Thread by @BrendonStilesMD

Time to weigh in with a thread on the #ADAURA trial presented at #ASCO20. I have been thinking about it carefully and listening to the chatter on #Twitter and other sites. Have also watched w/ interest the back and forth b/t @jackWestMD and @n8pennell #lcsm

(By the way, @JackWestMD and @n8pennell make @drewMoghanaki and me look like amateurs…) #lcsm

This will be insufferably long (@lcsmchat long!), so I apologize in advance. #lcsm

I should preface my comments by acknowledging that I have consulted and been on AdBoards for @AstraZeneca – my detractors may point this out and it is important to give that caveat. That said, I have learned a lot at those meetings. #lcsm

However, if I don’t like what @AstraZeneca is doing, I won’t hesitate to speak up. For example, I think the PACIFIC-4 trial giving durvalumab for 2 years to inoperable early stage patients who have received #SBRT is crazy. #lcsm

Although I agree that #SBRT alone isn’t enough based on path response rates, what “inoperable” patient can tolerate ICB for two years? Their non-cancer life expectancy may only be 2-3 years. And if they are early stage do they even need extra therapy? #lcsm

(Notice how in the last tweet I managed to take a dig at my #RadOnc friends even though it is completely off topic!) #lcsm

Also important disclosure is that @lcrf_org, the not-for-profit that I chair, funded a lot of the work that helped develop osimertinib. I am very proud of that and really want the drug to succeed. Probably leads to more inherent bias on my part than any payment. #lcsm

The #ADAURA trial presented at #ASCO20 addresses an important question: Why do we NOT give adjuvant therapy based on targeted molecular alterations, when we know that those drugs are better for patients in the stage IV setting? #lcsm

This cohort is important given their poor survival with surgery and adjuvant chemo. Our group and others have found worse survival in stage II/III never smokers (presumably enriched for driver mutations) than in ever smokers. #lcsm jtcvs.org/article/S0022-…

The control arm in #ADAURA and in the older RADIANT studies also show disappointing outcomes in these patients after surgical resection. #lcsm

It is also important to note that adjuvant chemotherapy in general…sucks. At best, we probably only get a 5% overall benefit to survival over surgery alone. Clearly we can do better here. Why not apply advances that have already been made in stage IV? #lcsm

So first off, #ADAURA was a well-designed trial. Investigators staged patients well, allowed for standard of care treatment, and fit the design into real world practice. #lcsm

The difference in DFS is remarkable with a HR of 0.17. Yes, I would like to see OS, but this is a remarkable start – DFS differences better than LACE meta-analysis, better than E1505 (bevacizumab), better than MAGRIT (MAGE-A3), and much better than CTONG 1103. #lcsm

I believe DFS is an important end point to patients. Oncologists generally see stage IV patient who will ALWAYS have cancer. I see patients who have had their cancer resected who hope and think they do not have cancer. It is a very different mindset. #lcsm

Almost every single one of my patients I see for surveillance (over half of my clinic visits), is there b/c they want to know if their cancer has come back. The #scanxiety weighs on them immensely. If I tell them it has come back, it is devastating. #lcsm

This makes DFS meaningful to me - but of course we have to ask the individual patients. #lcsm

We should also understand the difficulty of OS as an endpoint in the adjuvant space. Consider E1505. Began enrolling in 2007, published not until 2017. Negative trial. An incredible cost and loss of patients’ efforts. #lcsm

What are the chances if we wait 10 years for an OS readout that the field will have already moved past that drug or treatment scenario?
Answer - high.
Does this not devalue the efforts of the patients who bravely entered into the trial? #lcsm

Furthermore, when this trial started, osimertinib wasn’t approved in first line setting and it was unknown whether it was the “best” drug. To say that to power the trial to DFS was a purposeful money grab is disingenuous….

Like others have suggested, I wish that progressing patients in control arm all get osimertinib - it is the best drug out there. BUT…if they don’t isn’t that reflective of real world practice rather than “rigging the trial”? We need to change real world practice. #lcsm

It has also been criticized that all patients didn’t get adjuvant chemo. Well…why would we give all patients adjuvant chemo when benefit has only been shown to be around 5%? Most stage II and III patients don’t get it. pubmed.ncbi.nlm.nih.gov/29849954/

That leads me to another point. 74% of you though that a #MedOnc was most important determinant of who gets adjuvant. Ahhhh….the hubris! While I agree that your voice and an MDT are important, you underestimate the surgeon’s role. #lcsm

Surgeons definitively stage the patients, are often the first to broach adjuvant therapy, and heavily influence both referral and decision patterns for patients considering adjuvant therapy. #lcsm

I can’t believe that less than 50% of stage II-III patients who successfully got through a cancer operation don’t get adjuvant therapy b/c the oncologist said “no”. The surgeons influenced them. We have a unique relationship with our patients.

Finally…will the remarkable difference in DFS lead to an OS benefit? I believe it still will. Yes, I have seen other trials where similar differences didn’t hold up. But how could the trial not be stopped with such drastic separation?

I am sensitive to the financial issues and the cost of the drug. I applaud those who have raised the issue. But it is disappointing to me to see this distract from the science and from efforts of the patients who volunteered for the trial. #lcsm

Yes, we should raise our voice about drug prices – but this is a systemic issue w/ many contributing factors. When we see a drug that we know benefits patients, we should focus on the science, the outcomes (including harms), and on the individual patients in front of us. #lcsm

The cost conversation should come, but don’t let that blind you to the science and to meaningful outcome differences for patients. #lcsm

Yes, IF the FDA should approve, I would describe the data about adjuvant osimertinib to my patients, including risk/benefit, side effects, and costs.

But I would also strongly recommend that my patients take the drug. We can do better for our patients. #science #lcsm