Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

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natelaugh
Posts: 84
Joined: Wed Apr 03, 2019 11:40 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby natelaugh » Wed Oct 16, 2019 11:22 pm

Hi All,

My dad oncologist email that Regorafenib + Nivolumab is not an approved regimen at Kaiser. We got a pet/ct scan and it shows progression/recurrence. The cancer has spread to his liver, lung and lymph node. 5FU monotherapy didn't work for my dad.

Nate.
Caregiver to 80M
DX:CC,RC,desc
11/2018 rightPain
1/19/19 scopy,path
1/23 CTscan
2/19 surgery
2/26-2/28 NGTube
2/28-3/14 TPN bc ileus
3/2 2nd surgeryCloseOpenWound
3/4-3/28 woundVac
size: 6cm Adenocarcinoma
grade Poorly
Stage IIIC T3N2aMx
PositiveLymph:5of28
BaselineCEA:68
LVI:Y
PNI:N
Surgical margins:clear
MSI:MMR (MLH1, MSH2, MSH6, PMS2) Intact nuclear expression
Lynch status:N
Laparascopic, partial colectomy
CEA:3/28/19 2.8
Chemo:4/16/19-9/17/19 5FU,12cycles,every 14days,leucoverin,zofran,Dexamethasone

Pyro70
Posts: 155
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Sat Oct 19, 2019 3:06 pm

natelaugh wrote:Hi All,

My dad oncologist email that Regorafenib + Nivolumab is not an approved regimen at Kaiser. We got a pet/ct scan and it shows progression/recurrence. The cancer has spread to his liver, lung and lymph node. 5FU monotherapy didn't work for my dad.

Nate.


Regonivo isn’t an approved regimen anywhere. Ideally a patients would go on a clinical trial. But if that isn’t available Regonivo is a viable option and many (maybe too many) oncologists have been offering it off label.

Unfortunately, the initial results from people I’m following are not encouraging. Most people have progression, some have stability. But that’s what we would expect from Regorafenib monotherapy. We really should be seeing some responses (tumor shrinkage) if this combo really works.
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

mpbser
Posts: 934
Joined: Wed Apr 19, 2017 11:52 am

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby mpbser » Sun Oct 20, 2019 3:53 am

"Unfortunately, the initial results from people I’m following are not encouraging. Most people have progression, some have stability. But that’s what we would expect from Regorafenib monotherapy."

Can you clarify? Are you saying that the results of most people you are following who are taking Regonivo have progression and stability?

That's discouraging.
Wife 4/17 Dx age 45
5/17 LAR
Adenocarcinoma
low grade
1st primary T3 N2b M1a
Stage IVA
8/17 Sub-total colectomy
2nd primary 5.5 cm T1 N0
9 of 96 nodes
CEA: < 2.9
MSS
Lynch no; KRAS wild
Immunohistochemsistry Normal
Fall 2017 FOLFOX shrank the 1 met in liver
1/18 Liver left hepatectomy seg 4
5/18 CT clear
12/18 MRI 1 liver met
3/7/19 Resection & HAI
4/1/19 Folfiri & FUDR
5/13/19 HAI pump catheter dislodge, nearly bled to death
6-7 '19 5FU 4 cycles
NED

Pyro70
Posts: 155
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Sun Oct 20, 2019 7:14 pm

7 patients that I know of have had their first CT scans or stopped therapy.
4/7 have died or are in hospice and stopped therapy
2/7 are stable with slight increase in tumor size (could be pseudo progression)
1/7 is stable with no change in tumor size
0/7 have had a response (tumor shrinkage)

There is some discussion that the these 7 patients had a lower ECOG than in the Japanese trial where all but one had an ECOG of 0. Like for Regorafenib monotherapy it May be important to start this while the patient is still relatively fit.

I’m reaching out to the 7 to better understand their baseline, but responses have been understandably slow.
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

Rock_Robster
Posts: 375
Joined: Thu Oct 25, 2018 5:27 am
Location: Melbourne, Australia

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Rock_Robster » Sun Oct 20, 2019 8:35 pm

Thanks Pyro70 for your efforts keeping track of this; it’s incredibly helpful to have in the absence of further trial data.

