Thoughts?

[Lamount]

Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I–III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial - Nature Communications

The authors previously reported the primary outcomes of a randomized phase II trial comparing neoadjuvant durvalumab (anti-PD-L1) alone or in combination with stereotactic radiotherapy in patients with early-stage NSCLC. Here, the authors report the secondary outcomes of the trial and post hoc...

www.nature.com

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[RadRadRad]

It’s a trial with radiation in it !
If sbrt was a drug the major path response difference would be celebrated and this would be new soc😂

 

[NotMattSpraker]

Im very interested in the concept. Im very surprised at the paper, it's just written so weird. It's titled as if durva alone is a standard of care for ES NSCLC and the methods are incompletely reported. I wonder if this is because biology-driven human clinical trials are often powered by funding, not an up front hypothesis.

"Sample size calculation for this trial was based on the previously reported primary endpoint of MPR". What?

Makes me think of Stiles paper, similar approach, just written differently. Wonder if these groups are related?

I could see the rad bios getting hyped on this, any thoughts?

Surgical resection after neoadjuvant durvalumab and radiation is feasible and safe in non-small cell lung cancer: Results from a randomized trial - PubMed

In this randomized trial, the addition of sub-ablative focal radiation to durvalumab in the neoadjuvant setting was not associated with increased mortality or morbidity compared with neoadjuvant durvalumab alone.

pubmed.ncbi.nlm.nih.gov

 

[RadOncMegatron]

Did I read this right? They randomized people with curable cancer to certain death using Durva alone and highly likely death with Durva + Palliative SBRT? Please tell me I didn’t read carefully…

 

[NotMattSpraker]

Did I read this right? They randomized people with curable cancer to certain death using Durva alone and highly likely death with Durva + Palliative SBRT? Please tell me I didn’t read carefully…

See!

They had surgery. It's a cool concept. This is trying to enhance the standard of immuno--> surgery with... I guess... immunogenic RT.

Formenti loves 8x3, Ralph seems to hate it. I will admit that people put an awful lot of faith in 8x3 based on a very cool but very, very small study that is partially in animals.

Im just here to eat popcorn and enjoy the show.

 

[RadOncMegatron]

See!

They had surgery. It's a cool concept. This is trying to enhance the standard of immuno--> surgery with... I guess... immunogenic RT.

Formenti loves 8x3, Ralph seems to hate it. I will admit that people put an awful lot of faith in 8x3 based on a very cool but very, very small study that is partially in animals.

Im just here to eat popcorn and enjoy the show.

Ok, glad to hear there was surgery. If so then cool concept, but I have my doubts.

 

[elementaryschooleconomics]

See!

They had surgery. It's a cool concept. This is trying to enhance the standard of immuno--> surgery with... I guess... immunogenic RT.

Formenti loves 8x3, Ralph seems to hate it. I will admit that people put an awful lot of faith in 8x3 based on a very cool but very, very small study that is partially in animals.

Im just here to eat popcorn and enjoy the show.

Ralph hates almost everything.

It's easier to list all the things Ralph doesn't hate:

1) People doing research that involves a pipette (living)
2) People doing research that involves a pipette (deceased)
3) Run-on sentences
4) Erotic fanfiction where RadOncs are paid a Pediatrician's salary

 

[communitydoc13]

Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I–III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial - Nature Communications

The authors previously reported the primary outcomes of a randomized phase II trial comparing neoadjuvant durvalumab (anti-PD-L1) alone or in combination with stereotactic radiotherapy in patients with early-stage NSCLC. Here, the authors report the secondary outcomes of the trial and post hoc...

www.nature.com

Is PFS even an appropriate endpoint here? I mean, this is not a paper that you reference in tumor board to support 8x3.

Disease free survival essentially the same in both groups with equivalent numbers disease free in both arms despite the difference in MPR. This indicates that MPR may not be the most important endpoint for resectable patients.

DFS does not favor the inclusion of XRT.

How do they even define PFS in the setting of patients treated to NED? Where are these number coming from. Extraordinarily confusing.

