ESMO 2020

[Palex80]

This year's ESMO Congress is kicking off. It's virtual and no abstracts have been published yet.

Here are my radiation oncology related picks:

• Consolidation ipilimumab and nivolumab vs observation in limited stage SCLC after chemo-radiotherapy – results from the ETOP/IFCT 4-12 STIMULI trial

• Patient reported outcomes from a randomized phase II trial comparing standard-dose with high-dose twice daily (BID) thoracic radiotherapy (TRT) in limited stage small cell lung cancer (LS SCLC)

• Pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): Results of the GORTEC 2015-01 “PembroRad” randomized trial

• Primary results of the phase III JAVELIN head & neck 100 trial: Avelumab plus chemoradiotherapy (CRT) followed by avelumab maintenance vs CRT in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN)

• 3-years follow-up of double-blind randomized phase II comparing concurrent high-dose cisplatin chemo-radiation plus Debio-1143 (Xevinapant) or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck

• Osimertinib adjuvant therapy in patients (pts) with resected EGFR mutated (EGFRm) NSCLC (ADAURA): central nervous system (CNS) disease recurrence

• An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement. Primary end-point analysis of Lung ART (IFCT-0503, UK NCRI, SAKK) NCT00410683.

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[elementaryschooleconomics]

• An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement. Primary end-point analysis of Lung ART (IFCT-0503, UK NCRI, SAKK) NCT00410683.

Oh I've been looking forward to this one in particular.

 

[Krukenberg]

These will be some interesting data! Glad to see loads of definitive immunoRT trials starting to report out. Also looking forward to lungART

 

[Gfunk6]

Medical Oncology - dragging RO into the future whether it likes it or not. Seriously though, a lot of thought provoking studies. I look forward to reading more.

 

[FrostyHammer]

Oh I've been looking forward to this one in particular.

I wouldn't hold my breath, it's a poorly designed trial. I've heard that chemo is optional and other such major issues.

 

[elementaryschooleconomics]

I wouldn't hold my breath, it's a poorly designed trial. I've heard that chemo is optional and other such major issues.

Yeah agreed - I've heard swirling rumors about design as well. To be continued!

Edit: Saw this immediately after posting -

 

[Krukenberg]

This year's ESMO Congress is kicking off. It's virtual and no abstracts have been published yet.

Here are my radiation oncology related picks:

• Consolidation ipilimumab and nivolumab vs observation in limited stage SCLC after chemo-radiotherapy – results from the ETOP/IFCT 4-12 STIMULI trial

• Patient reported outcomes from a randomized phase II trial comparing standard-dose with high-dose twice daily (BID) thoracic radiotherapy (TRT) in limited stage small cell lung cancer (LS SCLC)

• Pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): Results of the GORTEC 2015-01 “PembroRad” randomized trial

• Primary results of the phase III JAVELIN head & neck 100 trial: Avelumab plus chemoradiotherapy (CRT) followed by avelumab maintenance vs CRT in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN)

• 3-years follow-up of double-blind randomized phase II comparing concurrent high-dose cisplatin chemo-radiation plus Debio-1143 (Xevinapant) or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck

• Osimertinib adjuvant therapy in patients (pts) with resected EGFR mutated (EGFRm) NSCLC (ADAURA): central nervous system (CNS) disease recurrence

• An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement. Primary end-point analysis of Lung ART (IFCT-0503, UK NCRI, SAKK) NCT00410683.

do you know where the abstracts would be posted publicly?

 

[gamma123]

do you know where the abstracts would be posted publicly?

#ESMO20: slides, webcasts, abstracts, videos & news

Slides, webcasts, abstracts, video interviews, medwireNews articles covering the ESMO Congress

oncologypro.esmo.org

 

[medgator]

 

[Krukenberg]

I think this amazing PACIFIC data is yet another argument against dose escalation in NSCLC. Durva is a huge contributor to their long term survival, and my approach will be don’t do anything that could compromise their ability to receive it, or to survive long enough to benefit from it. Kind of like the argument against induction chemo in many disease sites.