In REGONIVO, the ORR in MSS CRC patients was 29%, suggesting of your n=7 sample we would expect 2 patients to have had stable disease or regression. This actually doesn’t sound that far from what you’re describing (ie 1 stable, 2 stable or slight increase [which sounds like would likely still meet RECIST criteria for a response]). Whilst it’s disappointing to not see significant reduction of disease burden in your cohort, I’m not sure it could reasonably be expected either if we apply the REGONIVO results to a sample of 7 (even ignoring the reasonable statistical deviation we would expect from such a small sample).

As you say the groups are likely heterogenous as well, ECOG scores may be one area - also pretreatment and response to PD-1 inhibitors seemed to potentially be relevant (though perhaps moreso for gastric cancer than CRC).

So I don’t take this to mean that rego + nivo does or doesn’t work; simply that it can’t be concluded at this point. In short I’m perhaps disappointed but not surprised or discouraged yet :-)

Rob
Male 37; Melbourne, Australia
10/2018 Dx 3.5cm RC adenocarcinoma, 12cm from AV
Mod diff, EMVI+ LVI+ PNI-
3 LN; 4 liver mets, resectable
pT3pN1aM1a; Stage IVa. MSS, NRAS (G13R)
CEA: Oct-18= 12; Nov-18= 14, Mar-19= 2.4, Aug-19 <2.0
11/18 - FOLFOX x 6
3/19 - Liver resection
4-5/19 - 25 x pelvic radiation; complete met. response, TRG 3
07/19 - ULAR (robot), temp ileo, 1/27 LN
08/19 - Missed liver spot
08-11/19 - FOLFOX x 1, FOLFOXIRI x 1, FOLFIRI x 5
12/19 - Planned liver resection #2 & stoma reversal

Rock_Robster
Posts: 375
Joined: Thu Oct 25, 2018 5:27 am
Location: Melbourne, Australia

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Rock_Robster » Sun Oct 20, 2019 8:43 pm

Pyro70 wrote:
natelaugh wrote:Hi All,

My dad oncologist email that Regorafenib + Nivolumab is not an approved regimen at Kaiser. We got a pet/ct scan and it shows progression/recurrence. The cancer has spread to his liver, lung and lymph node. 5FU monotherapy didn't work for my dad.

Nate.


Regonivo isn’t an approved regimen anywhere.

Is this quite right? Maybe I’m being semantic but my understanding is that individual drugs get approved, not combinations (I could be wrong though so please correct me!). Oncologists may then choose to use the drugs in combination (and at doses) selected for the patient - eg offering 5FU monotherapy vs FOLFOX. The issue here I think is that nivolumab is an approved drug but not usually funded by insurance for MSS patients due to near-zero response as monotherapy.

Would be interesting to see if the manufacturer is willing to fund or subsidise some regonivo treatment though to get more data out there faster.
Male 37; Melbourne, Australia
10/2018 Dx 3.5cm RC adenocarcinoma, 12cm from AV
Mod diff, EMVI+ LVI+ PNI-
3 LN; 4 liver mets, resectable
pT3pN1aM1a; Stage IVa. MSS, NRAS (G13R)
CEA: Oct-18= 12; Nov-18= 14, Mar-19= 2.4, Aug-19 <2.0
11/18 - FOLFOX x 6
3/19 - Liver resection
4-5/19 - 25 x pelvic radiation; complete met. response, TRG 3
07/19 - ULAR (robot), temp ileo, 1/27 LN
08/19 - Missed liver spot
08-11/19 - FOLFOX x 1, FOLFOXIRI x 1, FOLFIRI x 5
12/19 - Planned liver resection #2 & stoma reversal

Pyro70
Posts: 155
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Mon Oct 21, 2019 8:12 am

Rock_Robster wrote:
Pyro70 wrote:
natelaugh wrote:Hi All,

My dad oncologist email that Regorafenib + Nivolumab is not an approved regimen at Kaiser. We got a pet/ct scan and it shows progression/recurrence. The cancer has spread to his liver, lung and lymph node. 5FU monotherapy didn't work for my dad.

