the Plenary session, frankly.

By the time the ASCO selection committees cotton on to the fact what many of us know – that immuno-oncology is not only hot, but here to stay and actually changing the way we think about and treat some advanced cancers – some of these new checkpoint inhibitors will already be approved by the FDA.  As one thought leader grumpily said to me:

“It’s not something they understand, nor does it involve the traditional things like breast or prostate cancers, plus it’s all political anyway.”

Ouch. Still, there was a lot to learn from this data, not just in terms of the results in an area of high unmet medical need, but also in our understanding of the immune system and where some future opportunities lie.

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Today I thought it would be a good idea to answer a question sent in by a premium subscriber.  He asked,

“What’s the deal with TIL and how does that relate to checkpoint inhibitors and PD-L1 expression?”

This is a good question and there were some interesting top-line debates about this at AACR recently, which are well worth discussing and highlighting.

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In the second part of our mini-series on immuno-oncology, I thought it would be a nice idea to share a recent interview conducted with one of Roche/Genentech’s leading researchers in this field.  I was particularly interested in their approach because while BMS and Merck have clearly focused on anti-PD-1, Roche and Genentech have effectively zigged with their development of an anti-PD-L1 inhibitor.  Does this matter?

Here, we explore the general background to this approach and, in particular, where the company are going with their anti-PD-L1 inhibitor, MPDL3280A.

Topics discussed:

anti-PD-L1, anti-PD-1, anti-CTLA-4, checkpoint point inhibitors, T cells, biomarkers.

Drugs mentioned:

MPDL3280A, nivolumab, MK-3475, ipilimumab (Yervoy), lirilumab, BMS-986016 (anti-LAG3), bevacizumab (Avastin), erlotinib (Tarceva), vemurafenib (Zelboraf), cobimetinib.

If you are interested in more background on how the PD-1 and PD-L1 inhibitors work, you can check out the mechanism of action (MOA) in our video preview from ASCO last year, which explains this in fairly simple terms.

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Check point immunotherapy is probably on everyone’s hot topic list in oncology at the moment and rightly so.

ECCO Congress BannerOne of the key sessions I’m looking forward to at ECCO is the Saturday Lung Cancer Symposium on new therapeutic targets. It includes not only a presentation on PD-1 and PD-L1 Immune checkpoint antibodies, but also overviews of progress in several other pathways, namely PI3K-AKT-mTOR, RAS-RAF-MEK and ALK+/Hsp inhibitors. This should be an excellent session that allows a broad overview of many of the key areas of research in the disease.

Aside from a late breaker on the two-year ipilimumab data in metastatic melanoma, the check point abstracts I managed to find in the #ECC2013 program appear to be all posters.  Here are my quick notes ahead of the presentations for Premium Content subscribers:

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