ADAURA

[scarbrtj]

Off-top-of-head impressions 'bout ADAURA trial. From one rad onc's perspective.
1) This makes surgery more likely, radiation less likely, in the minds of many treating physicians for lung cancer (EGFR mutated lung ca). Won't be huge shifts, but anyone with an imagination can see all the trend lines.
2) Osi costs about $200K/year from what I've heard. This is 3 years of therapy after surgery. So at least $600K per patient. Holy moly.
3) People harping on the "oligometastatic paradigm" (saving rad onc) need be mindful that this paradigm gets robbed by successes with drugs like osi.
4) The real question: would anyone think about or push for osi after lung SBRT for the right patient?

But for real: the oncological success some of these drugs are having... I'm very jealouse.

---

Members don't see this ad.

 

[taserlaser]

Quick bullet point thoughts:

No doubt some oncologists and patients will be swayed by this trial. Huge boom for pharma here. Everyone here though knows RT is very cost effective. Will things change in a cost constrained Oncology paradigm? In other countries other than US, maybe. Marketing plays a role here - any trial that doesn’t show OS gets poo pooed by some ROs where this has not shown OS difference (yet? Or ever, we don’t know)

Quick criticisms and thoughts on ADAURA from VP:



Some med oncs I’ve worked with, for patients on TKI, if they have had good disease control and now have oligoprogression have referred for SBRT. Maybe get more out of that line if drug. Lot of questions remain in these circumstances.

 

[BruiservonWillebrand]

In my practice, there are not many operable Stage II and, even moreso, Stage III patients.
I would view those curves as suggesting only a small benefit to surgery in the surgery + osi paradigm, maybe surgery can be taken out of the mix or treatment de-escalated to radiation.
I would not expect to see many EGFR mutated early stage cancers as the patients with these Stage I tumors are coming from the cohort with COPD or meeting lung cancer screening guidelines.
I think in upcoming staging there is going to be a distinction for EGFR+ and EGFR- tumors like in HPV+/- oropharynx and grade/receptor for breast cancer.

 

[RickyScott]

Didn’t vp and jack west rip apart this trial on plenary session? (Control arm didn’t get tagresso at progression, pet, mri not used in staging so enriching stage 4 disease, drug is tumor static ....) usually I disregard minor criticisms, but these seemed very valid

 

[StIGMA]

1) all of these drugs have significant side effects.
2) Overall egfr+ stage I- II is a small number of anyone’s practice
3) many/most of the stage III are/will progress. The delayed timeline of progression will generate srs, sbrt, etc. and eventually simple palliation similar to many of the kinase mutant patients we see now with a delayed ‘chronic cancer management’ disease course. I’ve seen many lung patients with 4x+ srs plans, + sbrt, + palliative treatments all in their disease course because these targeted agents delay the progression so much. If we weren’t involved, many of these patients wouldn’t be alive so long.

 

[evilbooyaa]

I am definitely more interested in adjuvant therapy after SBRT with either IT or targeted agents after this trial. Everyone loves PFS so I think most med oncs will probably offer the therapy.

 

[Ray D. Ayshun]

The tumor static thing seems important. In stage Iv disease as second line therapy osi has a pfs of 1-1.5 years. It seems like using pfs as a readout in the shorter run in patients with no evidence of disease on imaging at the outset is like using bcr at 2 years as an endpoint for ltadt. This is pausing disease in people that probably need locoregional treatment, and taking away an option they could have in the future when they actually need it. IMHO.

 

[StIGMA]

The tumor static thing seems important.

cells die with it. “tumor static” is misleading. They just don’t die from drug-mediated genomic damage.

 

[Ray D. Ayshun]

cells die with it. “tumor static” is misleading. They just don’t die from drug-mediated genomic damage.

Perhaps that's true in a petri dish, but if that's the case, why did this trial allow for treatment with osi for up to 3 years? If it's truly a cytotoxic therapy, they should

Chappelle Show Wrap It Up Box GIFs | Tenor

Click to view the GIF

tenor.com

 

[StIGMA]

, why did this trial allow for treatment with osi for up to 3 years?