Nate.


Regonivo isn’t an approved regimen anywhere.

Is this quite right? Maybe I’m being semantic but my understanding is that individual drugs get approved, not combinations (I could be wrong though so please correct me!). Oncologists may then choose to use the drugs in combination (and at doses) selected for the patient - eg offering 5FU monotherapy vs FOLFOX. The issue here I think is that nivolumab is an approved drug but not usually funded by insurance for MSS patients due to near-zero response as monotherapy.

Would be interesting to see if the manufacturer is willing to fund or subsidise some regonivo treatment though to get more data out there faster.



You might be right about approval regarding drug combos. To clarify: for MSS CRC patients, Nivolumab is not an approved drug anywhere in the world. This means typically insurance companies won’t pay for it (although We’ve heard of it happening in some cases). However, Nivolumab is an approved drug for other cancers (and MSI CRC). This means doctors are allowed to prescribe it “off-label” for other applications if they think there is a benefit, yet typically the insurance will refuse reimbursement. In the US, in most cases BMS will supply Nivolumab for free for patients trying Regonivo.
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

Pyro70
Posts: 155
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Mon Oct 21, 2019 8:16 am

Rock_Robster wrote:Thanks Pyro70 for your efforts keeping track of this; it’s incredibly helpful to have in the absence of further trial data.

In REGONIVO, the ORR in MSS CRC patients was 29%, suggesting of your n=7 sample we would expect 2 patients to have had stable disease or regression. This actually doesn’t sound that far from what you’re describing (ie 1 stable, 2 stable or slight increase [which sounds like would likely still meet RECIST criteria for a response]). Whilst it’s disappointing to not see significant reduction of disease burden in your cohort, I’m not sure it could reasonably be expected either if we apply the REGONIVO results to a sample of 7 (even ignoring the reasonable statistical deviation we would expect from such a small sample).

As you say the groups are likely heterogenous as well, ECOG scores may be one area - also pretreatment and response to PD-1 inhibitors seemed to potentially be relevant (though perhaps moreso for gastric cancer than CRC).

So I don’t take this to mean that rego + nivo does or doesn’t work; simply that it can’t be concluded at this point. In short I’m perhaps disappointed but not surprised or discouraged yet :-)

Rob


Yes we can’t draw any definitiv conclusions. But to clarify ORR is the number (or percent of patients) that have had at least 30% tumor shrinkage (sum of PR and CR). It does not include stable patients.

If you include stable patients (growth less than 20% and no new lesions, I think) it’s called the DCR (disease control rate) which for Regonivo was like >80%...
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

Rock_Robster
Posts: 375
Joined: Thu Oct 25, 2018 5:27 am
Location: Melbourne, Australia

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Rock_Robster » Mon Oct 21, 2019 8:26 am

Pyro70 wrote:
Rock_Robster wrote:Thanks Pyro70 for your efforts keeping track of this; it’s incredibly helpful to have in the absence of further trial data.

In REGONIVO, the ORR in MSS CRC patients was 29%, suggesting of your n=7 sample we would expect 2 patients to have had stable disease or regression. This actually doesn’t sound that far from what you’re describing (ie 1 stable, 2 stable or slight increase [which sounds like would likely still meet RECIST criteria for a response]). Whilst it’s disappointing to not see significant reduction of disease burden in your cohort, I’m not sure it could reasonably be expected either if we apply the REGONIVO results to a sample of 7 (even ignoring the reasonable statistical deviation we would expect from such a small sample).

As you say the groups are likely heterogenous as well, ECOG scores may be one area - also pretreatment and response to PD-1 inhibitors seemed to potentially be relevant (though perhaps moreso for gastric cancer than CRC).

So I don’t take this to mean that rego + nivo does or doesn’t work; simply that it can’t be concluded at this point. In short I’m perhaps disappointed but not surprised or discouraged yet :-)

Rob


Yes we can’t draw any definitiv conclusions. But to clarify ORR is the number (or percent of patients) that have had at least 30% tumor shrinkage (sum of PR and CR). It does not include stable patients.

