LU-002 closed and will not move to phase III as it did not meet prescribed PFS criteria

[rymd]

First negative consolidative metastatic SBRT lung trial I'm aware of. Is immunotherapy too good? perhaps treating earlier rather than after four cycles? Looking forward to seeing the presentations and eventual publications

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[TheWallnerus]

Would this be basically a different finding than suggested by SABR COMET; ie, SABR COMET failed to be reproduced

Prasad predicted phIII trials would be negative (but this not even a phIII I guess?)

 

[temujim]

Aggressive stats for PFS reduction with target HR 0.6 in phase 2. Radiation is good, but geez.

 

[RickyScott]

Would this be basically a different finding than suggested by SABR COMET; ie, SABR COMET failed to be reproduced

Prasad predicted phIII trials would be negative (but this not even a phIII I guess?)

But oligomets is going to save us?

 

[medgator]

But oligomets is going to save us?

Radiopharmaceuticals and oligimets were good for at least 60 add'l residency slots a year, amirite Ben Smith?

 

[OTN]

Treatment of oligoprogression is where it's at. I don't offer or recommend consolidative therapy, unless it's a situation where a patient can no longer tolerate systemic therapy. I'm not surprised this turned out to be negative.

 

[Palex80]

Would this be basically a different finding than suggested by SABR COMET; ie, SABR COMET failed to be reproduced

Yes, indeed.
Barely 20% of SABR COMET patients had an NSCLC.

 

[Palex80]

Aggressive stats for PFS reduction with target HR 0.6 in phase 2. Radiation is good, but geez.

 

[Fpg1245]

Aggressive stats for PFS reduction with target HR 0.6 in phase 2. Radiation is good, but geez.

Is there such a high bar PFS for systemics?

 

[fiji128]

Isn't one of the issues with SABR COMMIT, in terms of taking the results as gospel as many have, is that only 99 patients were enrolled with 33 in the SOC arm and 66 in the SBRT arm. Not a nock on this early trail per se but I was always doubtful about all the conclusions people were willing to draw from such a small trial.

Was hopeful LU-002 and BR-002 would show something pro rad onc but doesn't look like it. I wonder if those "academics" claiming that all the SBRT that would be needed for oligometastatic disease justified their program numbers in the face of loosing stage IA breast and hypofrac will now be willing to reconsider their programs training complement size (not holding my breath).

 

[Chartreuse Wombat]

Isn't one of the issues with SABR COMMIT, in terms of taking the results as gospel as many have, is that only 99 patients were enrolled with 33 in the SOC arm and 66 in the SBRT arm. Not a nock on this early trail per se but I was always doubtful about all the conclusions people were willing to draw from such a small trial.

Was hopeful LU-002 and BR-002 would show something pro rad onc but doesn't look like it. I wonder if those "academics" claiming that all the SBRT that would be needed for oligometastatic disease justified their program numbers in the face of loosing stage IA breast and hypofrac will now be willing to reconsider their programs training complement size (not holding my breath).

Another criticism of SABR-COMET is that there were dramatic differences in the primary site according to treatment arm. Of the 16 prostate cancer patients enrolled; 14 were on the SABR arm. Prostate has excellent survival compared to lung for example and it is possible that this imbalance can explain the results.

As to overestimating effect size does anyone have the hypothesized HR for the study?

 

[Chartreuse Wombat]

I went to the CTEP website.

From the protocol

The most recent update of SABR-COMET has OS HR of 0.47.

Many trials are "underpowered" because of a overly optimistic effect size. In this case there was limited (read none) info on how the control arm would do. From the protocol

Will wait for the results to be presented/published to decide if there is a signal at all.

 

[taserlaser]

Another criticism of SABR-COMET is that there were dramatic differences in the primary site according to treatment arm. Of the 16 prostate cancer patients enrolled; 14 were on the SABR arm. Prostate has excellent survival compared to lung for example and it is possible that this imbalance can explain the results.

As to overestimating effect size does anyone have the hypothesized HR for the study?

It is an absolute valud criticism. However for what it’s worth, I think Palma mentioned at some point they took a look at their results without the prostate patients and still had a signal, but take that as hearsay.

