Recently there has been a glut of encouraging new research published on the topic of breast cancer that is well worth perusing as a group, since new combination studies may emerge from these kind of data.
In this month’s Journal Club edition, we explore five such articles plus some related research in support of the main themes.
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There’s nothing like a bit of controversy and heated debate at the annual meeting of the American Society of Clinical Oncology (ASCO) – every year seems to have something of note that generates intense debate and this June was no exception.
The main focus of this year’s intrigue was the APHINITY trial where pertuzumab (Perjeta) was added to the standard of care treatment – trastuzumab (Herceptin) plus chemotherapy for one year – in HER2+ adjuvant breast cancer.
The reality is that the findings from this trial are both subtle and nuanced so what did thought leaders really think about the data – what does the magnitude of the benefit mean and for whom should we be considering this approach for?
To find out, in the fourth post in our breast cancer series we interviewed some experts and curated sentiments around APHINITY to determine what the consensus was and where things are going next.
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#ASCO17 Poster Hall aka rugby scrum
There were a lot of gems in the poster halls at ASCO this year, a fact that is partly a reflection of the wealth of new data with various IO combos and also the early cutoff date.
Now I jested before the meeting that these sessions were akin to a rugby scrum and lo and behold (see photo right) they were even more jam packed than usual!
If you wanted to best the eager and energetic Wall St analysts then remembering your ruck and maul skills were not a bad thing to have in muscle memory… It was not something I attempted in the Go-Cart this year for fear of bowling people over in the stampede to nab the QR codes 🙂
Much of the previous readouts have been with monotherapy in immunogenic tumours such as melanoma, lung, bladder, gastric, renal cell carcinoma etc. Objective response rates in metastatic triple negative breast cancer (TNBC) have generally been under 20%, however.
Lately, the focus has turned to the deepening of responses in these tumours with various combination approaches and also moving earlier in the disease setting, where immunotherapies might be expected to be more effective with a lower tumour burden.
While in Chicago, we spoke to a breast cancer specialist about where IO combos are going and his thoughts on future opportunities in our third post in a series on various aspects of new developments in breast cancer.
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It amuses me to realise that I’ve been writing about and following PARP inhibition since 2006 or so, when the field was in that twilight zone of early drug development between preclinical and clinical, thus just beginning to hit some sort of consciousness and broader interest in cancer research.
The AACR Molecular Targets meeting in 2009 was the first scientific meeting I covered as a science writer on the old Pharma Strategy Blog, which focused on early drug development from preclinical to phase 2 – after that I would rapidly lose interest and move on to the next new shiny scientific lure to research and discuss. No doubt this eager new writer ran about like an overenthusiastic little puppy in the poster halls chatting to scientists about their research, much to the amusement of the more staid press room, who at that time probably never ventured out of the darkened basement gloom.
In one of the press briefings there, I met an engaging and thoughtful scientist who was presenting his poster on PARP and synthetic lethality. He kindly took the time to explain in plain English a commonsense analogy that was most helpful for grasping complex concepts. Having sat through several long talks from luminaries in the field such as Drs Hillary Calvert and Alan Ashworth that covered double strand breaks and DNA repair mechanisms, it was a most welcome respite in the hurly burly of the conference!
Imagine his imagery…
You have a four legged coffee table or wooden chair and one of the legs breaks off or is damaged. The table remains standing, albeit less stable than before. Now a second leg breaks, and inevitably, the table is so unstable that it falls over.
Once you grasp that simple analogy for synthetic lethality, you have the basic idea of DNA double strand breaks and how inefficient repair can lead to vulnerabilities in the tumour that can be exploited.
The scientist I spoke to in Boston back in 2009 was Dr Mark O’Connor.
He was involved in DNA damage response research at a little known private company in Cambridge, UK called KuDos, who were subsequently acquired by AstraZeneca. Nearly a decade on and Dr O’Connor is still at the company; he now heads up their DNA damage response area.
Dr Mark O’Connor, AZN
With olaparib (Lynparza) since approved by the FDA in ovarian cancer and slated for the ASCO 2017 plenary session for HER2- breast cancer, things have certainly changed a lot since those early heady days of KuDos and the R&D journey has not been without its notable ups and downs along the way.
In Chicago earlier this month, I had the pleasure of catching up again with Dr O’Connor to learn more about the journey, and importantly, where things are going next. It’s quite an interesting roller coaster ride, to be sure!
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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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If there’s one topic that has generated a LOT of questions from BSB readers this month it is Puma Biotech’s neratinib in adjuvant breast cancer.
The FDA briefing documents came out yesterday and that started another flurry of ‘what do you think of them?’ style questions so here goes. I will say that while many are eulogizing ‘benign’ or ‘friendly’ on close reading and studying them, I’d say caveat emptor.
Things are not always what they seem.
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Prof Peter Schmid, Barts Cancer Institute
Peter Schmid FRCP, MD, PhD is Professor of Cancer Medicine at Barts Cancer Institute in London, where he is also Clinical Director of the St. Bartholomew’s Breast Cancer Centre and leads the cancer immunotherapy group.
