Biotech Strategy Blog

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

Posts tagged ‘chemotherapy’

At AACR last week we had the long awaited initial readouts for three key phase 3 studies in lung cancer, namely CheckMate–227, IMpower150, and KEYNOTE–189 in the same session on the same day.

This had me thinking about how it might end up being, “a killer and a chiller and a thriller when I get the (PD–1) gorilla in Manila,” with sincere apologies to Muhammed Ali and Dr Jean-Charles Soria for (mis)appropriating their past themes 😉

Chicago River Bridge at #AACR18

For those attending the event, you might well be forgiven for thinking from the first two adjectives that I’m referring to the weather, as it was certainly cold enough (!), or even the results this week from AstraZeneca’s unfortunately named ARCTIC study exploring the IO-IO combo of durvalumab plus tremelimumab in the third line setting with a miss in both PFS and OS endpoints.

In reality, we should be warmed and heartened to see three positive immunotheraopy trials appear at once and presented in the same session at the same meeting.  It isn’t always the case as regular attendees at ASCO well know.

When all is said and done, what do thought leaders specialising in lung cancer really think about the data that was presented in Chicago, and what were the convergence and discord on the various key issues under consideration?  There is, after all, a lot of subtlety and nuance to consider in 1L NSCLC.

To find out more, we interviewed not one, but four, lung cancer specialists in Chicago for their personal perspectives.  What they had to say as a group was both candid and absolutely fascinating, so it made sense to curate their insights around various key topics together into one detailed post for easy reading… 

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As part of our annual AACR Preview series, we usually explore new developments in at least one tumour type and one new target of interest.

Bladder cancer cells infected with BCG Source: Dr M Glickman, MSK

This year is no different and there were plenty of opportunities to discuss.

We have already covered lung cancer given the intensive interest in the phase 3 trials being presented in the 1L setting, but I also wanted to cover another key tumour type that is generating a lot of keen interest in clinical development for numerous reasons.

Tomorrow we will be exploring a cancer target in detail, but there is much to cover in terms of new preclinical and clinical developments in certain carcinomas.

Without much ado about nothing since there is plenty of important things to discuss, so here’s a look at our second tumour type to watch out for given the sheer numbers of trials, including a variety of different targets to think about.

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Geneva: At the ESMO IO 2017 conference underway in Geneva, the data of the meeting is the IMpower150 phase 3 trial data that will be presented later today by Dr Martin Reck (Grosshandsdorf).

Genentech/Roche have announced a press release ahead of the presentation (Link).

This is the first phase 3 lung cancer immunotherapy trial that combines a VEGF inhibitor (bevacizumab/Avastin), along with a PD-L1 checkpoint inhibitor (atezolizumab/Tecentriq) together with chemotherapy (carboplatin plus paclitaxel).

While we’ve not seen the actual data curves yet, we spoke to Dr Dan Chen (Genentech) about what we can expect to see later today in Geneva, and importantly, we also discussed the significance of the findings from the IMpower150 study.

As Dr Chen told BSB, “this trial is a lot of firsts.”

If you have an interest in lung cancer or immunotherapy, do follow #ESMOImmuno17 on Twitter, as this is data could potentially be practice changing and have a major impact on the lung cancer treatment landscape.

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While there continues to be an almost obsessive and fervant attention and focus on cancer immunotherapy, let’s not forget that chemotherapy and/or targeted therapy combinations are still the standard of care in many cases.

Plaza de Cibeles, Madrid

There are also numerous pipeline trials still ongoing and especially in the case of diseases with a low number of somatic mutations, other approaches may continue to have more utility and clinical benefit than say, monotherapy with checkpoint blockade.

So what’s in store in our second ESMO17 Preview series?

Following on from the Top 5 IO abstracts earlier this week, next up in the spotlight is the Targeted Therapy Top 5 Selections…

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We’ve come a long way over the last two years in the oncology market, with several novel approaches approved, numerous major phase 3 trials evolving and a huge turnaround for many companies in terms of early pipeline activity.

ASCO 2016 Posters 3

The melée at the ASCO 2016 Poster Hall

Unfortunately, this also means that the tendency of lemming activity also increases in the rush to copy everyone else and not be left behind.  Just a couple of years ago, some industry friends grumbled that there were over 20 checkpoint inhibitors chasing them in development; they may be surprised to know that now there are nearly 70!  This is both unprecedented and unsustainable, and yet it’s also a function of the perceived success these agents have had on the cancer R&D landscape to date.  Everyone wants one for fear of being left behind… except that many are indeed way behind already.