The recent virtual rounds he gave indicated thar Comet 10 will finish accruing quite soon and comet 3 will finish accrual probably next year. It sounded harder to accrue to comet 3 with a lot of equipoise lost at present, and l personally wonder about the selection bias that will occur and wonder about what kind of patients in this circumstance will end up on comet 3

 

[TheWallnerus]

These results causing sweaty Palma I bet!

 

[OTN]

Are there any trials looking at SBRT for oligoprogression vs up-front treatment of mets at diagnosis? That's where my practice has landed, and I think it works brilliantly.

 

[Palex80]

Are there any trials looking at SBRT for oligoprogression vs up-front treatment of mets at diagnosis? That's where my practice has landed, and I think it works brilliantly.

Well, if SBRT up-front does not work (as per LU-002), then the question would be if SBRT for oligoprogression works.
ETOP HALT is looking at that for EGFR-mutated NSCLC.

ClinicalTrials.gov

clinicaltrials.gov

 

[communitydoc13]

33 in the SOC arm and 66 in the SBRT arm

completely crappy numbers.

We are hurting ourselves with small, signal hunting trials. Prostate also the disease site with the best evidence for treating primary site of disease in the metastatic setting.

Are there any trials looking at SBRT for oligoprogression vs up-front treatment of mets at diagnosis? That's where my practice has landed, and I think it works brilliantly.

https://www.redjournal.org/article/S0360-3016(22)03266-7/abstract

Not a vs. trial but significant benefit in NSCLCa regarding PFS. I advocate for SBRT with oligoprogressive lung.

As always, small numbers.

 

[evilbooyaa]

Another criticism of SABR-COMET is that there were dramatic differences in the primary site according to treatment arm. Of the 16 prostate cancer patients enrolled; 14 were on the SABR arm. Prostate has excellent survival compared to lung for example and it is possible that this imbalance can explain the results.

As to overestimating effect size does anyone have the hypothesized HR for the study?

Subset analysis excluding prostate/breast still held in OG SABR-COMET. Numbers were at least presented if not in the f/u paper.

 

[NotMattSpraker]

Well, if SBRT up-front does not work (as per LU-002), then the question would be if SBRT for oligoprogression works.
ETOP HALT is looking at that for EGFR-mutated NSCLC.

ClinicalTrials.gov

clinicaltrials.gov

LU002 was after induction chemo.

In renal, upfront works! Maybe.

 

[evilbooyaa]

There's up-front (meaning before systemic) which Iyengar did on some of his studies
Then there's consolidative (I think what Palex meant in his response) which is what LU-002 did
Then there's oligoprogressive - would still offer that for NSCLC based on CURB.

I'll wait for the presentation/paper before making a decision on what to do for oligomet NSCLC s/p induction chemo. I predict there is an effect size, but maybe not 40% in the IO +/- chemo era, and thus not 'statistically' significant.

 

[Palex80]

Wait, wait, wait…

The whole idea behind SBRT for oligomets is that:

- systemic treatment is not sufficient to control macroscopic disease in these patients and you can enhance prognosis by killing of all visible tumor deposits

- SBRT induces some immunologic phenomenon (I am not going to say abscopal)

Now, people are trying to twist the initial hypothesis?

In my opinion, „development of polymetastatic disease“ is simply biology-driven. No SBRT is going to change that. The train has left.

 

[A_DeMichele]

Does the FDA still approve cancer drugs based on PFS?

 

[RickyScott]

Most randomized phase 2 trials are not confirmed in subsequent phase 3. Astro presentation by Corey langer some years ago pointed this out with respect to sabr comet.

 

[RadRadRad]

Does the FDA still approve cancer drugs based on PFS?

I thought some got approved based on path cr rate but may be wrong

As far as I can tell path cr matters if from drugs but not if from radiation 😂

 

[Mandelin Rain]

But what about…. Overall survival?

Anyone consider that endpoint?

 

[Palex80]

Does the FDA still approve cancer drugs based on PFS?

Dostarlimab for rectal cancer?

 

[drowsy12]

But what about…. Overall survival?

Anyone consider that endpoint?

rad oncs should not throw stones when it comes to this endpoint, IMO. if OS was the endpoint we were judged by, then we could close down most shops tomorrow.

