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For historical reference, we originally wrote up our perspectives on the 1L NSCLC landscape in January this year then followed that up with a provocative post outlining out predictions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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Berlin: Checkpoint Charlie
With a series of inconsistent results involving phase 3 trials involving checkpoint antibody therapy, even in similar indications, it’s time to get down and dirty and look at some of the factors that might be influencing the outcomes since three of the five approved anti-PD(L)1 products have now been similarly affected.
It’s an interesting and intriguing conundrum, to be sure…
Instead of obeying traffic rules, with immune checkpoints maybe we need to consider following immunology rules instead 🙂
The potential hidden answers, however, might be surprising to some readers.
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The latest company immunotherapy announcement is from Lilly and Nektar Therapeutics, for a strategic collaboration to co-develop NKTR–358, which targets the IL–2 receptor complex, thereby impacting regulatory T cells (Tregs). It is thought that this target may have particular relevance to autoimmune disorders and other chronic inflammatory conditions. This agreement involves an initial payment of $150 million, with the potential for up to $250 million in additional development and regulatory milestones.
Source: Nektar Therapeutics
Preclinical data on this novel compound was recently presented on July 10th at the World Congress of Inflammation.
We first spoke to Nektar at SITC in November, including an interview with one of their leading scientists (Dr Jonathan Zalevsky) together with the academic PI (Dr Adi Diab), and I’m delighted to say that the dynamic duo graciously agreed to a follow-up discussion at ASCO last month on the emerging IO pipeline.
In our current analysis and commentary on the IO pipeline, we also look briefly at the Lilly deal with NKTR–358 in autoimmune disease.
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In our latest thought leader interview we explore the intersection between epigenetic therapy and immunotherapy.
Gems from the ASCO17 poster hall
Much of the IO focus to date has been on monotherapies rather than combos, although that situation is slowly changing.
What we can also expect to see are the emergence of regimens, long the bedrock of traditional cancer therapy approaches.
As we learn how to bucket more discrete populations based on the underlying biology of the tumour microenvironment, so we will see a more IFTTT (If this then that) approach evolve in order to fix or improve a situation before or after attempting the core therapy. It might require a focus on changing the immunosuppressive or inhibitory factors, for example, or addressing factors that induce primary resistance upfront. The possibilities are endless.
Obviously, there are a number of ways to do this from chemotherapy and radiotherapy to epigenetic agents to targeted therapies – these traditional treatments are not going to go away, but I can see a future where we see more integration based on a patient’s underlying immune status. It won’t be the zero sum game many analysts seem to think it might be.
In the past, we have covered chemotherapy, radiotherapy and targeted therapies and looked at how they might be employed with immunotherapies in various guises. In this latest thought leader interview, we look at a different approach, epigenetic therapy and other novel immunotherapies.
Here, we combine two popular types of posts – Gems from the Poster Halls with an Expert Interview – for detailed look at one particular area of research that is beginning to look quite intriguing.
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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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La Tour Eiffel par nuit
Paris, France: It’s the dog days of summer and my reading stack of interesting science and cancer research papers is particularly high at the moment despite reading voraciously over the last few weeks…
So much excellent research keeps on piling up as fast as one can get through it.
It’s beginning to feel like Ravel’s Bolero…
Still, there’s one particular batch of important papers that draws together some interesting findings in an area we have been following for a little while now and these data most certainly advance the field in more ways than one.
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Traditionally we’ve seen the evolution of oncology companies with chemotherapies, then those with targeted therapies, whether TKIs or antibodies.
Increasingly, we’re seeing the rise of an entirely new empire – those with a raft of immunotherapies in their pipeline.
Gems from #ASCO17 Poster Halls
Then there are those with a more mixed portfolio approach of targeted compounds and novel immunotherapy agents… which leads to some interesting combination approaches that target the cancer immunity cycle and address issues that exert inhibitory factors dampening down the immune system responses.
Our latest fireside chat and expert interview focuses on an up and coming biotech company with a pipeline that combines protein targeted antibodies with novel approaches that can potentially reprogram various immune cells in the tumour microenvironment.
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Florence, Italy: Today at the EACR-AACR-SIC Conference on “The Challenges of Optimizing Immuno and Targeted Therapies,” Tom Powles MRCP MD, Clinical Professor of Geniturinary Oncology at Barts Cancer Institute in London, gave a special lecture on the IMvigor211 trial (NCT02302807).
This was a phase 3 study of the PD-L1 checkpoint inhibitor atezolizumab compared with chemotherapy in participants with locally advanced or metastatic urothelial bladder cancer.
Prof Tom Powles (Barts Cancer Institute)
Readers may recall we interviewed Prof Powles back in August 2015 about the potential for the PD-L1 checkpoint inhibitor atezolizumab in urothelial bladder cancer? (See post: Atezolizumab PD-L1 Checkpoint Inhibitor will Change Bladder Cancer Treatment.)
We also featured the atezo data presented by Dr Jonathan Rosenberg (MSKCC) at ESMO 2015 on Episode 7 of the Novel Targets Podcast, where we also heard Prof Powles tell us about the long durable responses he had obtained in clinical practice in some of his patients.
Subsequently on May 18, 2016 the US Food and Drug administration (FDA) granted accelerated approval to atezolizumab (Tecentriq) for urothelial bladder cancer (link to news release).
Fast forward a year to May 9, 2017 and the surprise announcement that the confirmatory phase 3 trial (IMvigor211) failed to meet its primary endpoint (link to Genentech press release).
So what happened? Why did the atezo phase 3 trial end up being negative when we saw durable responses in the randomised phase 2 trial and other PD-1 checkpoint inhibitors have shown an overall survival benefit in the same indication?
Many in the media only want to write about positive data, but in science we often learn as much from our failures as we do from our successes, perhaps even more sometimes.
IMvigor211 was expected to be a positive trial especially after the recent Merck success gaining an overall survival benefit for pembrolizumab, so the negative result is noteworthy and one that anyone in the field of cancer immunotherapy drug development will want to understand.
Professor Powles kindly spoke to BSB and shared his perspective.
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One of my favourite pastimes at cancer conferences is discussions with up and coming young researchers about their current experiments and what they learn from them.
The poster hall rugby scrum at #ASCO17
In the spotlight today is one of the gems from the poster halls at ASCO this month…
Here we explore how liver mets, which is a common site of metastases, can influence the response of cancer immunotherapy.
The findings from this research highlight some intriguing biology as well as offer some hints about where to go next.
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Yesterday, we had a sarcoma expert in the spotlight looking at the new developments from the American Society of Clinical Oncology (ASCO).
In part two of our sarcoma mini-series, we have another interview for our readers, this time from the perspective of the CEO, Dr Carlos Paya. They had some interesting data in Chicago so what was their reaction to it and where are they going next?
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