 

[Lamount]

I think this amazing PACIFIC data is yet another argument against dose escalation in NSCLC. Durva is a huge contributor to their long term survival, and my approach will be don’t do anything that could compromise their ability to receive it, or to survive long enough to benefit from it. Kind of like the argument against induction chemo in many disease sites.

I am interested to see where LU 004 goes

 

[RickyScott]

I think this amazing PACIFIC data is yet another argument against dose escalation in NSCLC. Durva is a huge contributor to their long term survival, and my approach will be don’t do anything that could compromise their ability to receive it, or to survive long enough to benefit from it. Kind of like the argument against induction chemo in many disease sites.

That has been my philosophy as well, especially since benefit of io were greater if started within 14 days of radonc. Am very careful about sparing esophagus as well.
Enrolled some patients on pacific trial and you didn’t need 60 gy to 95% if worried about toxicity. Would accept lower doses 54 and point doses of 60. Haven’t had a case of pneumonitis in a while.

 

[Krukenberg]

This year's ESMO Congress is kicking off. It's virtual and no abstracts have been published yet.

Here are my radiation oncology related picks:

• Consolidation ipilimumab and nivolumab vs observation in limited stage SCLC after chemo-radiotherapy – results from the ETOP/IFCT 4-12 STIMULI trial

• Patient reported outcomes from a randomized phase II trial comparing standard-dose with high-dose twice daily (BID) thoracic radiotherapy (TRT) in limited stage small cell lung cancer (LS SCLC)

• Pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): Results of the GORTEC 2015-01 “PembroRad” randomized trial

• Primary results of the phase III JAVELIN head & neck 100 trial: Avelumab plus chemoradiotherapy (CRT) followed by avelumab maintenance vs CRT in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN)

• 3-years follow-up of double-blind randomized phase II comparing concurrent high-dose cisplatin chemo-radiation plus Debio-1143 (Xevinapant) or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck

• Osimertinib adjuvant therapy in patients (pts) with resected EGFR mutated (EGFRm) NSCLC (ADAURA): central nervous system (CNS) disease recurrence

• An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement. Primary end-point analysis of Lung ART (IFCT-0503, UK NCRI, SAKK) NCT00410683.

well looking at the abstracts all the immunoRT trials here were negative...disappointing. The bright spot is Debio-1143 looks like a real-deal radiosensitizer: HR for OS 0.5!!

 

[Palex80]

LungArt statistics look strange to me, looking forward to the full presentation.

 

[RadRadRad]

Pacific trial also makes it harder to pull trigger on resection for low volume stage 3 disease. My understanding is that can’t get adjuvant immunotherapy approved for these patients

 

[medgator]

Pacific trial also makes it harder to pull trigger on resection for low volume stage 3 disease. My understanding is that can’t get adjuvant immunotherapy approved for these patients

Still don't understand why stage III nsclc goes to surgery in the first place....

 

[medgator]

LungArt statistics look strange to me, looking forward to the full presentation.

 

[FrostyHammer]

Pacific trial also makes it harder to pull trigger on resection for low volume stage 3 disease. My understanding is that can’t get adjuvant immunotherapy approved for these patients

Don't tell that to surgeons... They love cutting things without proper data backing it up, and misleading patients accordingly.

 

[medgator]

Don't tell that to surgeons... They love cutting things without proper data backing it up, and misleading patients accordingly.

You'd think tumor boards and Pulmonary seeing the patient first would help avoid that, at least in lung cancer, much less hope in prostate obviously

 

[Ray D. Ayshun]

Pacific trial also makes it harder to pull trigger on resection for low volume stage 3 disease. My understanding is that can’t get adjuvant immunotherapy approved for these patients

Pacific trial performed on "unresectable" stage III NSCLC, whatever that means. In any case, would be nice to know how "resectable" patients would do with chemort and adjuvant io.

