Medical Director, LCC Cancer Center | Honest, data-first oncology trial analysis (PFS ≠ OS). Community practice perspective.
New Jersey, USA
Joined February 2010
- Tweets2.7K
- Following2.3K
- Followers2K
- Likes1.5K
One caveat on ‘SoC’: the control arm got no pembro, which most PD-L1 CPS ≥1 US patients would get. In the PD-L1+ (TAP ≥1) subgroup, the triplet’s OS gain wasn’t significant (HR 0.82; exploratory). No head-to-head data vs pembro + trastuzumab + chemo.
Sadly I’m not surprised. Journals quietly signing off on inflated framing has been all too common for years. Calling a descriptive OS a “positive OS result” is a textbook case, and I agree it should have been caught.
“Prespecified descriptive OS analysis.” Those words should give us pause. Calling this a “positive OS result” in a phase 3 trial manuscript is misleading when OS was outside the formal testing strategy. The results are encouraging, but an OS benefit has not been formally demonstrated in this analysis.
I’m surprised this framing passed journal review. Oncologists and patients shouldn’t need to close-read a manuscript like English professors to understand whether a trial formally demonstrated an OS benefit. Put the bottom line up front.
@Timothee_MD @oncology_bg @SusanGKomen @BCRFcure @OncoAlert @Annals_Oncology @myESMO @ASCO @AACR @SABCSSanAntonio
Thanks for sharing.
Agree. The OS p is nominal, and it's open-label with 7.9% of controls withdrawing consent at randomization vs 3.3% on ribo.
A 2.1-point gap when most relapsed controls didn't get a 1L CDK4/6i isn't a reason to change US practice imo.
NATALEE 6-y results are out! #ESMO26
2.1 delta in survival at 6 years.
Thanks @Annals_Oncology for reporting subsequent therapy data!
👉Only 44.4% of control arm patients with distant recurrence received a first-line CDK4/6i
Does this survival difference truly inform clinical practice in settings where CDK4/6i are standard of care for metastatic disease?
In my opinion, the answer is no.
Agree access at recurrence is a problem. But if US patients get the CDK4/6i at relapse and OS barely moves, then persistent iDFS here mostly means delaying the same outcome, not changing it.
NATALEE study @myESMO shows persistent iDFS and emerging OS signal. Given treatment options for MBC, the treatment upon recurrence matters. Fewer than half the patients in the ET-alone arm get CDK46i on recurrence. Which poses the question: how relevant are OS data to US/OECD outcomes? In the online publication, the OS difference is smaller, and not statistically significant, in US/Western Europe.
annalsofoncology.org/article…
Sobering, agreed. It missed its own pCR bar, though with no chemo comparator and pCR a weak surrogate in HR+ disease, that's all it can tell us.
Three cases of grade 2 ILD and a death are a lot to see in patients treated with curative intent. The 2022 interim data already suggested anastrozole added nothing.
In HER2-low disease, T-DXd's proven benefit is still metastatic.
Probably first negative trial for Trastuzumab deruxtecan. Talent trial. For early stage HR positive Her2 low EBC @myESMO #esmo26 @OncoAlert
Agree, and that monopoly is already eroding. Editors still decide what gets printed. They no longer get the last word on what it means.
Two percentage points is small. We accepted it for taxanes, sure, but that doesn't make it the right bar. NATALEE's OS p-value is nominal, and we don't know how many controls got a CDK4/6i at relapse (in monarchE only 47% got one in 1L), so some of this could be CDK4/6i vs none rather than early vs late. Also open-label, and 7.9% of controls withdrew consent at randomization vs 3.3% on ribo.
Today at #ESMO26, the 6-year results of NATALEE will be presented. Ahead of the presentation, my personal view on the survival gains with adjuvant CDK4/6 inhibitors…
The 6-year OS rates in NATALEE were 91.86% vs 89.73%: an absolute gain of 2.1 percentage points (HR 0.809; 95% CI 0.661–0.989; nominal one-sided p=0.019).
The absolute 7-year OS gain in monarchE was 1.8 percentage points (HR 0.842; p=0.027). I do not think these gains should be dismissed as “only 2%.”
In the EBCTCG analysis, adding taxanes to anthracycline-based chemotherapy—an approach we have accepted as standard for years—provided an absolute 5-year OS gain of approximately 1.9 percentage points. The populations and follow-up periods differ, so we cannot directly compare treatment efficacy. However, the standards we use to judge a few percentage points of survival benefit should be consistent.
