Biotech Strategy Blog

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

Posts tagged ‘triple negative breast cancer’

Is pembrolizumab superior to atezolizumab in neoadjuvant TNBC?

Checkpoint fight at the Alamo in San Antonio? Say it ain’t so!

This is the $64M question that will be on many people’s mind after seeing two SABCS headlines today:

“Neoadjuvant and Adjuvant Treatment with Pembrolizumab Improves Pathologic Complete Response Rates for Patients with Triple-Negative Breast Cancerwith Lymph Node Involvement.”

“Combining Atezolizumab with Neoadjuvant Chemotherapy Does Not Improve Pathologic Complete Response Rates for Patients with Triple-Negative Breast Cancer.”

In order to answer the question fairly, there are plenty of critical points we can look at in order to address it.

That’s the topic of today’s post in a nutshell… and yes, we do come to a firm conclusion.

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Insights from KEYNOTE-522 in early stage TNBC

Cui bono?

Imagine arriving at ESMO19 at the crack of dawn for a press briefing and you’re not presenting until after 4.30pm!

To whom is it a benefit is a fundamental principle in modern day medicine given the often vast array of options that oncologists may have at their disposal.

Conversely, we also need to know nec refert – for whom it doesn’t matter or doesn’t benefit – since we don’t want to over-treat people either.

Between those two extremes might be a couple of sweetspots i.e. one subset who may need a boost from chemotherapy and another in whom chemo plus IO therapy might be a better option.

For sure, we are not advocating that all people with early stage triple negative breast cancer (TNBC) should receive the same thing and certainly not everyone will need checkpoint therapy, no matter what the intent-to-treat (ITT) curves or response rates might try to imply.

There’s a lot of factors to think about and consider so here we look at the KEYNOTE–522 data in neoadjuvant and adjuvant TNBC and unearthed with some solid evidence that might help us understand and think about what needs to be done.

Following on from our in-depth ESMO19 Preview on TNBC and what to watch out for, we also now have a thought leader interview to share plus several other commentators chipping in…

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Controversies in triple negative breast cancer at ESMO19

One of the expected highlights of the forthcoming European Society for Medical Oncology (Twitter #ESMO19) will be data for breast cancer immunotherapy.

In the first of our pre-ESMO19 previews we are taking a closer look at three breast cancer immunotherapy presentations that we think are noteworthy.

As a reminder, the abstracts are not yet available, so we’re not writing about data that’s not yet been presented, but instead are looking at why the presentations may be of scientific/medical interest, and what the questions we hope they will answer. In cancer biology as we heard from Professor Gerard Evan in a recent expert interview, it’s not about “what” happened, but “why”?

We have “boots on the ground” in Barcelona from Sept 27th to October 1st providing daily posts for BSB subscribers with our unique blend of data, analysis and commentary.

Do download the ESMO19 app if you want to check out what already looks like it will be a busy, informative and interesting congress in Barcelona. Hopefully the rain that struck the recent World Lung meeting in Barcelona will have gone away, leaving us with a sunny and dry spell one normally associates with Spain!

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How confident can we be in the reproducibility of the IMpassion130 results in TNBC?

One of the emerging challenges of the IMpassion130 trial of the combination of nab-paclitaxel and atezolizumab versus nab-paclitaxel alone in triple negative breast cancer (TNBC) is that pathologists can’t reliably read PD-L1 on immune cells.

Georgia State Capitol in Atlanta

This issue came up in an insightful talk by David Rimm MD PhD (@RimmPathology), Professor, Departments of Pathology and Medicine (Oncology) at Yale in an education session at this year’s AACR annual meeting in Atlanta where he spoke about, “Predicting immunotherapy response with protein-based tools: PD-L1 and beyond.”

BSB readers will recall Dr Rimm was a hard hitting discussant of the CheckMate–227 trial data for the combination of nivolumab and ipilimumab in first-line non-small cell lung cancer (NSCLC) at AACR18. He correctly predicted that tumor mutational burden (TMB) as a biomarker would predict PFS but not overall survival, based on an analysis of their cohort at Yale. He turned out to be right!