 

[medgator]

Pacific trial performed on "unresectable" stage III NSCLC, whatever that means. In any case, would be nice to know how "resectable" patients would do with chemort and adjuvant io.

Why? What's the value of surgery in those patients, esp if a pneumonectomy is required?

 

[Ray D. Ayshun]

Why? What's the value of surgery in those patients, esp if a pneumonectomy is required?

Sorry, I meant that I'd like to know how patients healthy enough to undergo surgery and with a low enough disease burden would do with the pacific regimen. 3 yr OS of 66% in the Lung ART trial is pretty crazy.

 

[FrostyHammer]

Pacific trial performed on "unresectable" stage III NSCLC, whatever that means. In any case, would be nice to know how "resectable" patients would do with chemort and adjuvant io.

"Unresectable" should really mean "unresected" in the sense that for one of a variety of reasons a surgeon wasn't able to get their hands on that patient.

 

[Ray D. Ayshun]

"Unresectable" should really mean "unresected" in the sense that for one of a variety of reasons a surgeon wasn't able to get their hands on that patient.

Sure. Going in the opposite direction of what's been said, I bet surprise n2 does a lot better with surgery as we'd ignore the mediastinum. I'm concerned surgeons will start conflating pn2 with cn2.

 

[Haybrant]

Still don't understand why stage III nsclc goes to surgery in the first place....

If you really think there isn’t a spectrum then you should rethink what you feel about lung cancer. Getting it out is better and many will benefit from surgery but it needs to be very selected patients. If surgeon is offering resection on someone that seems reasonable for (again highly selected) I would be happy. I’m talking after chemo RT not definitive

 

[RollTideRadOnc]

If you really think there isn’t a spectrum then you should rethink what you feel about lung cancer. Getting it out is better and many will benefit from surgery but it needs to be very selected patients. If surgeon is offering resection on someone that seems reasonable for (again highly selected) I would be happy. I’m talking after chemo RT not definitive

Is there truly evidence to support the notion that surgery is better? I suspect this is just inherited bias along the same lines of what we always hear: “Well in my vast experience...” or “In this unplanned and inconclusive subset analysis...”

most of these halstedian intuitions turn out to be wrong in the long run...

 

[medgator]

If you really think there isn’t a spectrum then you should rethink what you feel about lung cancer. Getting it out is better and many will benefit from surgery but it needs to be very selected patients. If surgeon is offering resection on someone that seems reasonable for (again highly selected) I would be happy. I’m talking after chemo RT not definitive

Any data?

 

[Haybrant]

Is there truly evidence to support the notion that surgery is better? I suspect this is just inherited bias along the same lines of what we always hear: “Well in my vast experience...” or “In this unplanned and inconclusive subset analysis...”

most of these halstedian intuitions turn out to be wrong in the long run...

You think 60 Gy is enough to control lung cancer then stop escalating with SBRT. As immunotherapy improves local control matters more.

Also subset analysis of Albain

 

[medgator]

You think 60 Gy is enough to control lung cancer then stop escalating with SBRT. As immunotherapy improves local control matters more.

Also subset analysis of Albain

Funny to see people give sclc or a bad skin ca more than they'll give gross disease in nsclc

 

[Krukenberg]

You think 60 Gy is enough to control lung cancer then stop escalating with SBRT. As immunotherapy improves local control matters more.

Also subset analysis of Albain

toxicity of 74 Gy to the mediastinum > benefit, and immunotherapy ain’t changing that. Comparison to sbrt of peripheral stage 1 lung cancer is apples to oranges. 60Gy and call it a day so you don’t threaten their ability to benefit from durvalumab

 

[Lamount]

toxicity of 74 Gy to the mediastinum > benefit, and immunotherapy ain’t changing that. Comparison to sbrt of peripheral stage 1 lung cancer is apples to oranges. 60Gy and call it a day so you don’t threaten their ability to benefit from durvalumab

RTOG 0617 is odd with higher dose having more local failure. This coupled with the significant benefit observed with IO in PACIFIC makes me wonder if 74 Gy was worse because of immunosuppression. If so, the detriment may not just be related to dose but also to treatment duration.