Molecular measures of robust immune response correlating positively with outcomes is not surprising. I swear, someone should just look at how these markers scale with the age of the patient. Maybe they have.

Certainly not meeting the standard of truth being evident in simple graphics! To paraphrase Edward Tufte.

 

[Ray D. Ayshun]

Is PFS even an appropriate endpoint here? I mean, this is not a paper that you reference in tumor board to support 8x3.

Disease free survival essentially the same in both groups with equivalent numbers disease free in both arms despite the difference in MPR. This indicates that MPR may not be the most important endpoint for resectable patients.

DFS does not favor the inclusion of XRT.

How do they even define PFS in the setting of patients treated to NED? Where are these number coming from. Extraordinarily confusing.

Molecular measures of robust immune response correlating positively with outcomes is not surprising. I swear, someone should just look at how these markers scale with the age of the patient. Maybe they have.

Certainly not meeting the standard of truth being evident in simple graphics! To paraphrase Edward Tufte.

Does this dfs favor the inclusion of immunotherapy?

 

[communitydoc13]

Does this dfs favor the inclusion of immunotherapy?

No comparative arm regarding IO. All pts got IO upfront and most (not randomized) adjuvantly as well. There was a notable disparity in median time on IO adjuvantly with XRT patients getting more on average. I would not read into any of that too seriously.

Group is so heterogeneous, I wouldn't know how to compare DFS numbers to historic standards.

 

[NotMattSpraker]

No comparative arm regarding IO. All pts got IO upfront and most (not randomized) adjuvantly as well. There was a notable disparity in median time on IO adjuvantly with XRT patients getting more on average. I would not read into any of that too seriously.

Group is so heterogeneous, I wouldn't know how to compare DFS numbers to historic standards.

Unless I missed something, they didnt even really report out how they powered the study. All they say is based on historical response data. They didnt give any numbers.

This is all about the cells. I couldn't make any kind of real comparison of the clinical outcomes between the arms given the methods in the paper.

 

[A_DeMichele]

negative trial?

 

[Palex80]

negative trial?

The primary outcome was reached, the trial was positive for that outcome. But that was already reported, and it was a self-fullfilling prophecy.

Indeed however, like you point out, the idea that the "immunomodulatory" 3 x 8 Gy would "boost" the Durvalumab efficacy concerning overall disease control long-term, did not materialize. And that was the important part of the trial.

As always, an obligatory meme:

 

[RadRadRad]

I have Medoncs pushing hard for chemoimmuno then surgery based on path cr rates

I think the fact that this trial shows so much higher major path response rates with addition of radiation is a useful tool to help push back. (Along with the category 1 nccn recommendation, the crappy pfts, the medical comorbidities, the fact the tumor isn’t even resectable….😂)

 

[thesauce]

I have Medoncs pushing hard for chemoimmuno then surgery based on path cr rates

I think the fact that this trial shows so much higher major path response rates with addition of radiation is a useful tool to help push back. (Along with the category 1 nccn recommendation, the crappy pfts, the medical comorbidities, the fact the tumor isn’t even resectable….😂)

We have entered an era where we are simply in direct competition with medoncs. They will twist and distort the facts and evidence to allow them to offer only what they offer. In the 99% of cases where it doesn’t work, they’ll come up with an excuse and turn around and do it again. For the 1% where it works, they’ll highlight this in the next tumor board as justification.

 

[medgator]

We have entered an era where we are simply in direct competition with medoncs. They will twist and distort the facts and evidence to allow them to offer only what they offer. In the 99% of cases where it doesn’t work, they’ll come up with an excuse and turn around and do it again. For the 1% where it works, they’ll highlight this in the next tumor board as justification.

All the more reason why multi specialty owned centers are the wave of the future, assuming ASTRO PAC doesn't succeed in trying to kill off the in office ancillary exemption for radiation equipment

 

[Lamount]

Is PFS even an appropriate endpoint here? I mean, this is not a paper that you reference in tumor board to support 8x3.