Can't speak specifically to this trial, but in general:
1) $$$
2) coming on/off drugs potentiates resistance, so rationale is it's safer to keep on continually. Who knows if this is the case for any particular drug. It's not a question drug companies care about too much, see #1.
3) there are cytostatic/growth suppressive effects. Still, tumors shrink substantially on these drugs (cell death). It's not 100%.

 

[RickyScott]

significant portion of control arm didnt get tagresso when recurred/metted out (trial done overseas) and absence of pet/MRI staging should lead to a nice OS benefit- VP
control arm malpractice (VP): 1)very low adjuvant chemo and no radiation in stage III control 2) absent pet/mri staging leads to comparing placebo vs tagresso for stage 4 disease) 3) recurrence treated with gefitinib/erlotinib in control arm clearly will lead to OS benefit

 

[scarbrtj]

Perhaps that's true in a petri dish,

For those who (granted not many) don't know

 

[Mandelin Rain]

Can't speak specifically to this trial, but in general:
1) $$$
2) coming on/off drugs potentiates resistance, so rationale is it's safer to keep on continually. Who knows if this is the case for any particular drug. It's not a question drug companies care about too much, see #1.
3) there are cytostatic/growth suppressive effects. Still, tumors shrink substantially on these drugs (cell death). It's not 100%.

4) $$$

 

[Ray D. Ayshun]

4) $$$

Sure it's money, but even the durva folks didn't try for 3 years. This is naturally all about money, but the protocol and endpoint is such BS the docs should've said no. This result seems inevitable.

 

[Palex80]

Tyrosine kinase inhibitors do not work as adjuvant treatment in terms of OS.
They failed to show a benefit in all other localized diseases as a adjuvant treatment, when they actually work in the metastatic setting.
Look at kidney cancer --> trials with TKIs were negative
Look at NSCLC after CRT --> trial was negative
Look at liver cancer --> no benefit

It simply does not work. These drugs can prolong PFS in most situations and prolong OS in metastatic patients, but they do not offer and OS benefit in patients without residual disease after surgery or CRT.

Even the "mother of all TKIs" --> imatinib only showed OS benefit when given as adjuvant treatment in only one out of 3 randomized trials!

ADAURA is hyped. The main problem of the trial is that it's missing a crossover design. If ALL the patients progressing on the control arm got Osimertinib (which is s.o.c. in developed countries, but not s.o.c. in developing countries where the trial also took place), then no OS-benefit would ever materialize.

 

[scarbrtj]

Observation #2:

For a patient sent to me (this is gonna be rare, obv) who was operated on and was found to have pN2 disease, and is EGFRm, and I'm asked to consider postop RT, I would not now. I would say let's not do RT and just do osi. (What med onc would make this referral? As I said, will be uncommon.) I am generally for postop RT/chemo in Stage III-A, but I'm much less enamored now for Stage III-A EGFRm.

 

[Palex80]

For a patient sent to me (this is gonna be rare, obv) who was operated on and was found to have pN2 disease, and is EGFRm, and I'm asked to consider postop RT, I would not now. I would say let's not do RT and just do osi. (What med onc would make this referral? As I said, will be uncommon.) I am generally for postop RT/chemo in Stage III-A, but I'm much less enamored now for Stage III-A EGFRm.

Why?
You should still give that patient adjuvant chemotherapy. That's a proven treatment with a well known survival benefit. ADAURA allowed for adjuvant chemotherapy and I do not see any reason to withhold it. You can still consider giving osimertinib as adjuvant treatment after chemotherapy, but I do not see why you should drop chemotherapy now.
As far as RT is concerned: That's a totally different question, one that ADAURA was not adressing. We rarely perform PORT for N2, only clear indication is R1 -resection (which I would still do with out without osimertinib) and we consider it in patients with multiple involved nodes with ECE for instance.

 

[scarbrtj]

Why?
You should still give that patient adjuvant chemotherapy. That's a proven treatment with a well known survival benefit.

Adj RT? I want to throw it in too most times.