Moreover, 95.4% of patients in monarchE had already received chemotherapy. This survival gain represents an additional benefit on top of chemotherapy and endocrine therapy.
Patient selection, toxicity, treatment duration, and cost certainly deserve discussion. However, the survival benefit of adjuvant CDK4/6 inhibitors in appropriately selected patients should not be underestimated.
Not ready to call NATALEE an OS win. The p=.019 is one sided and nominal, on the 5th look at survival.
More than twice as many control pts dropped out right after randomization, and post-relapse CDK4/6i use in the control arm hasn't been reported .
NATALEE at 6 years:
Ribociclib + NSAI vs NSAI alone in HR+/HER2− early breast cancer:
• 6-year OS: 91.86% vs 89.73%
• OS HR 0.809 (95% CI 0.661–0.989); nominal 1-sided P=0.019
• Absolute OS benefit: 2.1%
• 6-year iDFS: 83.23% vs 77.92%
• iDFS HR 0.741 (95% CI 0.646–0.849)
• Absolute iDFS benefit: 5.3%
Is OS significant?
Looking forward to full data .@Timothee_MD @myESMO
@OncBrothers @OncoAlert
#ESMO26 #BreastCancer #NATALEE
HR 0.58 is right where the phase 2b was, and they used a real pembro control, which I give them credit for.
Unfortunately this is RFS on top of a pembro backbone that was itself approved on RFS. COMBI-AD showed big adjuvant RFS and DMFS gains with no significant OS difference.
Patients who recur now have good salvage options, so treating earlier isn't necessarily curing more people.
Fever in 52% vs 8% means nobody was really blinded. I'd want OS before calling this a new standard.
These results with adjuvant Moderna personalized vaccine added to pembro for melanoma look good to me, and are a positive indicator for the adjuvant and perioperative lung cancer trials. #LCSM
Usage isn't survival, and popularity isn't clinical benefit. A pharma-funded tool that's wrong often enough to matter sounds more like a bioethics case study than a success story.
AI is already inside the doctor’s visit, even when patients don’t realize it. More than half of physicians consult OpenEvidence AI tools regularly.
The evidence on where AI helps most is becoming clear: diagnostic accuracy and the guideline-driven management of chronic conditions like hypertension, diabetes, and high cholesterol.
Great chatting about how AI can help doctors improve accuracy on @CBSMornings with @GayleKing, @NorahODonnell, and @nateburleson.
Travesty
Just got the saddest denial - denied SBRT C spine for a painful oligomet from NSCLC - but was recommended to do a level 1 2D plan not even level 2 IMRT ! Do better @OscarHealth - my note was exceedingly clear on maximizing pain control and control in a serious location
Most patients are treated in community practices, not academic centers. Many of us would enroll if trials came with funding and research staff. The accrual problem is structural. Asking critics to hold off until they run an RCT doesn't fix it.
I would like more academic oncologists and clinical investigators to lead RCTs or at least help accrue to RCTs. We hear a lot of critiques. But when it comes to implementation we struggle to accrue nationally to most oncology phase III trials.
We are also struggling with just getting investigator initiated oncology phase III trials off the ground.
Well said. There’s no quality data that this cocktail is standard of care, and presenting it as settled is misleading. @ShrutiGkidney’s work tried to move us forward in a data vacuum, and that’s exactly what we should be encouraging.
We should be supportive of generating more high-quality data in this area, which is exactly what @ShrutiGkidney did here with the largest multicenter TTE to date. The data are imperfect, as are the RCTs, but more data is a good thing.
The gist of this request is true with concerns of corruption in the ranks. However, most of these "guidelines" are not in fact guidelines ironically despite being stamped with that moniker.
Agree that fast deep FLC reduction in bx confirmed dx imp, but not aware of solid evidence supporting the Mayo package other than perhaps single institution experience/observation.
This appears to be expert extrapolation based on mechanism rather than something that has been meaningfully tested.
@ShrutiGkidney your trial asks q that everyone else gets outside of Mayo. It also uses right method when RCT not feasible, and enriched with true cast nephropathy.
With respect, this explains the process, not whether it's actually better (far more exorbitant ), and I haven't seen any head-to-head data against AI working off primary literature.