 

[Palex80]

rad oncs should not throw stones when it comes to this endpoint, IMO. if OS was the endpoint we were judged by, then we could close down most shops tomorrow.

 

[ramsesthenice]

View attachment 379671

Wait, wait, wait…

The whole idea behind SBRT for oligomets is that:

- systemic treatment is not sufficient to control macroscopic disease in these patients and you can enhance prognosis by killing of all visible tumor deposits

- SBRT induces some immunologic phenomenon (I am not going to say abscopal)

Now, people are trying to twist the initial hypothesis?


View attachment 379672

In my opinion, „development of polymetastatic disease“ is simply biology-driven. No SBRT is going to change that. The train has left.

100% and this is why the upfront approach failed. SBRT is only going to have a decent shot in people with good biology. It will never show a benefit in largely unselected patients except maybe in indolent cancers like prostate or RCC. These results are not surprising. Not saying it wasn’t worth a shot. But not surprised.

 

[drowsy12]

There was some selection - patients were only able to be enrolled if they had good response to initial treatment. It may in the end be that this doesn’t work in the immunotherapy era, as perhaps patients selected to be ‘good’ are already biologically favorable as selected by systemic therapy response, and local therapy doesn’t help these folks.

So if anything one can argue that selection was one of the problems. But I agree with Palex, the trial was designed to ask this specific question, and it didn’t seem to help

 

[theradiator]

Let's not overreact. When RTOG 0631 came out, did you abandon spine SBRT? At this time, LU-002 is an outlier because all of the other multiple oligometastasis trials from lung cancer have been positive.

 

[Palex80]

At this time, LU-002 is an outlier because all of the other multiple oligometastasis trials from lung cancer have been positive.

 

[ramsesthenice]

There was some selection - patients were only able to be enrolled if they had good response to initial treatment. It may in the end be that this doesn’t work in the immunotherapy era, as perhaps patients selected to be ‘good’ are already biologically favorable as selected by systemic therapy response, and local therapy doesn’t help these folks.

So if anything one can argue that selection was one of the problems. But I agree with Palex, the trial was designed to ask this specific question, and it didn’t seem to help

We can agree to disagree. They didn't have to have a good response, just no progression after 3 months of chemo. Not sure that really tells us much about their biology or selection at that point.

But your point is taken especially with immunotherapy. The trials will be tricky because there is a huge difference between IO and chemo...there are far more subjects with durable responses to IO than chemo. If you do SBRT for stable disease, even 6+ months after starting, it will probably be very hard to show a significant benefit. I would bet a lot of money that this exact trial after immunotherapy would also be negative. Stepping in at the time of oligoprogression on IO is probably where the best benefit will be.

 

[drowsy12]

Based on your prior posts you see other disease sites (GI, GU, right?) more often may not see much metastatic lung cancer. Look at response rates in metastatic trials. Tons of people progress. So stable disease is already a biological selection factor, though agree only allowing PR and not SD would be more of a selection

 

[evilbooyaa]

Does the FDA still approve cancer drugs based on PFS?

Serious question? Like pretty much all of them are approved on PFS...

We can agree to disagree. They didn't have to have a good response, just no progression after 3 months of chemo. Not sure that really tells us much about their biology or selection at that point.

But your point is taken especially with immunotherapy. The trials will be tricky because there is a huge difference between IO and chemo...there are far more subjects with durable responses to IO than chemo. If you do SBRT for stable disease, even 6+ months after starting, it will probably be very hard to show a significant benefit. I would bet a lot of money that this exact trial after immunotherapy would also be negative. Stepping in at the time of oligoprogression on IO is probably where the best benefit will be.

My hypothesis - they saw a huge response in the pre-IO era (Gomez trial) and assumed it would be the same benefit in the IO era. Expecting to see a 40% improvement in PFS in the ICI era is a BIG swing. They likely claimed it would be such a big thing so that it would be easier to meet accrual enrollment based on their power calculations.

Is there some benefit, but not SS, since the IO patients did better than historical controls (as would be expected)? Idk, so I'll wait for the presentation before I throw the baby out with the bath water. Maybe the trial is just underpowered. Maybe in IO era treating oligomets aggressively is 'dead'.