 

[scarbrtj]

As far as RT is concerned: That's a totally different question, one that ADAURA was not adressing. We rarely perform PORT for N2

The chemo is of course important and "standard." However ~half the osi patients didn't get adjuvant chemo (I don't know why). I "believed" chemo->RT the best adjuvant treatment for all N2 patients; the data is just annoyingly sparse* to make a strong case (hence, I guess, why others do PORT "rarely" as you say). ADAURA says that osi is a great adjuvant treatment for N2 disease postop. It says that it's so great it makes me want to lay the linac down here. Whereas before I wasn't reluctant in picking it up in N2.

*"...having recently closed a pilot study of adjuvant immunotherapy for early stage lung cancer patients with high risk features for distant failure following lung SBRT after having been unable to accrue a single patient after 2 years as the study PI, despite vigorous attempts to identify and enroll patients."
- Gregory Videtic on JACR advisor today

 

[radiation]

I agree with what many posters have said above. How people are "cured" with targeted therapies? Almost all pts develop resistance at some point, and as soon as you take many of these people off treatment that have massive regrowth. I bet that PFS curve falls off a cliff after you stop taking Tagrisso at 3 years. Can you justify lifelong treatment of such an expensive drug?

Also ~80% of stage II patients recurred in the observation arm. That is unusually high and speaks to possible understaging of pts.

 

[Gfunk6]

I agree with the above poster. Targeted inhibitors delay but don’t replace radiation. I’ve treated dozens of patients with SBRT on targeted inhibitors when 1-3 mets progress. Med Oncs always want to avoid going to second line cyctotoxic chemo for as long as possible.

 

[OTN]

I agree with the above poster. Targeted inhibitors delay but don’t replace radiation. I’ve treated dozens of patients with SBRT on targeted inhibitors when 1-3 mets progress. Med Oncs always want to avoid going to second line cyctotoxic chemo for as long as possible.

Strongly agree. Decent part of my practice now, but it take some pavement pounding to talk to my medoncs about the data.

What's the largest number of lung mets you've treated in a patient? I treated a colon cancer patient with slowly-progressing oligometastatic disease over the course of a few years. Treated a total of 8 metachronous lung lesions. He did incredibly well until he failed throughout the liver. Never had any toxicity from his SBRT courses, either short- or long(ish)-term.

 

[RickyScott]

Seems like a major theme of vinay prassads work is deceitful/suboptimal controls

 

[BobbyHeenan]

The word from Prasad and critics as mentioned is to watch out for:

1. Poor up front staging. If they didn't have PETs and MRI brains that's not standard of care. We know this drug improves OS in stage IV so if you get more patients on your study that are secretly stage IV it'll have bigger benefit
2. Poor treatment of SOC arm. How many patients didn't get chemo or thoracic XRT that usually do in this patient population? How many got standard of care osemirtinib at progression (versus say an inferior drug)?

 

[Mandelin Rain]

Seems like a major theme of vinay prassads work is deceitful/suboptimal controls

He's not wrong

 

[Gfunk6]

Strongly agree. Decent part of my practice now, but it take some pavement pounding to talk to my medoncs about the data.

What's the largest number of lung mets you've treated in a patient?

Generally I treat three maximum. I've definitely treated three lung mets simultaneously in a handful of patients.

 

[Palex80]

ADAURA says that osi is a great adjuvant treatment for N2 disease postop.

Based on a PFS benefit? This is stage III, you should be looking for an OS benefit, not a PFS benefit, irrelevant of how great it looks.

 

[scarbrtj]

Based on a PFS benefit? This is stage III, you should be looking for an OS benefit, not a PFS benefit, irrelevant of how great it looks.

I wonder if someone, the first time hearing unfamous Whitney Houston sing, said "Call me after she sells a record." That PFS delta is big enough to stick a chest spreader through. The OS benefit is already trending. And, in the meantime, you or I have great data that adding XRT in N2 (regardless of when you or I choose to do so) gives survival benefits? Aside from some ancient meta-analyses? I bet (nay, know) you do ENI for a lot of breast e.g.; no convincing OS benefits there. In theory, you have to have PFS benefits to get OS benefits. In theory. No one ever died of cancer who was disease free from the cancer (which is one theory as to why SBRT for oligomets can improve OS).