Will be interesting to see how LU004 pans out, looking at 60/15 w/concurrent IO for stage III NSCLC (I think just phase I/II right now).

 

[seper]

Pacific trial also makes it harder to pull trigger on resection for low volume stage 3 disease. My understanding is that can’t get adjuvant immunotherapy approved for these patients

In my region, MedOncs and surgeons are now outright competing over these patients after 60 Gy

 

[FrostyHammer]

You think 60 Gy is enough to control lung cancer then stop escalating with SBRT. As immunotherapy improves local control matters more.

Also subset analysis of Albain

You mean the unplanned "find some way to pull a p value out of the data to save face for surgery" subset analysis of Albain?

 

[medgator]

In my region, MedOncs and surgeons are now outright competing over these patients after 60 Gy

They resect after 60?

 

[medgator]

RTOG 0617 is odd with higher dose having more local failure. This coupled with the significant benefit observed with IO in PACIFIC makes me wonder if 74 Gy was worse because of immunosuppression. If so, the detriment may not just be related to dose but also to treatment duration.

Will be interesting to see how LU004 pans out, looking at 60/15 w/concurrent IO for stage III NSCLC (I think just phase I/II right now).

It was dumb to ignore the 63-66 Gy crowd when they did that study. I understand why they picked two far apart doses but it still does nothing to qualm fears that 60 may not be enough dose. And I've definitely seen local failures on durva

 

[Haybrant]

You mean the unplanned "find some way to pull a p value out of the data to save face for surgery" subset analysis of Albain?

While I get this to make the claim which was made “why does any single person with III dz get surgery” is equally as out there (and surrogate pharma shill) as saying albain has No merit. You can’t take albain subset and apply it to every stage III but to then to also say that no stage III will benefit from surgery is also disingenious. There is a spectrum and some will, 60gy isn’t enough

 

[salubalu]

They resect after 60?

Our surgeons would resect after 60 pretty routinely

 

[Palex80]

Funny to see people give sclc or a bad skin ca more than they'll give gross disease in nsclc

It's called evidence. The trial for dose escalation was negative.

But you know, some even give less for unresectable oesophageal cancer (-->50.4 Gy). Know why? There was a negative trial for dose escalation there as well...

Oh, and to those that have always been skeptic about the Minsky-trial (just like me), there's a recent trial confirming dose escalation simply does not work.

 

[Palex80]

It was dumb to ignore the 63-66 Gy crowd when they did that study. I understand why they picked two far apart doses but it still does nothing to qualm fears that 60 may not be enough dose. And I've definitely seen local failures on durva

It's a bit like low grade glioma.

Two studies compared doses of 45-50.4 Gy vs. 59.4-64.8 Gy. Both trials were negative. What do most people give nowadays? 54 Gy.

 

[medgator]

It's called evidence. The trial for dose escalation was negative.

But you know, some even give less for unresectable oesophageal cancer (-->50.4 Gy). Know why? There was a negative trial for dose escalation there as well...

Unless it's in the cervical esophagus...

 

[medgator]

It's a bit like low grade glioma.

Two studies compared doses of 45-50.4 Gy vs. 59.4-64.8 Gy. Both trials were negative. What do most people give nowadays? 54 Gy.

Many of us felt that 74 was too high and 60 is too low in nsclc. Pacific doses were 60-66 iirc

 

[Palex80]

LungArt statistics look strange to me, looking forward to the full presentation.

Ok, I watched the stream now.

My comments:

1. Only 11% got IMRT --> potential issues with cardiac/pulmonary toxicity?

2. 500 patients recruited over 11 years in 4 countries. I counted something like 40+ investigators on the last slide, meaning quite a few of those institutions probably included less than 1 patient/year. Quality of delivered treatment?