SABR-COMET 3 and SABR-COMET 10 results can't come fast enough. Canadians, save us!

 

[deleted1111261]

one positive study shouldn't make us all treat

one negative study shouldn't make us all not treat

this just adds to the body of work that we look at to make our decision, in addition to our own personal experiences.

i know people are not sold on oligomet treatment for breast b/c of recent negative study, but i feel that we have all seen with our own eyes SBRT controlling disease, keeping people off of chemo and appearing to change outcome.

not all of what we do can be studied or "proven"

anyone ever see a study comparing RT to no RT for pain for bone mets? no, you haven't, b/c study doesn't exists. but that doesn't mean it doesn't work.

 

[IonsAreOurFuture]

Does the FDA still approve cancer drugs based on PFS?

https://www.nejm.org/doi/full/10.1056/nejmoa052258

The trial that showed Letrozole superior to Tamoxifen had 8,010 patients. That's >80 times more than the 99 pts in SABR-COMET.

The DFS event difference was 1.9%:
8.8% in the letrozole arm and 10.7% in the tamoxifen arm. No OS difference. The DFS curves look almost superimposed.

Based on this trial, prescribing for antihormones drastically changed.

 

[drowsy12]

As compared with tamoxifen, letrozole significantly reduced the risk of an event ending a period of disease-free survival (hazard ratio, 0.81; 95 percent confidence interval, 0.70 to 0.93; P=0.003), especially the risk of distant recurrence (hazard ratio, 0.73; 95 percent confidence interval, 0.60 to 0.88; P=0.001). Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group. Women given letrozole had a higher incidence of skeletal and cardiac events and of hypercholesterolemia.

 

[TheWallnerus]

https://www.nejm.org/doi/full/10.1056/nejmoa052258

The trial that showed Letrozole superior to Tamoxifen had 8,010 patients. That's >80 times more than the 99 pts in SABR-COMET.

The DFS event difference was 1.9%:
8.8% in the letrozole arm and 10.7% in the tamoxifen arm. No OS difference. The DFS curves look almost superimposed.

Based on this trial, prescribing for antihormones drastically changed.

Letrozole conspiracy. And I’m not really joking.

As compared with tamoxifen, letrozole significantly reduced the risk of an event ending a period of disease-free survival (hazard ratio, 0.81; 95 percent confidence interval, 0.70 to 0.93; P=0.003), especially the risk of distant recurrence (hazard ratio, 0.73; 95 percent confidence interval, 0.60 to 0.88; P=0.001). Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group. Women given letrozole had a higher incidence of skeletal and cardiac events and of hypercholesterolemia.

Statistically significant vs clinically significant vs relative difference vs absolute difference.

 

[thesauce]

I have always found it interesting how skewed the entire perception of cancer trial data is.

I saw a recent NEJM paper where 2 years of nivolumab + chemo improved PFS by less than TWO MONTHS and it was hailed as this amazing thing by a medonc I spoke to.

Yet here we are cutting the risk of breast cancer recurrence (potentially life or death) by half a percent per year with 5 DAYS of uneventful, atoxic RT and it’s being questioned in favor of making their lives miserable with 5-10 years of ET.

In the end, the data doesn’t matter and never really did. It just comes down to who sees the patient first and who talks the loudest at tumor board. No one has ever been able to give me a good explanation for why we aren’t giving consolidative RT for lymphoma (HD or NHL). Study after study showed benefit but medoncs were able to just cut it out through referral patterns and speaking the loudest.

 

[theradiator]

I have always found it interesting how skewed the entire perception of cancer trial data is.

I saw a recent NEJM paper where 2 years of nivolumab + chemo improved PFS by less than TWO MONTHS and it was hailed as this amazing thing by a medonc I spoke to.

Yet here we are cutting the risk of breast cancer recurrence (potentially life or death) by half a percent per year with 5 DAYS of uneventful, atoxic RT and it’s being questioned in favor of making their lives miserable with 5-10 years of ET.

In the end, the data doesn’t matter and never really did. It just comes down to who sees the patient first and who talks the loudest at tumor board. No one has ever been able to give me a good explanation for why we aren’t giving consolidative RT for lymphoma (HD or NHL). Study after study showed benefit but medoncs were able to just cut it out through referral patterns and speaking the loudest.