 

[Haybrant]

The money is in med onc and systemics and the issue is that pharma has the smarter people they will figure out ways to make these trials positive by any statistically magical means or trial design needs necessary. And academics are in their pockets, they will disingenuously help promote their studies and why not pharma is bringing them the loot now. No reason why this will change in the foreseeable future.

 

[RickyScott]

The money is in med onc and systemics and the issue is that pharma has the smarter people they will figure out ways to make these trials positive by any statistically magical means or trial design needs necessary. And academics are in their pockets, they will disingenuously help promote their studies and why not pharma is bringing them the loot now. No reason why this will change in the foreseeable future.

Another point from malignant -the Published papers are often written by medical writers, so what is the author’s actual role(company designs trial).?
Some of our younger faculty are so willing to sell out medstudent because it may slightly improve their visibility. Imagine if many thousand of dollars were at stake? Also, lessens for protons here.

 

[Palex80]

I wonder if someone, the first time hearing unfamous Whitney Houston sing, said "Call me after she sells a record." That PFS delta is big enough to stick a chest spreader through. The OS benefit is already trending.

The reason is simple: Many relapsing patients in the control arm did not get Osimertinib, they got chemotherapy or inferior TKIs. Why?
Because the trial was designed and carried out like that. It is sad.

I am not saying that Osimertinib is a bad drug. It is a great drug and I am happy that we have it. But recommending it as adjuvant treatment based on the ADAURA trial data is not right, in my humble opinion.

And, in the meantime, you or I have great data that adding XRT in N2 (regardless of when you or I choose to do so) gives survival benefits? Aside from some ancient meta-analyses?

No, which is precisely the reason why I seldom do it.

I bet (nay, know) you do ENI for a lot of breast e.g.; no convincing OS benefits there. In theory, you have to have PFS benefits to get OS benefits. In theory. No one ever died of cancer who was disease free from the cancer (which is one theory as to why SBRT for oligomets can improve OS).

Oh, no... Are we going to go back to the breast ENI-discussion? Please no... I refuse to have this discussion again!

 

[scarbrtj]

Oh, no... Are we going to go back to the breast ENI-discussion?

We'll always have breast ENI.

 

[evilbooyaa]

Strongly agree. Decent part of my practice now, but it take some pavement pounding to talk to my medoncs about the data.

What's the largest number of lung mets you've treated in a patient? I treated a colon cancer patient with slowly-progressing oligometastatic disease over the course of a few years. Treated a total of 8 metachronous lung lesions. He did incredibly well until he failed throughout the liver. Never had any toxicity from his SBRT courses, either short- or long(ish)-term.

Synchronously 2 for sure, 3 I would feel comfortable doing. 4 or more at the same time I probably would not just due to concerns of meeting relevant constraints.

Metachronously I don't think there is really a limit if patient is not showing obvious signs of loss of pulmonary function. Yes after say #5 we get a tad bit nervous, but data suggests that a full 'ablative dose' may not be necessary in oligomet patients, which may make treating more of them more palatable.

 

[scarbrtj]

We'll always have breast ENI.

Context. I had to do it.

 

[Mandelin Rain]

Context. I had to do it.

You need to photoshop in a thumb to see if "rule of thumb" applies. Whose thumb? I don't know.

 

[Palex80]

Context. I had to do it.

 

[Neuronix]

Avastin had excellent DFS improvements in recurrent glioblastoma.

(Honestly I have no doubt this will translate to OS benefit. This is all just hype to promote the drug and academic careers.)

 

[Ray D. Ayshun]

View attachment 316163

At the least, could we have a rule that the dfs endpoint is no less than 2x the length of the treatment course?

 

[Mandelin Rain]

View attachment 316163

Ever ask someone if they'd rather have their cancer come back sooner or later if given a choice? Now, I understand that people make all sorts of foolish choices everyday, but this one doesn't seem particularly "out there."

 

[Palex80]

Ever ask someone if they'd rather have their cancer come back sooner or later if given a choice?

So, then we should be giving every GS8-10 prostate cancer patient ADT following prostatectomy, right?
I am sure ADT will prolong DFS in most of them.

