There’s been another disturbance in the force – as luck would have it, after mentioning renal cell carcinoma (RCC) in yesterday’s post, BMS subsequently put out a press release on the CheckMate–214 study exploring the combination of nivolumab plus ipilimumab in the previously untreated metastatic setting.
The results to date were mixed, so what does this mean and what’s impacted by the findings?
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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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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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As we start to see early readouts from new IO combos and also new trials emerge to begin enrolling patients, it’s going to be intriguing to see how the new cancer immunotherapy landscape evolves.
Some of these trials will be random in that the drugs are what the company has, others will be based on existing or new collaborations, while others will be based on rationally based science… not all will be successful, though.
Of course, it’s easy for all of us to be an armchair critic and grumble about the flaws, the problems, and even the weaknesses in clinical trials, but what about rational approaches that attempt to scientifically address the acquired resistance that develops on montherapies?
Here’s one approach I really like – we’ve written about the underlying biology behind it previously, but what about the clinical trials, and what does the company evaluating the combos think?
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Until recently, we followed the race to market in EGFR T790M lung cancer with Clovis’s rociletinib and AstraZeneca’s osimertinib (Tagrisso). In phase 2, AstraZeneca caused quite a stir when they came from behind and leapfrogged their biotech rival with a large global randomized controlled trial seemingly out of nowhere. They never looked back.
Can they do the same thing with durvalumab (Imfinzi), one of their IO therapies that targets PD-L1?
If there’s one thing that many astute observers of the IO space have learned this week it’s that irrational exuberance and the hopeful sentiment that ‘everything’ will just tweak the immune system and work positively no matter what has thankfully come to an end.
We’ve seen several highs and lows already with Merck’s pembrolizumab gaining accelerated approval in 1L NSCLC in allcomers when combined with chemotherapy and AstraZeneca reporting positive phase 3 data for durvalumab in unresectable (stage 3) NSCLC based on meeting the study endpoint (PFS).
There is much to be learned because the nivolumab disaster in 1L NSCLC last year was not a singular aberration given that durvalumab has seen some missteps in the past and even atezolizumab had some unexpected news with urothelial cancer this week (Check out our insights), as compared to chemo in the second line setting. Just like mutations, there will be many more to come, perhaps even some additional ones before the year is out.
What about today’s news from AstraZeneca in unresectable NSCLC?
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We’re overdue a roundup and discussion on various key topics of interest to BSB readers, so here goes…
Today’s topics include an in-depth look at the impact of some negative events:
- Kite and the cerebral oedema death with axi-cel
- Genentech’s atezolizumab OS miss in urothelial cancer
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We’ve been saying for a while that 2017 and onwards would be when we start to see a few IO combination trials start to shake out. Interestingly, that process seems to have already started, if recent news is any thing to go by.
With this in mind, the annual meeting of the American Association for Cancer Research (AACR) coming up this weekend gives us a timely moment to explore combinations that are looking interesting… or not.
In the last of our AACR 2017 Conference Previews, we take a look at what to expect on this year’s program in the IO and Checkpoint arena. In short, it’s quite a lot and not without some controversy either!
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Today for the second AACR 2017 Preview, I wanted to switch things up a bit and turn from looking at an important trend to a specific tumour type. One of the reasons for this is that we received questions from readers about recent data presented at medical meetings in this sphere.
It’s also not something that we have covered extensively here on BSB, so looking at something in a different light is often a good idea since insights and intelligence can sometimes jump out afresh.
Given that there are also some important clinical trial results emerging here, this is something we can expect to return to in Washington DC when the data is presented at AACR next month. What can we learn ahead of the event though? It turns out the answer is quite a lot.
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With the advent of single agent checkpoint blockade and success in melanoma, lung and urothelial carcinomas has come the realisation that the majority of patients do not respond and even some that do have a response of short duration. Immune escape and adaptive resistance are not an uncommon occurrence.
There has been much focus of late in looking at ways to address this by uncovering the relevant mechanisms underlying the biology of the disease and this is an avenue we can expect to see more research evolve. We already know that JAK1/2 upregulation and PTEN loss have lead to resistance with checkpoint blockade – what about other possible mechanisms?
Indeed, at the ASCO-SITC meeting in Orlando last week, another such target emerged and clinical evaluation is already underway, making it a worthwhile area to explore.
Here we take a look at the science and biology, as well as the emerging clinical landscape to see which companies are involved and may get a jumpstart on the combination niche.
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As we move from monotherapies to combinations in the immuno-oncology space, we start to see some intriguing ideas being explored from additional checkpoints to vaccines to neoantigens to immune agonists to oncolytic viruses. There are numerous ways to evaluate how to boost or jumpstart more immune cells upfront in the hope of seeing better efficacy.
One way to do this is to better understand the tumour microenvironment.
Wall of people at ASH16 in San Diego
If we know what’s wrong under the hood, we might be better able to make the immune system get going… more gas, faulty starter motor, dead battery, loose wire, broken fan belt? All these things and more might be a problem so you can see that diagnosing the issue up from from basic and translational work might be instructive for clinical trials.
If you don’t know what problem you’re trying to fix or repair then you might as well be throwing mud at the wall. Just as we don’t expect a car mechanic to suggest changing the battery or starter-motor without first diagnosing the issue, so understanding the tumour microenvironment in each different cancer or disease might also be a helpful strategy.
At the recent American Society of Hematology annual meeting (#ASH16), there was a fascinating sceintifc workshop that focused on this very concept – what’s going on under the hood and how do we go about fixing it?
Here we explore these ideas via an interview with a thought leader and specialist in the field. What he had to say was very interesting and candid indeed.
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