I would like to point out that medical oncologists don’t diagnose breast cancer or lymphoma any more that we do and nor do they admit their own patients any more. This is a call to arms to get more aggressive in directing patient care for our patients and even politely inserting ourselves when possible.

 

[thesauce]

I would like to point out that medical oncologists don’t diagnose breast cancer or lymphoma any more that we do and nor do they admit their own patients any more. This is a call to arms to get more aggressive in directing patient care for our patients and even politely inserting ourselves when possible.

I would say that they definitely diagnose both of those more than we do. It doesn’t have to be that way, though.

Just curious, who is diagnosing lymphoma in your neck of the woods?

 

[Barcelona PSG]

The LU002 SBRT doses are not that ablative to begin with. Reminds me of Alliance A021501 pancreas trial that used 33Gy in 5 fractions.
So many publications on BED of >100Gy and its implications on local control, and NRG decided to use these doses. Kind of difficult to grasp why. Anyone has any insights?

 

[thesauce]

View attachment 379860

The LU002 SBRT doses are not that ablative to begin with. Reminds me of Alliance A021501 pancreas trial that used 33Gy in 5 fractions.
So many publications on BED of >100Gy and its implications on local control, and NRG decided to use these doses. Kind of difficult to grasp why. Anyone has any insights?

That’s a good catch

 

[theradiator]

I would say that they definitely diagnose both of those more than we do. It doesn’t have to be that way, though.

Just curious, who is diagnosing lymphoma in your neck of the woods?

To be fair they are being referred cases for leukocytosis that turn into lymphoma but the actual diagnosis is performed by IR and sometimes a surgeon for excisional biopsy. Are your med oncs still performing bone marrow biopsies or are they being farmed out to IR or even APPs? So I guess it depends on the definition of diagnose whether directing care or actually obtaining tissue.

 

[temujim]

View attachment 379860

The LU002 SBRT doses are not that ablative to begin with. Reminds me of Alliance A021501 pancreas trial that used 33Gy in 5 fractions.
So many publications on BED of >100Gy and its implications on local control, and NRG decided to use these doses. Kind of difficult to grasp why. Anyone has any insights?

Safetyism

 

[drowsy12]

We can wait until we see the data, but in my opinion the dose is unlikely to be the culprit, unless local recurrence is high. Issue is that RT did not stop new mets from coming on. The SINDAS trial used lower doses also and was positive, in the EGFR population.

 

[thesauce]

To be fair they are being referred cases for leukocytosis that turn into lymphoma but the actual diagnosis is performed by IR and sometimes a surgeon for excisional biopsy. Are your med oncs still performing bone marrow biopsies or are they being farmed out to IR or even APPs? So I guess it depends on the definition of diagnose whether directing care or actually obtaining tissue.

They are not doing bone marrow biopsies

 

[IonsAreOurFuture]

Safetyism

Maybe they got concerned with the 3 toxic deaths in SABR-COMET. SABR-COMET-10 is mostly giving 35 Gy in 5 fractions, I think, instead of the 50 Gy in 5 fx of the original trial.

We are also in the immunotherapy era now for LU-002, whereas Canada during SABR-COMET was largely just chemo and anti-hormones a decade ago. Time flies, but it was ASTRO 2018 when SABR-COMET landed, more than 5 years ago, so most of the patients were treated almost a decade ago and Canada has been slower on the immunotx uptake than the US.

We are in a brave new world of systemic therapy now.

 

[IonsAreOurFuture]

View attachment 379860

The LU002 SBRT doses are not that ablative to begin with. Reminds me of Alliance A021501 pancreas trial that used 33Gy in 5 fractions.
So many publications on BED of >100Gy and its implications on local control, and NRG decided to use these doses. Kind of difficult to grasp why. Anyone has any insights?

You are correct, definitely not ablative doses.

Not that it means anything in humans necessarily, but I remember the early publications of the abscopal response mostly having a sweet spot around 8 Gy in 3 fractions or 6 Gy x 5 fx, but not in 20 Gy x 1. It seems like the most convincing case reports were around 9-10 Gy x 3, so maybe they were thinking along those lines, counting on immuno or chemo to act like "SBRT-helper"?