You can imagine the tall guy on the left of the picture looking at his watch and wondering, “Ah so many new posters, so little time!”

Meanwhile, as the rate of approved cancer therapies increases, so does the inexorable march in terms of hyper-aggressive basket pricing.  I would argue that at some point, it no longer acceptable or even conscionable to change a premium or even market rate for drugs that give an incremental improvement of a mere 2 months of extra life.

Equally, one thing that many industry observers and the media love to do, and wrongly in my view, is to compare the individual drug prices on an annualized basis.  This is silly for several reasons:

  1. So far, not all patients are treated for a full year
  2. If patients are treated until progression and that happens early, then therapy is stopped
  3. What people should be looking at is the average treatment cost based on the length of therapy – some people will receive a few months and some much more than that
  4. What’s the true cost of a cure or remission to a patient and their family?
  5. How do we quantify the impact of the long lasting durable remissions?

These questions will become increasingly important as we see a more aggregated therapy approach emerge over the next few years.

By this, I mean that we are now going beyond monotherapy and even combinations; those trials have already long started and are the low hanging fruit that has been rapidly snapped up by the early players, as we eagerly wait for their data readouts.

If you have new agents coming-out of preclinical and into phase 1 development over the next year, there are a number of important questions to consider:

  • What are you going to do and where do you start?
  • How do you gain an edge when coming from (way) behind?
  • How do you develop unique positioning that could sustain your molecule in a sea of similar competitors?
  • Is it realistic to expect the 17th and 50th checkpoint to have equivalent efficacy as what went on before and will all of these seriously make it to market?

You can see now why even the FDA’s Dr Richard Pazdur was moved to grumble about the surfeit of me-toos here and company expectations that the FDA should consider them – it’s on a massive scale that we haven’t seen before.  For once I agree and empathize with him over that dilemma, it’s madness to think they will all be as good as pembrolizumab or nivolumab.

What we are starting to see emerge now is a surprising synthesis of ideas and a merging of disparate approaches. How will this affect oncology R&D over the next 1–5 years?

A couple of smart readers wrote in asking about these emerging trends, what have we identified so far, and where do we see the oncology space going in the near to medium term future. Now that AACR and ASCO are behind us, what can we learn about the new developments and where they all fit in the oncology landscape strategically?

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Lung cancer, along with metastatic melanoma, has been very much to the forefront of attention in cancer immunotherapies with both nivolumab (Opdivo) and pembrolizumab (Keytruda) garnering approval as monotherapy from the FDA in second line treatment of NSCLC. A third molecule, atezolizumab (Tecentriq) has also been submitted to the authorities for this indication and a decision is expected soon.

Morgan Grafitti Wall

Street art in the Chicago West Loop

While no one is in any doubt that the response rates with monotherapy are low (in the 20% range) and the majority of people do not respond, the important thing so far is that when they do, they appear to be very durable responses. People are living longer, much longer than the 2–3 months of incremental improvement we are used to seeing with chemotherapy or targeted therapies.

The race is now on to see how we can improve things for the 80% of people with lung cancer who don’t respond to single agent therapy:

  • What can we do to help them?
  • Which combinations look more encouraging?
  • Should we treat beyond progression?

To answer these questions, we interviewed Dr Stephen Liu and discussed his views on some of the cancer immunotherapy combination studies presented at ASCO last week.

Dr Stephen Liu

Dr Stephen Liu at ASCO 2016

Dr Liu is a lung cancer expert at the Lombardi Cancer Centre at Georgetown University, and is actively involved in numerous clinical trials, particularly in Developmental Therapeutics.

Georgetown’s founding principle is Cura Personalis, which translates as care of the whole person. It “suggests individualized attention to the needs of others, distinct respect for unique circumstances and concerns, and an appropriate appreciation for singular gifts and insights.”

Dr Liu embodies this ideal, advocating for his patients for access to the best research advances, including genomics and clinical trials of promising agents.  At ASCO, he kindly highlighted some of the important findings from Chicago and offered context on why they matter to the field.

He told us one combination was “potentially transformative” and could be “practice changing” in lung cancer with more data.

Intrigued? To find out what these important trials are and which ones to watch out for, subscribers can log-in to read the article.