Disease free survival essentially the same in both groups with equivalent numbers disease free in both arms despite the difference in MPR. This indicates that MPR may not be the most important endpoint for resectable patients.

DFS does not favor the inclusion of XRT.

How do they even define PFS in the setting of patients treated to NED? Where are these number coming from. Extraordinarily confusing.

Molecular measures of robust immune response correlating positively with outcomes is not surprising. I swear, someone should just look at how these markers scale with the age of the patient. Maybe they have.

Certainly not meeting the standard of truth being evident in simple graphics! To paraphrase Edward Tufte.

"Disease-free survival was defined as the time from randomization to recurrence of lung cancer and/or death from any cause, whichever occurred first. To specifically deter-mine the impact of treatment on oncologic outcomes, we conducted an unspecified post hoc analysis assessing progression-free survival (PFS) in all patients who underwent the planned surgical resection. Progression-free survival was defined as the interval from surgical resection to lung cancer recurrence or death from lung cancer."

Seems like PFS in this case specifically looked at progression and cancer related deaths, as opposed to DFS which looked at all death. PFS was assessed from time of surgery whereas DFS was assessed from randomization (4 pts in each arm didn't even get surgery). PFS, in this case, has the feel of a "per-protocol, cause-specific survival". Given that the non-cancer related deaths SEEM unlikely to related to toxicity, it seems fair to me to present this "PFS" as they did.

Study was clearly flawed in number of ways, not the least of which that 20% of pts have EGFR mutation, for whom Durva was almost certainly unhelpful.

My take is that this presents an interesting way forward for RT in resectable stage III patients in the post-CHECKMATE 816 world... but certainly needs a better trial to evaluate it going forward. Wonder if AZ is considering a "PACIFIC-35" (or whatever number they are up to now), looking at this in the phase III setting such that it is powered to assess DFS or "PFS"

 

[medgator]

My take is that this presents an interesting way forward for RT in resectable stage III patients in the post-CHECKMATE 816 world... but certainly needs a better trial to evaluate it going forward. Wonder if AZ is considering a "PACIFIC-35" (or whatever number they are up to now), looking at this in the phase III setting such that it is powered to assess DFS or "PFS"

Some of us never see stage 3 pts go to surgery. And i sleep perfectly fine at night outside of the occasionally large T4 where i might push it

 

[Lamount]

If neo IO/RT was shown to decrease recurrences for resectable stage III, most surgeons I know would refer in a heartbeat... they are as happy as anyone to have fewer pts recur and with this approach, there would likely less attrition than neo IO/chemo

 

[communitydoc13]

an unspecified post hoc analysis assessing progression-free survival (PFS) in all patients who underwent the planned surgical resection. Progression-free survival was defined as the interval from surgical resection to lung cancer recurrence or death from lung cancer

I mean …yikes!

This is almost an unethical presentation of things IMO.

Their analysis of PFS uses a definition that is not strictly standard IMO (I believe death by any cause is typically included in PFS) and is contingent on the assignment of 4/7 total deaths in the combined arm to causes other than lung cancer and 0/6 deaths in the monotherapy arm to causes other than lung cancer.

Meanwhile, the number of patients alive in both arms with NED is the same.

It's just a total crap presentation. It's misleading. I would have preferred that the authors left the creative PFS tangent out of the paper and focused on the cellular aspect of stuff...but they would probably not be getting a Nature communications paper out of that.

I want to stay in the game too.

 

[evilbooyaa]

It's resectable cancer. Just take the damn thing out. Neoadjuvant IO alone? Where is data for doing Surgery alone +/- neoadjuvant IO?
SBRT 8Gy x 3 is bull**** to me and doesn't matter and will never affect a real oncologic endpointe. It will never make one lick of difference in a curative scenario. Every evaluation of 8Gy x 3 in humans in a curative intent scenario has been basically negative to anyone who doesn't want to twist them into a pretzel to achieve a positive outcome and continue their careerism.