3. A lot of the patients had incidental N2, they actually represent the biggest subgroup in the study with over 40%, despite the fact that 90% of all patients had preoperiative PET. This means that a lot of the patients in the trial had single, small positive N2 nodes. This certainly influences lowers overall risk for recurrence.

4. Accrual goal was revised from 700 to 500 patients after the investigators felt they wouldn't be able to get enough patients in the trial. The hypothesis was conveniently altered to facilitate this. This is bad.

5. DFS was the primary endpoint. Death counts as an event in DFS.
Without PORT there were 19 additional deaths due to tumor progression, with PORT there were 21 additional events due to cardiac/pulmonary toxicity, treatment toxicity and other primaries. This raises the question if:
a) PORT actually killed patients through toxicity
b) There was an inbalance between the groups with more "sick" patients getting PORT.
With a median follow up time of less than 5 years, I do not think that secondary primaries because of PORT would actually become an issue. Cardiac/Pulmonary toxicity might however be an issue within such a timeframe.

6. Incomplete resected tumors and extracapsular spread in N2 nodes were exclusion criteria, meaning if you based your indication for PORT based on these two factors, LungArt is basically irrelevant. The only relevant issue is the apparent excessive toxicity with PORT.

 

[Ray D. Ayshun]

It's called evidence. The trial for dose escalation was negative.

But you know, some even give less for unresectable oesophageal cancer (-->50.4 Gy). Know why? There was a negative trial for dose escalation there as well...

Oh, and to those that have always been skeptic about the Minsky-trial (just like me), there's a recent trial confirming dose escalation simply does not work.

It looked like there was a potential LPFS benefit to dose escalation in adeno, though only 100 had it, and in turn it was presumably underpowered if we really want to know. In any case, that's the histo type where we need the help.

 

[scarbrtj]

Ok, I watched the stream now.

My comments:

1. Only 11% got IMRT --> potential issues with cardiac/pulmonary toxicity?

2. 500 patients recruited over 11 years in 4 countries. I counted something like 40+ investigators on the last slide, meaning quite a few of those institutions probably included less than 1 patient/year. Quality of delivered treatment?

3. A lot of the patients had incidental N2, they actually represent the biggest subgroup in the study with over 40%, despite the fact that 90% of all patients had preoperiative PET. This means that a lot of the patients in the trial had single, small positive N2 nodes. This certainly influences lowers overall risk for recurrence.

4. Accrual goal was revised from 700 to 500 patients after the investigators felt they wouldn't be able to get enough patients in the trial. The hypothesis was conveniently altered to facilitate this. This is bad.

5. DFS was the primary endpoint. Death counts as an event in DFS.
Without PORT there were 19 additional deaths due to tumor progression, with PORT there were 21 additional events due to cardiac/pulmonary toxicity, treatment toxicity and other primaries. This raises the question if:
a) PORT actually killed patients through toxicity
b) There was an inbalance between the groups with more "sick" patients getting PORT.
With a median follow up time of less than 5 years, I do not think that secondary primaries because of PORT would actually become an issue. Cardiac/Pulmonary toxicity might however be an issue within such a timeframe.

6. Incomplete resected tumors and extracapsular spread in N2 nodes were exclusion criteria, meaning if you based your indication for PORT based on this two factors, LungArt is basically irrelevant. The only relevant issue is the apparent excessive toxicity with PORT.

I feel you re: maintaining some "hope against hope" for N2 PORT. Actually quite a bit of indirect data from the past that it was good. (All hail the PORT meta-analysis. New PORT who dis?) But as the years go by, I realize something that is... how to put it... like a pebble in the shoe for those of us who dole beam. When looking at dose escalation in lung ca (RTOG 0617, worse survival with more dose), breast TARGIT (sign. more non-breast ca deaths when external beam used) data, dose escalation data in esoph and brain (all negative as you point out... although trends in worse surv with more dose less clear), and actually several other disparate data points, one realizes...