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Miami Beach

Miami Beach Lifeguard Tower

This week I’ve been at an American Association for Cancer Research (AACR) conference in Miami on “Targeting the Vulnerabilities of Cancer,” part of their Precision Medicine Series (Twitter #AACRpm16).

What’s interesting about AACR small specialist meetings is as well as listening to high quality talks, they create a relaxed atmosphere for networking and catching up with experts informally. The conference this week was relevant to anyone with an interest in cancer drug discovery.

Dr Bernie FoxAlthough cancer immunotherapy remains the hottest topic in cancer drug development, we shouldn’t forget that there are other therapeutic targets worth exploring; several potential new opportunities were highlighted in Miami.

As readers know we don’t share unpublished data on the blog, so what I’ve done is provide a top-line summary of some of the strategic themes and key take homes I took from several of the presentations.

As an aside, If you haven’t already done so, do listen to the latest episode of the Novel Targets podcast – Of Mice and Men – it features excerpts of interviews recorded at the recent AACR annual meeting in New Orleans. I was surprised by some of what I heard!

For more information on forthcoming AACR meetings and workshops, check out the events calendar on the AACR website.

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Driving St Charles StreetcarAfter exploring the science behind chemotherapy improving T cell trafficking into the tumour yesterday – which is one of the key rate limiting issues that need to be addressed with immunotherapies such as checkpoint blockade – some obvious follow-up questions comes to mind:

  1. Does the compelling data in mice translate to humans?
  2. Can chemotherapy turn a cold tumour into a hot one?
  3. Will patients have improved outcomes as a result – or not?

It’s easy to dismiss traditional therapies in favour of appealing new developments, but what happens when we combine them?  Do we get additive effects, synergies or a negative impact?

As part of our ongoing AACR coverage, we explored this conundrum in the context of new data readouts, as well as the broader competitive landscape.

What we found was really interesting!

BMS, Merck and Genentech/Roche all have trials ongoing in the metastatic colorectal cancer space, with very different approaches being taken.  Does it matter?  Which one’s driving the bus?  We summarise these trials and offer some strategic insights on this niche.

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One of the unintended consequences of the rise of cancer immunotherapy has been the fall in interest from patients who might be candidates for entry into clinical trials for other therapies, such as chemotherapy and targeted agents, for example.

St Charles Streetcar New OrleansA number of industry friends have uniformally expressed concern over how difficult it has been enroll such trials and bemoaned the broader – and often not anticipated – effect to the extent that some trials have even been terminated.

This situation often occurs, not because of lack of efficacy or severe side effects, but simply a lack of enthusiasm and low accrual rates. Quite a few patients consider chemo to be nothing short of ‘poison’ and don’t want anything to do with it as a result, unless it can be avoided.

Here’s my advice to those in this situation – stop moaning, start re-thinking, and re-positioning your agent in a different light to the investigators who enroll these studies. If they lack heart, in a highly competitive world, you have to stand out and thus, everything flows from the basic rationale of what you’re trying to accomplish.

What exactly do we mean by that?

Yesterday, we discussed one of the rate limiting steps in the cancer immunity cycle – getting more T cells into the tumours so that that subsequent immunotherapy can be even more effective.

One way to do that?

Chemotherapy!

At AACR recently, we came across some intriguing ideas and approaches that are being discussed and explored, which may open many people’s eyes and minds. It rapidly became clear during discussions with several experts that all is not what it seems, and smart companies are already taking advantage of the new science that is emerging as well as a deeper understanding of the underlying biology of how the immune system behaves in cancer patients.

Here, we offer insights from our latest interview with a thought leader in the field for his perspective on how we can improve response rates and outcomes with cancer immunotherapy.

Fair warning: I must confess that it opened my own mind to fresh ideas and different approaches in an unexpected way – you may experience the same sentiments.

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Aggressive lymphoma… the very phrase is enough to send chills down your spine!

ASH Annual MeetingIn the past, much of the focus at previous American Society of Hematology (ASH) meetings in this area has focused on the myriad of chemotherapy regimens and dose/schedule optimisations that followed in trying to boost patient outcomes.

This year, I’m pleased to say that things have quite a different flavour with numerous new therapeutics and promising combinations in development.

Some of these are inevitably hypothesis testing, while others will be up-levelling to large randomised controlled multi-centre trials.

As part of our ongoing preview series, we take a look at the different categories to watch out for beyond chemotherapy.  These include monoclonal antibodies, antibody drug conjugates, targeted therapies and yes, even immunotherapies.

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