The Colon Club

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.

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.

"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.

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.

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

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.

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.

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%...

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...

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.

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

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.

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

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.

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