Biotech Strategy Blog

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

Posts tagged ‘AstraZeneca’

On finding new targets and boosting existing therapies

Science drives oncology new product development and the AACR special conferences are always a good place to look for insights into where the field is both emerging and also going in the future.

At the recent AACR Tumor Immunology and Immunotherapy conference, several presentations stood out for us as being noteworthy for either building on an existing story or the new perspectives they offered, some of which involved new targets we’d not heard before.

In this post, we take a take at some of the data presented, how it builds upon what we already know, and possible directions it may take us in.  After all, the best way to predict the future is to invent it.

It’s time to shine some light on novel targets, biomarkers, and emerging combination approaches…

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A false dawn in adjuvant EGFR mutant lung cancer? Dr Ross Camidge provides a critical review of ADAURA

Not in Chicago: A hallmark of the annual meeting of the American Society of Clinical Oncology (ASCO) is “practice changing” clinical trial data often featured in the plenary session.

This year one of the noteworthy phase 3 trials presented at the meeting (link to ASCO20 Abstract LBA5), was the AstraZeneca sponsored “ADAURA” trial for osimertinib as adjuvant therapy in patients with stage 1B-IIIA EGFR mutation-positive NSCLC after complete tumor resection.

We’ve been following the clinical development of osimertinib since the initial presentation of the phase 1 data in 2013 (link).

Source: ASCO20 Press Briefing by Dr Roy Herbst

At first glance it’s hard not to be wowed by the separation of the disease-free survival (DFS) curves in ADAURA, which show a benefit for patients who received the EGFR inhibitor osimertinib compared to those who received placebo. A 0.17 hazard ratio is certainly not something we see every day.

Indeed, if you were in the media and listened to Dr Herbst on the #ASCO20 press briefing last week – to use a “Britishism” – you would have thought this trial was “the best thing since sliced bread.”  The data monitoring committee recommended unblinding the study early.

Dr Ross Camidge Colorado

D Ross Camidge, MD PhD

Anyone leaving the story there and doing a superficial report about this data is, however, doing a disservice to their readers. The US academic lung cancer community are not all singing Handel’s Hallelujah chorus for the ADAURA trial and in this post, we take a critical look at why this might be the case.

For good measure, we interviewed a global thought leader who was prepared to offer some candid expert commentary.

Dr Ross Camidge is Professor of Medicine/Oncology and holds the Joyce Zeff Chair in Lung Cancer Research at the University of Colorado school of medicine. He kindly spoke to BSB and shared his perspective on adjuvant therapy in EGFR mutant lung cancer.

Dr Camidge characterized the disease-free survival in the ADAURA trial as a potential “false dawn” and told BSB:

“I do not believe the data should be practice changing or at least not yet. I think when you show there is an overall survival benefit then it will be practice changing…

So far there is no reason to suggest that disease free survival is going to translate into an overall survival advantage as it has not in any other comparable targeted therapy trial in EGFR mutant lung cancer. If this trial is the exception though, it will certainly not be of the same magnitude as the DFS benefit. However, the real unanswered questions are who needs this drug in this setting and if they need it, who can stop it safely and when.”

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Flying high in the DDR oncology niche

Recently, PARP inhibitors have been back in the news for several reasons, including the publication of the olaparib (AstraZenca/Merck) advanced mCRPC data in the New England Journal of Medicine from the phase 3 PROfound trial and the announcement regarding achievement of the key secondary endpoint of overall survival. As Dr José Baselga quite rightly noted, this is very good news indeed because:

“Overall survival in metastatic castration-resistant prostate cancer has remained extremely challenging to achieve.”

We’ve rather more trial misses in this disease setting than successes from various therapies over the last few years including ipilimumab, PROSTVAC, alisertib, and atezolizumab, to name a few off the top of my head.

Related to mCRPC, let’s also not forget the upcoming PDUFA date later this month for Clovis’s rucaparib in the very same indication.