If you include stable patients (growth less than 20% and no new lesions, I think) it’s called the DCR (disease control rate) which for Regonivo was like >80%...

Thanks Pyro - that’s an important correction if the 30% is shrinkage only. In this case it would indeed seem the group of 7 is underperforming the expectation...
Male 37; Melbourne, Australia
10/2018 Dx 3.5cm RC adenocarcinoma, 12cm from AV
Mod diff, EMVI+ LVI+ PNI-
3 LN; 4 liver mets, resectable
pT3pN1aM1a; Stage IVa. MSS, NRAS (G13R)
CEA: Oct-18= 12; Nov-18= 14, Mar-19= 2.4, Aug-19 <2.0
11/18 - FOLFOX x 6
3/19 - Liver resection
4-5/19 - 25 x pelvic radiation; complete met. response, TRG 3
07/19 - ULAR (robot), temp ileo, 1/27 LN
08/19 - Missed liver spot
08-11/19 - FOLFOX x 1, FOLFOXIRI x 1, FOLFIRI x 5
12/19 - Planned liver resection #2 & stoma reversal

boswind
Posts: 71
Joined: Fri Apr 11, 2014 12:04 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby boswind » Mon Oct 21, 2019 8:28 pm

Pyro70 wrote:7 patients that I know of have had their first CT scans or stopped therapy.
4/7 have died or are in hospice and stopped therapy
2/7 are stable with slight increase in tumor size (could be pseudo progression)
1/7 is stable with no change in tumor size
0/7 have had a response (tumor shrinkage)

There is some discussion that the these 7 patients had a lower ECOG than in the Japanese trial where all but one had an ECOG of 0. Like for Regorafenib monotherapy it May be important to start this while the patient is still relatively fit.
. . .


Pyro70,
I think there is another factor that needs to be considered in explaining why the overall outcome of the 7 patients is not as good as that shown in the ASCO 2019 presentation. The majority of 50 patients in the ASCO 2019 presentation are Asians while the majority of the 7 patients you indicated are Caucasians (?). Last year I read an article stating that statistically Asian patients had better response to regorafenib than Caucasian patients. Furthermore, Asian patients generally have worse side effects.
01.24.14 Male, DX @54 Rectosigmoid Cancer, MRI: T3N0M0
03.19.14 Completed 5-week Radia+Xeloda
05.07.14 Had surgery
02.25.15 CT showed stage 4.
03.15 - 08.15, folfox + Avastin
08.15 - 07.17, 5FU+leucovorin+Avastin
07.17 - 01.18, Folfuri + Avastin
02.18 - 03.19, Centuximab + Irinotecan
90 rounds of chemos received (as of 12.27.18)
MSS, KRAS wt, BRAF wt
03.19 - 05.19, Keytruda
05.19 - 9.19, Folfox+Avastin
10.22.19 - rechallenge Centuximab+Irinotecan

boswind
Posts: 71
Joined: Fri Apr 11, 2014 12:04 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby boswind » Fri Oct 25, 2019 5:33 pm

Here are the two articles from where I drew my statement above.

CORRECT Phase III trial
https://ascopubs.org/doi/abs/10.1200/jc ... suppl.3502
Dominating Caucasian patients
Arm of Regorafenib:
Median PFS: 1.9 months
Median OS: 6.4 months

CONCUR Phase III trial
https://www.ascopost.com/issues/august- ... al-cancer/
Dominating Asian patients
Arm of Regorafenib:
Median PFS: 3.2 months
Median OS: 8.8 months
01.24.14 Male, DX @54 Rectosigmoid Cancer, MRI: T3N0M0
03.19.14 Completed 5-week Radia+Xeloda
05.07.14 Had surgery
02.25.15 CT showed stage 4.
03.15 - 08.15, folfox + Avastin
08.15 - 07.17, 5FU+leucovorin+Avastin
07.17 - 01.18, Folfuri + Avastin
02.18 - 03.19, Centuximab + Irinotecan
90 rounds of chemos received (as of 12.27.18)
MSS, KRAS wt, BRAF wt
03.19 - 05.19, Keytruda
05.19 - 9.19, Folfox+Avastin
10.22.19 - rechallenge Centuximab+Irinotecan

Pyro70
Posts: 155
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Sat Oct 26, 2019 12:15 am

boswind wrote:Here are the two articles from where I drew my statement above.