One of my favourite interview quotes of all time comes from his fellow Barts cancer researcher, Professor Tom Powles who told BSB about the results he had seen with the anti PD-L1 monoclonal antibody, atezolizumab (Roche/Genentech) in urothelial bladder cancer:
“I have a cohort of men and women now, who had been told they have 6 months to live who are now two or three years down the line.”
This encapsulates the hope that cancer immunotherapy offers. (See post: Atezolizumab PDL1 Checkpoint Inhibitor will change Bladder Cancer Treatment). You can also hear Prof Powles on the Novel Targets Podcast (Episode 7).
Barts Cancer Institute in the City of London is pioneering research into cancer immunotherapy in both the clinical and preclinical arenas.
Readers may recall we previously interviewed Professor Fran Balkwill last year about the work her research group is doing into modelling the tumour microenvironment. This is an exciting area that we can expect to hear more about. (See post: Modelling the Tumor Microenvironment).
So where are we with breast cancer immunotherapy in triple negative breast cancer (TNBC)?
It’s now two years since the first atezolizumab TNBC clinical trial data was presented by Dr Leisha Emens (Johns Hopkins) at the 2015 annual meeting of the American Association for Cancer Research (AACR), how time flies! (See post: Checkpoint Inhibitor Data Rocks AACR 2015)
As regular readers know, we like to follow stories over time and report on how the longitudinal data progresses.
Professor Peter Schmid kindly spoke to BSB at the 2017 AACR annual meeting in Washington DC where he presented more mature clinical trial data for the PD-L1 checkpoint inhibitor, atezolizumab, as a single agent in TNBC.
What are the key take homes from this data, and the ongoing challenges and opportunities in TNBC? Prof Schmid shared his unique perspective.
This is the first in a series of expert interviews from #AACR17.
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The White House in spring, Washington DC
With spring in the air and the clock rapidly running down on the annual meeting of the American Association for Cancer Research (AACR) in Washington DC in just two weeks time, it’s time to take a look at the seventh topic in our Preview series.
What’s hot on deck to day?
With increasing competition in the metastatic breast cancer space, particularly in HR+ HER2- disease, it’s time to explore key issues around CDK4/6 inhibitors as there’s a lot going on here, including some important presentations ahead.
A road map of what to expect and what to watch out for is often valuable if you want to avoid surprises.
We also examine key issues the companies here are facing as well as highlighting emerging scientific and clinical data of note on several relevant fronts.
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At the recent 2016 San Antonio Breast Cancer Symposium (SABCS16), Cascadian Therapeutics (NASDAQ: CASC) presented a poster (Abstract #P4–21–01) on:
“Efficacy Results of a Phase 1b Study of Tucatinib (ONT–380), an Oral HER2-Specific Inhibitor, in Combination With Capecitabine and Trastuzumab in HER2+ Metastatic Breast Cancer, Including Patients with Brain Metastases.”
Tucatinib is an oral tyrosine kinase inhibitor that is highly selective for HER2.
Cascadian’s tucatinib poster at #SABCS16
We’ve seen several new treatments approved for HER2 positive breast cancers in recent years including four targeted treatments: trastuzumab, pertuzumab, lapatinib and T-DM1.
Other companies such as Puma Biotech (NASDAQ: PBYI) also have oral TKIs in development. Puma’s drug, neratinib has, however been shown to have a high incidence of grade 3+ diarrhea, raising questions about its tolerance.
At SABCS16 (Abstract P02–11–03), the company presented the interim analysis of an open-label, multicenter phase 2 trial, which explored their compound:
“Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC).”
There has been a lot of interest and controversy in this space, so it’s time to take a look at the latest events in HER2+ breast cancer and consider the ramifications since there are a number of new developments that are well worth following, including neratinib (Puma Biotech) and pertuzumab (Genentech).
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The most common cause of breast cancer death is when metastatic ER+ tumors develop resistance to treatment. There remains an huge unmet medical need for new effective treatment options.
One translational clinical researcher leading the way in understanding the molecular and genomic landscape in ER+ metastatic breast cancer is Nikhil Wagle, MD (@Nikhilwagle), Deputy Director, Center for Cancer Precision Medicine at the Dana-Farber Cancer Institute (DFCI).
He’s shown the power of partnering with patients via social media to speed research, with over 3,000 men and women joining the Metastatic Breast Cancer Project that launched in October 2015.
At the 2016 San Antonio Breast Cancer Symposium, Dr Wagle kindly spoke to BSB about the genomics research that he and colleagues are undertaking, and what this may mean for how metastatic breast cancer is treated:
- What if you could help accelerate clinical trial enrollment via a network of educated and empowered patients?
- What if you could access real world data to help learn about exceptional responders?
For those of you in Pharmaland, here’s one approach that should captivate the imagination of what’s possible.
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