Biotech Strategy Blog

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

Posts tagged ‘anti-PD-1’

ESMO 2014 Bladder CancerCancer immunotherapy, the ability to harness the body’s own immune system to fight cancer, is showing early promise in bladder cancer.

“Breathing new life into bladder cancer treatment” was the title of the excellent discussion by Maria De Dantis (Vienna) of data presented at the recent ESMO Congress in Madrid.

Advanced bladder cancer has a particularly poor prognosis. Once the cancer has spread in the body, according to Cancer Research UK, the average survival time is approximately a year to 18 months.

There is clearly an unmet medical need for effective new treatments, with no major treatment advances for over 30 years. To date, targeted agents in the second-line setting have shown only incremental progression free survival and generally low overall response rates.

Which is why it’s exciting to see hope for patients with urothelial bladder cancer from new inhibitors of the PD-1 immune checkpoint signalling pathway.

At ASCO this year, data for Roche/Genentech’s anti PD-L1 (MPDL3280A) was presented (Abstract 5011) by Thomas Powles (Barts, London). Commenting on the data, in her post “Making a difference in advanced bladder cancer” Sally noted, “it wouldn’t have been out of place in the Plenary session, frankly.”

Recognizing the potential based on the promise of the early clinical data, on May 31st the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) to MPDL3280A in bladder cancer.

ESMO 2014 Bladder Cancer Session ChairsIf you need to catch up on immuno-oncology, we have a growing library of posts on Biotech Strategy Blog, and we’ll be continuing our coverage of the rapid progress in this area at the forthcoming annual meeting of the Society for Immunotherapy of Cancer (SITC), which takes place at National Harbor, MD from Nov 6 -9.

At ESMO 2014, phase 1 clinical trial data in bladder cancer was presented for both Pembrolizumab (Merck) and MPDL3280A (Roche/Genentech).

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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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“Nothing lasts forever, because nothing ever has.”

James Shelley, The Caesura Letters

This year’s annual AACR meeting was so good, we could probably write another 50 posts and still not be done! With ASCO fast approaching, however, it’s almost time to draw it to a close and the final post conference note will be published on Monday.

Today is the penultimate report and focuses on the key highlights that caught my attention in immuno-oncology, which covers the gamut from checkpoint inhibitors, co-stimulants, innate immunotherapy and CAR T cell therapy to bispecific antibody TCRs.

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Sometimes timing can be amusing when writing up data and conferences. Yesterday, while writing about the immuno-oncology developments in renal cell cancer (RCC), I was putting a table of the trials together and absent mindedly noticed that Merck didn’t have much going in this indication compared to BMS and Roche/Genentech.

Oddly, the company fixed that this morning with their announcement that they are expanding their combinations and collaborations for the anti-PD–1 antibody, MK–3475. One of the new trials includes a partnership with Pfizer for axitinib (Inlyta), enabling them to study a PD–1 + VEGF combination in RCC. The table in yesterday’s thought piece has now been updated to include this trial, although it is in the planning stage at present.

Today, I want to switch horses a little bit and talk about another immuno-oncology therapy, namely, ipilimumab (Yervoy).  Dr Charles Drake (Johns Hopkins) presented an update on the post chemotherapy trial (CA184–083) in CRPC at ASCO GU this weekend, which we wrote about from ESMO last Fall when the data was first presented (see here).  What’s interesting is that the trial, although negative, only just missed its endpoint.

Last week I came across some interesting new developments relating to ipilimumab that are well worth discussing here, particularly in relation to biomarkers, as they may have significant implications for the drug clinically.

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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 deligted 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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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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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 ASCO GI Keynote

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.

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This week the Cancer Conference Coverage moves to the joint IASLC-AACR symposium on the Molecular Origins of Lung Cancer in San Diego.  Having attended previous events (this is the third one they’ve hosted) and rather enjoyed them, this year I’m following it remotely.

What’s particularly nice about this type of specialist event is that they are especially useful for chatting informally with attendees and being able to ask a lot of questions that simply wouldn’t be feasible at larger meetings due to time and other constraints.

This review covers my thoughts on two immunotherapies, namely Merck’s anti-PD-1, which was previously presented at the World Lung Conference, plus a completely novel and very different approach that looks really quite exciting.

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Beyond the noise of the exciting the data in CAR-T cells, CLL, NHL and multiple myeloma, one of my favourite pastimes at cancer conferences is to look out for up-and-coming gems in the poster halls.

By this I mean interesting novel targets or very active agents in the pipeline.

One of the most eagerly awaited targets on my list was the Killer Immunoglobulin-like Receptor (KIR). It may be a key part of overcoming lymphoma resistance and inducing cell death. If you don’t kill the cancer cells, you likely won’t see remissions occurring.

Companies mentioned: Innate Pharma, BMS, Roche

Products mentioned: IPH2101, IPH2102 (lirilumab), ipilimumab, rituximab, obinutuzumab, anti-PD-1, anti-PD-L1

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Immuno-oncology is fast becoming one of the hottest topics in cancer research following the approval of the anti-CTLA4 checkpoint antibody, ipilimumab, in advanced melanoma, as well as emerging solid data from anti-PD-1 and PD-L1 antibodies in melanoma, lung and renal cancer at ASCO in June.

The big question on many people’s minds though, is what other checkpoint inhibitors are out there and can they safely be used either as single agents or in combination with the above agents, or even with existing standard of care combinations (chemotherapy and targeted therapies)?

I have long argued that what will really make a difference in this space is combinations and the ability of sponsors to successfully evaluate novel-novel agents in clinical trials. After all, BMS have a huge advantage with ipilimumab and the ability to combine it with their PD-1 or other immunotherapeutics, since their rivals will be greatly hampered by the $120K per person price tag for the commercial drug required as part of clinical trial costs.

This means most companies in this space are looking at other options in the search for better outcomes.

At the AACR-NCI-EORTC Molecular Targets conference in Boston this week, the last day was devoted to two sessions in immune-oncology and one of the plenary sessions included Dr Susan Topalian discussing an update on nivolumab and anti-PD-1/L1 therapies post ASCO. There was also ample opportunity to discuss immunotherapy with the many attendees in the busy poster sessions.

The first immunotherapy session on Weds morning particularly caught my attention and it seems a good opportunity to summarize some of the key observations emerging in this field. Here are my detailed notes from the session, which raise a lot of fascinating questions from the presenters about this field and – more importantly – where it’s going:

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