CORRECT Phase III trial
https://ascopubs.org/doi/abs/10.1200/jc ... suppl.3502
Dominating Caucasian patients
Arm of Regorafenib:
Median PFS: 1.9 months
Median OS: 6.4 months

CONCUR Phase III trial
https://www.ascopost.com/issues/august- ... al-cancer/
Dominating Asian patients
Arm of Regorafenib:
Median PFS: 3.2 months
Median OS: 8.8 months



One should be careful when comparing results of two trials. Differences in protocols and patient selection can make a big difference. Ideally we should be comparing subgroups within the same trial (ideally randomized, but with ethnicity that’s obviously not possible).

But you’re right, there could be a difference between Asian and non-Asian populations. I hope though there isn’t.

They did look at Japanese vs non-Japanese in the correct trial. OS was consistent, but side effects greater in the Japanese patients. Side effects in Regorafenib have been thought to correlate with efficacy, so maybe there is a bit of a difference.

https://www.ncbi.nlm.nih.gov/m/pubmed/25213161/

Regorafenib had a consistent OS benefit in the Japanese and non-Japanese subpopulations, with hazard ratios of 0.81 (95 % confidence interval [CI] 0.43-1.51) and 0.77 (95 % CI 0.62-0.94), respectively. Regorafenib-associated hand-foot skin reaction, hypertension, proteinuria, thrombocytopenia, and lipase elevations occurred more frequently in the Japanese subpopulation than in the non-Japanese subpopulation, but were generally manageable.
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

dxycn
Posts: 9
Joined: Thu Oct 09, 2014 10:07 am

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby dxycn » Sun Oct 27, 2019 8:29 am

look at this

https://www.targetedonc.com/news/combin ... udies-show

Avastin+ Tecentriq can improve PFS , That means Combinations with avstin or reg. or oter target agents and PD-1/PD-L1 Agents May Improve Outcomes in mCRC

Pyro70
Posts: 155
Joined: Mon Jan 21, 2019 4:25 pm

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Pyro70 » Mon Nov 04, 2019 4:15 pm

Latest results from the Regonivo patients I’m tracking:

*Total of 8 patients had their first scan or have stopped the combo.
*2 patients have a potential response (seeing cavitation, but shrinkage isn’t at the 30% required by RECIST for an official response).
*2 patients are stable
*4 patients have died or entered hospice

One current hypothesis is that patients with a lower performance status and/or more advanced disease don’t perform as well as those that take the combo earlier.
Dx Jan 2017 stage IVB w/ PC age 35
FOLFOX
SEP 17 HIPEC 1, anastamosis leak
XELODA
MAR 18 HIPEC 2
JUN 18, ileo reversal and 2nd anastamosis leak

Wewillfight
Posts: 15
Joined: Sun Mar 03, 2019 5:27 am

Re: Regorafenib + Nivolumab - Immunotherapy might work in MSS CRC

Postby Wewillfight » Mon Nov 04, 2019 5:48 pm

If you guys were to take a shot at one of these combos which would it be?

Stivarga/Opdivo? (REGONIVO)

Avastin/ Opdivo

Avastin or Stivarga / Pembo

Is there any indication that Avastin instead of Stivarga could be more beneificial

Obviously it is a roll of the dice but hoping to weight the dice in favour especially if throwing 20-50k at it
40 y/o
Diag Nov 2016 stage IIIc, surgery, colostomy, 2 lymph involved
6 months FOLFOX
NED
Nov 2018 recurrence , surgery , some spread to pertineum
Jan-June 2019 Folfiri+Cetux
Clear scans
August 2019: small bowel inflammation, partial blockage symptoms


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