Not to be outdone on the PARP front, just a few days GSK received FDA approval for niraparib as first-line monotherapy maintenance therapy for women with platinum-responsive advanced ovarian cancer – regardless of biomarker status – based on the phase 3 PRIMA study presented at ESMO last year and simultaneously published in the NEJM. Recall that the majority of women (51%) had homologous-recombination deficiency (HRD) and this subset saw the greatest benefit.

Flying high in the DDR space?

We have now seen clinical benefit in the PARP inhibitors in four tumour types driven by DNA damage repair (DDR) deficiencies, namely ovarian, breast, pancreatic, and prostate cancers.

How do we go about extending the concept of DDR in terms of the biology of other tumour types?

A number of related pathway targets have been investigated, including ATM/ATR, Chk1, Wee–1 and others, with mixed success.

It’s not the nature of oncology R&D to stand still, however; what if we could turn things on their head and think creatively about the problems still to be addressed?

One particular new company to the PARP space is doing just that… so what are they doing and what’s different about their approach?

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PARP inhibition in metastatic prostate cancer

Who’s King of the PARP castle?

After yesterday’s review and expert commentary on the phase 3 PROfound trial presented in the Presidential Session at ESMO 2019, we’re continuing our look at PARP inhibitors in advanced prostate cancer.

Perhaps surprisingly, there were a lot of insights to be found in the posters that were presented and discussed at the meeting for other PARPs in clinical development.

How do these stack up against olaparib? We’re not fans of cross-trial comparisons as they always come with a mandatory health warning, but if you want to consider the emerging landscape, it is important to be aware of the different patient populations, lines of therapy, and details of the trial designs.

For additional perspective at ESMO19, we spoke to a European prostate cancer expert who kindly talked about his clinical practice and also offered insights into a PARP clinical trial he and colleagues presented in Barcelona.

Who will be King of the PARP castle in advanced prostate cancer?

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Insights on osimertinib in 1L NSCLC from the lens of the FLAURA trial

Barcelona – It seems only in only four years we have gone from discussing the phase 1 osimertinib data in EGFRm lung cancer with one Boston expert to reviewing the survival data from the phase 3 study with another expert from the same city… how time flies!

Today was a crazy day with multiple different embargoes lifting at different times so to make things simpler we carved out three different tracks to make it easier for readers to focus and follow the stories they are most interested in.

The KRASG12C clinical trial readouts continue apace with a look at the new non-lung cancer data. That post already went live at 1.30am ET if you’re looking for that evolving story.  The main highlights post with a daily running live blog and multiple updates throughout the day can be found here.

Meanwhile this particular post will contain everything related to osimertinib and the FLAURA trial, as well as where we are on uncovering resistance mechanisms. To get started we have a new press release to look at as well as some independent expert commentary to put the data in context.

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Innate Pharma – converting science into the clinic

Every year for our annual AACR Preview coverage we like to mix things up and explore what’s happening with different targets, pathways, and even companies.

In this latest post for #AACR18, we take a look at a company that has historically been involved in R&D associated with the innate immune system. As new molecules have evolved against different targets, researchers have begun to realise that we can actually target both the innate and adaptive immune systems together rather than one or the other.

We have covered several clinical developments from Innate Pharma on lirilimumab, but they are actually more than a one compound biotech and have a growing pipeline of antibodies against several novel targets, some of which are unique to the company.

This isn’t just about the science behind the pipeline as we also explore facets of corporate strategy and where the company is headed in the near to medium term future.  While in London earlier this month, we caught up with Dr Mondher Mahjoubi (CEO) and Prof Eric Vivier (CSO) for a candid and detailed fire side chat.

There was plenty to discuss and some interesting new developments to highlight…

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A man on a Mission to #FinishCancer

Dr Bernie Fox (@BernardAFox) is a man on a mission to #FinishCancer, a Twitter hashtag he uses to reflect his vision.

A cancer immunotherapy rockstar, Bernard A Fox, PhD, is the Harder Family Endowed Chair for Cancer Research at Providence Center Center and Chief of the Laboratory of Molecular and Tumor Immunology at the Earle A. Chiles Research Institute in Portland, Oregon.

Fox is also a past president of the Society for Immunotherapy of Cancer (SITC) and CEO of UbiVac, a biotechnology company focused on therapeutic cancer vaccines.