For what UpToDate charges, one best option from a handful of experts is a tough sell now that the summarizing part is basically free.
In my experience newer models are vastly superior and delivering the data. I won't be renewing my
subscription.
Here is the inside story on how @UpToDate does what it does.
From my experience as an author/section editor for UpToDate for 20 years, here is how it works. It’s amazing!
Every day a team of people @UpToDate scour the top medical journals (and major meeting abstracts) for articles of importance. In my case they pertain to myeloma and related disorders. Any article that is felt to be important is sent to a expert MD medical editor at UpToDate who reviews the paper. If the information is felt to be important, the relevant chapter is updated with this content, summarized in a few sentences in Word track and then sent to the author of the chapter who is a top expert in the field.
As an author I have to review the update in detail and then make a decision whether to include the new information, and whether the way it has been incorporated is correct or needs to be edited.
Once I make a decision, it is then reviewed by an expert section editor. For 15 years for me, the section editor was Dr. Robert Kyle! (Currently I’m the section editor and we have about 6 experts serve as authors on over 40 chapters pertaining to myeloma and related disorders). The section editor independently decides whether the author made the right call and either approves or we have a back and forth till we agree.
The updated chapter is then reviewed again by the expert MD editor at UpToDate and then posted.
For important phase III trials or FDA approvals we usually make the update within a week. Sometimes by the next day! With so many important papers, every week there are 2-3 updates pertaining to my chapters that go through the above process! It’s hard work but it keeps me ridiculously current. And more importantly it keeps the content accurate and current. This is not random addition of new information. It’s vetted information that’s added.
Every UpToDate chapter is also peer reviewed annually. Each chapter also undergoes an annual author and editor review to make sure that the overall content and flow is good and to delete content that may be no longer important or accurate. The extraordinary process and rigor involved is why it’s such an invaluable irreplaceable resource. It is AMAZING and hard to replicate.
UpToDate is easy to navigate. But the newly launched UpToDate Expert AI takes it to the next level! It makes the entire content available to query just like you query a top ranked LLM. But it’s not searching the random internet or a stack of published articles. It’s primarily trained and derives vetted and adjudicated UpToDate content. It will not randomly hallucinate. It will not list 10 options for treatment newly diagnosed myeloma but will give you what experts currently feel is the best option based on the latest evidence. All answers are referenced and pointing to specific content sections in UpToDate (which also has links to source material). So you can immediately get all the background information if you need more detail.
Working with UpToDate has helped my career immensely. For the last 20 years it has been impossible for me to not know about every important study related to myeloma and related disorders as they get published! For 20 years, I have received a precise summary of every important article published in my field. More importantly I am forced to read them, review the source material, and make a judgment call. As a result I remember this stuff. A gift indeed!
Open evidence in present form makes way too many mistakes. Buyer beware. Other models are far more accurate.
Johns Hopkins just partnered with OpenEvidence, which reports 1.12 million license-verified US clinicians using it as of September. The line I noticed was not the headline. It was Hopkins’ vice dean for education raising “cognitive offloading”: trainees may lack skills expected of them when they practice unsupervised.
I’m a practicing oncologist, and this is the version of the problem I think about in clinic.
A fellow (and even me) can now get a guideline-concordant answer in seconds. What is harder to see is whether they could have built that answer themselves (I am worried about this skill; this is no joke), and whether they would catch it being wrong on a rare case.
Hopkins is floating a move from time-based to competency-based training (the evaluate doctors based on what they can do, not how much they spent in the hospital). That seems right to me, but competency has to be measured with the tool turned off at least some of the time.
The other issue is hospitals are not incentivized to graduate fellows earlier even if they met the competencies because they are cheap labor, so this competency thing I am not buying it, and I might be wrong.
Financial terms were not disclosed, and use cases are still being defined, so this is early.
Should board exams and fellowship evaluations assume AI access, or deliberately test without it?
We don't know all of the details however presumably this was stage one disease and the standard of care is surgery not recovery time.
I hope that the #RadOnc community and @ASTRO_org can take a step back and reflect on posts like this....
Maybe, but either way the regimen that won isn't the one tested in NHL-2. ASH won't change my mind. Epcor won on PFS in DLBCL-1 and missed US OS (HR 0.96). Pola never showed OS either. Show me survival.