The implication of this was that BMS subsequently withdrew their EU/US regulatory filings for CM227 in 1L NSCLC when the hazard ratios (HR) for high and low TMB turned out to be identical.

If you missed it, do listen to the episode 22 of the Novel Targets Podcast we produced from AACR18 (Link), where we took a closer look at TMB as a biomarker, and the phase 3 lung cancer clinical data presented at the meeting.

Will we see challenges emerge with the Ventana SP142 assay?  What about the implications for Merck’s KEYNOTE-355 trial in TNBC?

In this BSB post, we discuss these issues and explore many of the nuances that readers should be aware of in TNBC.

In addition to Dr Rimm’s candid and hard hitting interview, we also invited Professor Sherene Loi (@LoiSher) to review Dr Rimm’s commentary and offer a clinical perspective on the points he raised.

She’s a consultant medical oncologist at the Peter MacCullum Centre in Australia, where she holds the National Breast Cancer Foundation of Australia Endowed Chair and is head of the Translational Breast Cancer Genomics and Therapeutic Laboratory.

Professor Loi is also one of the authors of the paper published in The New England Journal of Medicine that reported the results of the IMPassion130 trial.

If you’d like to read Dr Rimm’s candid interview and Professor Loi’s clinical perspective, become a subscriber to BSB and support independent science journalism. As of today, 75% of our subscribers are repeat buyers – do consider joining them!

In the second part of the interview with Dr Rimm (to be published separately), we’ll hear about some of the new data his lab presented at AACR19 and where he sees the future for TMB and other immune biomarkers.

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An in-depth look at OLYMPIAD in HER2 negative breast cancer

Often times when we see promising data presented at a cancer conference, we interview a thought leader and post the expert opinion with additional commentary and insights.

ASCO17 OlympiAD Plenary

At ASCO, we decided to take a different approach, a twist on the usual fare… given that two of the phase 3 trials, OLYMPIAD and APHINITY, received significant attention and focus involved breast cancer, we reached out to numerous experts and curated their sentiments on both studies.  For completeness and fair balance, these included industry and academic opinions.

Today, we begin with the OLYMPIAD trial presented by Dr Mark Robson on behalf of his colleagues exploring the role of the PARP inhibitor, olaparib (Lynparza), in HER2-negative metastatic breast cancer with germline BRCA mutations.

There’s a lot to consider here, not least is where do we go next from here and which PARP combination approaches are researchers most excited about?

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Going Beyond PARP in DNA Damage Repair

We now turn our sights to targeted therapies and DNA Damage Repair (DDR). This is an important topic that has seen much focus in ovarian cancer of late and will likely see renewed interest in breast cancer at the forthcoming ASCO meeting next month. As we segue from one set of conference coverage to the next, there is inevitably going to be overlap, which is a good thing here as it helps with background and preparation in getting up to speed.

There is no doubt that DDR has had a bit of chequered history over the last decade, whether it be the spectacular (and sadly predictable) flop of Sanofi’s iniparib in triple negative breast cancer (TNBC), the negative ODAC incurred by AstraZeneca’s olaparib in ovarian cancer, or AbbVie’s more recent veliparib failures, to the much more positive events such as three PARP drugs now approved in different lines of therapy in ovarian cancer (olaparib, rucaparib and niraparib).

If ever there was a niche for the roller coaster ride that is oncology R&D, it has to be PARP inhibitors.  There’s much more to DDR than just PARP though.

Indeed, there are multiple intriguing targets to explore and also the potential for combinations with cancer immunotherapy approaches that may yield encouraging results in the future.

Can we go beyond ovarian cancer into other tumour types and if so, which ones look encouraging and how woluld we go about exploring those idesa? What makes one approach more successful than another?

Here we explore the world of DDR through the lens one company’s approach and look at what they’ve done, where are they now and where they hope to be. It certainly makes for an intriguing and candid fireside chat.

Want to learn more and peak ‘Through the Keyhole’?

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ASCO 2016 Preview 1 – Novel Combination Approaches

For years we’ve followed the trials and tribulations of targeted therapies seeing many approved and quite a few disappear forlornly (and officially) off to dog drug heaven. Many more sit in no-man’s land as companies eagerly wait in a holding pattern for other trial readouts in different tumour types. Sadly, sometimes these studies don’t generate enough compelling data either. With so much competition about, there are no shortcuts or low-hanging fruit in biotech or cancer drug development any more.