 

[Mandelin Rain]

So, then we should be giving every GS8-10 prostate cancer patient ADT following prostatectomy, right?
I am sure ADT will prolong DFS in most of them.

We essentially did just that with radiation for a decade or two. But, not a bad trial design TBH. The placebo group should get Flomax upon failure IMO. Maximizes chance of success.

 

[scarbrtj]

So, then we should be giving every GS8-10 prostate cancer patient ADT following prostatectomy, right?
I am sure ADT will prolong DFS in most of them.

Or survival

Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer - PubMed

Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.

pubmed.ncbi.nlm.nih.gov

 

[scarbrtj]

View attachment 316163

A 5% DFS benefit with no OS benefit in MA20 was hailed as practice changing by rad oncs in breast cancer. But a 40-50% improvement in DFS in a much more deadly cancer we throw shade on. We can be strange sometimes.

 

[Mandelin Rain]

A 5% DFS benefit with no OS benefit in MA20 was hailed as practice changing by rad oncs in breast cancer. But a 40-50% improvement in DFS in a much more deadly cancer we throw shade on. We can be strange sometimes.

Need to consider salvage options if failure occurs to be sure. Much tougher to salvage a breast case post lumpectomy and XRT than to start the drug you would have started anyway.

Yes, I'm playing both sides on this.

 

[Ray D. Ayshun]

A 5% DFS benefit with no OS benefit in MA20 was hailed as practice changing by rad oncs in breast cancer. But a 40-50% improvement in DFS in a much more deadly cancer we throw shade on. We can be strange sometimes.

I've honestly barely looked at this, so I'm probably wrong to post, but nevertheless.

Going back to that golf analogy in my mediastinal reRT thread, this new trial was a tap-in.

 

[radiation]

Context. I had to do it.

The biggest difference is when you give radiation, its done and you have received all the benefit. The benefit of the TKI is relate to how you take it and when the inevitable resistance comes into play. Progression after TKI stoppage is almost guaranteed

 

[radiation]

Also doesn't seem to matter if you give TKIs upfront or at salvage

https://www.annalsofoncology.org/article/S0923-7534(20)32565-5/fulltext

 

[scarbrtj]

The biggest difference is when you give radiation, its done and you have received all the benefit. The benefit of the TKI is relate to how you take it and when the inevitable resistance comes into play. Progression after TKI stoppage is almost guaranteed

One of the stupidest, or most brilliant, ideas crossed my mind as I read this. We were taught in radiobiology that the D-zero of most human tumors is around 2 Gy. The D-zero being the dose that kills about 67% of the tumor cells. So we could use XRT like a TKI. Give post-op lung RT (or breast ENI!) at say 2 Gy every three weeks or so maybe for two years. It might work out to be, mathematically, recurrence-preventing during that time (although likely not curative... but even then some would be cured by this). And no one would ever get acute radiation toxicity!

 

[Mandelin Rain]

One of the stupidest, or most brilliant, ideas crossed my mind as I read this. We were taught in radiobiology that the D-zero of most human tumors is around 2 Gy. The D-zero being the dose that kills about 67% of the tumor cells. So we could use XRT like a TKI. Give post-op lung RT (or breast ENI!) at say 2 Gy every three weeks or so maybe for two years. It might work out to be, mathematically, recurrence-preventing during that time (although likely not curative... but even then some would be cured by this). And no one would ever get acute radiation toxicity!

That's just stupid enough to work!

 

[Ray D. Ayshun]

One of the stupidest, or most brilliant, ideas crossed my mind as I read this. We were taught in radiobiology that the D-zero of most human tumors is around 2 Gy. The D-zero being the dose that kills about 67% of the tumor cells. So we could use XRT like a TKI. Give post-op lung RT (or breast ENI!) at say 2 Gy every three weeks or so maybe for two years. It might work out to be, mathematically, recurrence-preventing during that time (although likely not curative... but even then some would be cured by this). And no one would ever get acute radiation toxicity!

Analyze outcomes per protocol. Kinda like my idea that completing a two week course of daily golf will cure covid.