With so much data to cover recently, we haven’t have time for a perennial favourite, the monthly mailbag to answer BSB reader Q&A on hot oncology topics.
October has brought out quite a lot of controversy to consider, most of it happening in the last week!
Here, we consider questions on Immune Design’s phase 3 trial with their NY-ESO-1 vaccine, CMB305, which attracted both a lot of market attention and also questions from readers.
We also review a bunch of questions relating to 1L NSCLC and the upcoming readouts. This niche is probably potentially one of the most competitive spaces in oncology R&D at present and readers seem almost insatiable for information on this topic.
It is quite a turnaround considering the last decade of numerous failed trials or even non-inferiority studies that were being conducted.
Like many readers, I can well remember sitting in freezing cold, half empty halls wondering if the latest chemo or targeted therapy doublet was going to offer a mere 2-3 months improvement in PFS and no OS benefit or not. It was that binary and also depressing.
With the possibilities offered by immune checkpoint blockade, in a short space of time 1L NSCLC has gone from graveyard to uber intense with several companies vying to demonstrate improvements in overall survival by 6 months or more.
There’s a lot more to come here and not all of the lung trials will be positive – that’s expecting too much against the game of chance. Here, we look at numerous factors that could make a difference, both positive and negative.
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It really doesn’t feel like a year since we were at ESMO in Copenhagen, in what was probably the most exciting meeting of the year in many ways.
With the ASCO abstract deadline being in Jan/Feb, ESMO offers a great opportunity for companies to have another major slot in the calendar to present ground breaking data. In some ways, having positive data at a European meeting can actually amplify positive studies that might otherwise get lost in the noise at ASCO, which is almost becoming too big.
So what’s in store now that the meeting is upon us?
There are some large and small trials with important data on the first two days that bear thinking about and further discussion.
Here’s our take on the first batch of readouts, including some surprises…
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Madrid city center
Greetings from Vienna, Austria! Fresh off a red eye… we’re en route to one European cancer conference in Germany, while writing about another one in Madrid.
This latest preview looks at some of the key IO studies that are either intriguing or have potentially interesting results that BSB readers have written in asking us about.
There are some targeted therapies thrown in too for good measure too, as there are some IO-targeted combos to look at, as well as IO-IO approaches.
What I want to accomplish in this latest preview is point out some elements of what we call ‘interestingness’ where people should be watch or wary of either jumping to conclusions or making comparisons across trials and arriving at assumptions that may not turn out to be valid. My best advice here is to always be sceptical and assume there’s no concordance and that way you won’t be caught unawares. It’s easier said than done, though.
Indeed there were so many questions about ESMO that we needed two preview posts to cover many of the questions we received.
Part 2 should roll out tomorrow, wifi on the road permitting – stay tuned for more on ESMO17.
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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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