Readers of the Blog and Novel Targets Podcast listeners will recall we had the privilege to interview Dr Fox back at the American Association for Cancer Research (AACR) annual meeting in New Orleans in 2016: “AACR Cancer Immunotherapy Insights from Dr Bernard Fox.”

Fast forward 18 months… it is now time for a detailed update on this issue, as a few interesting events have since come to light in this niche with Genentech/Roche abandoning development of their OX40 agonist, coupled with several new publications from different labs suggesting that concurrent administration of an anti-OX40 antibody with an anti-PD1 antibody attenuated the effect of anti-OX40 and resulted in poor treatment outcomes in mouse models.

Dr Fox kindly spoke to Biotech Strategy Blog about some of the key learnings from this research, where he sees the future potential for OX40, and what his vision for cancer immunotherapy is.

Here’s a short clip from the fireside chat…

 

He’s definitely a man on a mission to #FinishCancer!

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MYSTIC Interim Analysis July 2017 shows PFS Miss

There has been considerable focus on the impact of cancer immunotherapy and checkpoint blockade in particular in non-small cell lung cancer (NSCLC) of late, with approval of several agents in the 1L and 2L metastatic setting, as well as positive results reported in stage 3 unresectable disease earlier this year.

To date, the approvals have focused on monotherapies in second-line (nivolumab, pembrolizumab and atezolizumab) allcomers, as well as in 1L in two cases i.e. for people who are PD-L1 High expressers (≥ 50%) for pembrolizumab or allcomers in combination with chemotherapy (pembrolizumab).

Today as part of their 2Q earnings call details, AstraZeneca ($AZN) announced that the MYSTIC trial exploring the combination of the anti-PD-L1 antibody, durvalumab (Imfinzi), plus anti-CTLA–4 antibody, tremelimumab, unfortunately missed the interim endpoint of progression-free survival (PFS).

This is the first dual IO-IO combo readout in this setting and while disappointing, the results aren’t entirely surprising, as regular readers will no doubt realise.

We are now awaiting several other trial readouts in 1L NSCLC, including Merck’s phase 3 confirmatory trial for pembrolizumab plus chemo and Genentech/Roche’s IMpower150 trial, which explores atezolizumab in combination with chemotherapy, with and without the anti-VEGF inhibitor, bevacizumab (Avastin).

For historical reference, we originally wrote up our perspectives on the 1L NSCLC landscape in January this year then followed that up with a provocative post outlining out predictions on what to expect earlier this month, including the projected miss in PFS for AstraZeneca’s IO combo.

So what does this latest data mean for AZN?

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Predictions in 1L NSCLC trials

Back in January this year, we posted an early look on what to expect from the evolving 1L NSCLC landscape following the controversial FDA submission of Merck’s pembrolizumab with chemotherapy. This lead to subsequent approval in May.

Checkpoint Charlie, Berlin July 2017

At that time, quite a few people were shocked and surprised that the phase 2 KEYNOTE–021 Cohort G data presented ESMO was neatly parlayed into accelerated approval in the US.

Since then, a lot has happened and now many readers are on tenterhooks as we await the next round of lung cancer trial results in the upfront setting.

First up is AstraZeneca’s MYSTIC trial exploring an IO-IO combination with durvalumab plus tremelimumab. Merck’s confirmatory trial for pembrolizumab plus chemo is also expected in the fall – will it support the accelarated approval – or not? Meanwhile, we also await Roche/Genentech’s IMpower150 study evaluating their checkpoint inhibitor, atezolizumab, in combination with chemotherapy by the year end.

These are quite different strategies with diverse endpoints so following them closely will be key to understanding what happens next.  Based on what we’ve seen in lung cancer to date, the roller coaster looks set to continue.  The C-suite shenanigans have only added to the intrigue and mystique – do they mean anything?  Who knows, but we’re focusing on the hard data i.e. science and the clinical clues that are available.

It’s all to play for and many readers wrote in asking for an update on the landscape and what to expect now that we’re much nearer to the shoes actually dropping.

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Going beyond PARP monotherapies

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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