The therapeutic window for RT can be annoyingly narrow. And RT has a reasonable probability of worsening outcomes when used injudiciously. I don't know if it's just 'cause we're much more stringent observers these days or systemics (or pre-tx workup/staging) external to rad onc have narrowed that window. Either way, the path toward routine RT nirvana seems a teeny bit more tricky now than 20y ago.

 

[FrostyHammer]

While I get this to make the claim which was made “why does any single person with III dz get surgery” is equally as out there (and surrogate pharma shill) as saying albain has No merit. You can’t take albain subset and apply it to every stage III but to then to also say that no stage III will benefit from surgery is also disingenious. There is a spectrum and some will, 60gy isn’t enough

I agree with you. Certainly surgery has some unquantified merit but the smoking gun has always been which (small) subset of pts it can benefit. IMHO the only patients surgery may benefit are all of the following: 1) younger and more fit, 2) single station N2 disease as detected on preop mediastinal staging (very important to r/o multi-station occult nodal involvement if surgery is pursued), 3) smaller nodal sizes ("smaller" is a subjective criterion), and 4) larger primary tumor bulk. Basically any patient that has a higher rick of LRF than DM. The higher the chances of LRF, the lower the risk of DM, the higher the potential benefit to surgery. Problem is that with the way NSCLC presents and spreads, together with the unique population, these pts are very few and far between.

 

[Haybrant]

I agree with you. Certainly surgery has some unquantified merit but the smoking gun has always been which (small) subset of pts it can benefit. IMHO the only patients surgery may benefit are all of the following: 1) younger and more fit, 2) single station N2 disease as detected on preop mediastinal staging (very important to r/o multi-station occult nodal involvement if surgery is pursued), 3) smaller nodal sizes ("smaller" is a subjective criterion), and 4) larger primary tumor bulk. Basically any patient that has a higher rick of LRF than DM. The higher the chances of LRF, the lower the risk of DM, the higher the potential benefit to surgery. Problem is that with the way NSCLC presents and spreads, together with the unique population, these pts are very few and far between.

Right this is good characterization but I don’t know I feel the number of patients that fit this esp in the screening era is actually a reasonable number, not huge but like 10-12% of stage IIIs maybe a little more

 

[FrostyHammer]

Right this is good characterization but I don’t know I feel the number of patients that fit this esp in the screening era is actually a reasonable number, not huge but like 10-12% of stage IIIs maybe a little more

10-12% sounds correct - it is the major minority for sure, so even when interpreting conservatively no way it even hits the 20% mark.

 

[Palex80]

10-12% sounds correct - it is the major minority for sure, so even when interpreting conservatively no way it even hits the 20% mark.

I would say that this number is definetely a lot higher in Europe.
In stage III patients, about 50% get surgery after neoadjuvant chemo, 25% are treated with chemo/rads and then another 25% actually receive some kind of palliative treatment, being too unfit for radical treatment. That is my assumption.

 

[Haybrant]

I would say that this number is definetely a lot higher in Europe.
In stage III patients, about 50% get surgery after neoadjuvant chemo, 25% are treated with chemo/rads and then another 25% actually receive some kind of palliative treatment, being too unfit for radical treatment. That is my assumption.

Wow that’s high; is that changing with pacific results now?

I would say that these pharma companies are expanding the groups they apply immunotherapy to purposely keeping the group huge and hoping that 20-30% that derive big benefit will power the full group. And med oncs totally buy into that and become their defacto shills. We need to give some push back where it’s due

 

[Palex80]

Wow that’s high; is that changing with pacific results now?

Not really. Pacific is still viewed as therapy for unresectable disease.
And maybe these numbers are just what I am telling you from my perspective, maybe it's different in other countries too. It's diverse and has certainly to do a lot with local expertise of surgeons, preference of pulmonologists, etc...

We should expect results for IO trials post-surgery in the coming years.
PEARLS has randomized patients with resected NSCLC (I believe it's stage II & III) to Pembrolizumab or Placebo. Results should be available soon.