ASCO16 Chicago 1

En route to Chicago and ASCO!

Then along came antibody drug conjugates (ADCs), with some encouraging results in a range of cancers in both solid tumours and hematologic malignancies that lead to the approval of several new therapies.

After that, the next big advance was immunotherapies, specifically checkpoint blockade, with encouraging single agent activity in melanoma, lung, and even urothelial bladder cancer. We’ve also seen the promise fo combining two different checkpoints such as nivolumab and ipilimumab together in metastatic melanoma, albeit with an increase in toxicities.

This is all very well and good, although the challenge remains that the majority of patients either respond to therapy and relapse, or do not respond at all, depending on the circumstances, the tumour type and the regimen. We still have a long way to go in moving the needle and creating a new paradigm shift on a broad scale.

So what happens when we start to combine modalities – such as targeted therapies with immunotherapies?

Uh-oh, I hear the distant cries of disagreement erupt…

  • Remember vemurafenib plus ipilimumab in metastatic melanoma was scuppered by severe hepatitis?
  • What about osimertinib plus durvalumab in NSCLC and the increased incidence of ILD?

Both of these statements are true, and yet… we should not assume that all mixed therapy combination approaches are doomed on the basis of a mere n of 2. What happens if some are synergistic or additive? What happens of there are hidden gems that teach us new ways of doing things rather than doing the same old thing just because it’s always been done that way?

With this in mind, I’d like to open the door on our first ASCO 2016 Preview series with a look at novel combination approaches in development that caught my eye.

What are the early hints and signals that we can learn from the data? Which companies are evaluating imaginative new ideas that may turn the tables on traditional thinking?  The ideas discussed here may well surprise a few people.

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Gems from the EBCC10 Poster Hall

EBCC10

EBCC-10 Cancer Conference

Amsterdam: The 2016 European Breast Cancer Conference organised by the European CanCer Organization (ECCO) is underway (Twitter: #EBCC10 – it’s the 10th official one they have organised).

We thought it would be a good opportunity to take a break from our coverage of #BMTTandem16 to look at some of the posters that are of interest at the meeting.

As regular readers know, we spend a lot of time reading posters – it’s where we pick up new trends and early data. Most go unnoticed or unpublicised in press releases.

For this post, I’ve highlighted four posters that I’m quite interested in and that merit further discussion.

They range from basic and translational research to clinical new product development. By chance, they are evenly split between immunotherapy (PD-L1 and TILs) and acquired drug resistance to different targeted therapies.

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Promising new agents in development for breast cancer

We’ve had a couple of requests come in for a revival of the old conference series… ‘Gems from the poster halls’ because quite a few folks are interested in the up and coming data from small to medium biotechs.

SABCS San Antonio CrowdA bunch of my Post Doc chums in this field were at the San Antonio Breast Cancer Symposium (SABCS) meeting and gleefully highlighted mobbed posters or areas where they thought the data looked potentially interesting.

From these, we selected a few for review in today’s look at the nuggets that can be gleaned from cool and intriguing trials or preclinical research that may influence future trials.

Companies covered in this article include Seattle Genetics, Jounce, Immunomedics, Syndax and MedImmune.

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SABCS Update on Triple Negative Breast Cancer

A lot has happened this month with San Antonio Breast Cancer Symposium (SABCS) and other data emerging that it could be subtitled:

A brief tale of two breast cancer drugs

SABCS San Antonio CrowdAt SABCS a couple of things looked pretty intriguing indeed. One we will cover in the New Year, along with an in-depth expert interview on the topic, while the other is the main focus of today’s note.

In the last post of 2014, it’s time to address some pertinent questions on triple negative breast cancer (TNBC) from subscribers – there is good news to report here, unlike the surprising MARIANNE results for Kadcyla and Perjeta in frontline HER2+ disease that were announced early this morning.

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A big thank you to all who have supported Biotech Strategy Blog Conference Coverage this past year. Wishing you good health, happiness and prosperity in 2015. See you on the other side!

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