Episode 108: Colorectal Cancer Series, Pt. 10 - Metastatic Colorectal Cancer (Part 2)
This week, we round out our discussion on metastatic colorectal cancer, focusing on more targeted therapies for this disease. If you have not done so already, be sure to check out episode 107 for the first part of our metastatic colorectal cancer discussion.
In our prior episode, we said that one the critical pieces of data that we need to assess is if the patient is MSI/MMR testing. Why does this matter and what is the role of immunotherapy in these patients?
The MMR and MSI status are critical predictive markers for patients with metastatic disease
In a large pooled analysis of patient level data from 4 randomized trials including over 3000 patients with metastatic disease published in 2014, the incidence of MMR deficient tumors was roughly 5%
Immunotherapy was first evaluated in the second or later lines in these patients after treatment with FOLFOX, FOLFIRI, or both
The KEYNOTE 164 trial looked at pembrolizumab monotherapy and it was found to have an ORR of about 33% with median PFS of 4 months
The CHECKMATE 142 trial looked at both nivolumab monotherapy and ipilimumab + nivolumab
The ORR for nivolumab monotherapy was a little over 30% with a 3 month disease control rate of 70%
The ORR for combination ipi/nivo was 55% with a 3 month disease control rate of 80%
Both of these studies led to the approval of immunotherapy in later lines
The pivotal KEYNOTE-177 trial led to the approval of pembrolizumab in the first line setting
Included over 300 patients who were randomized to either chemotherapy with or without bevacizumab or cetuximab vs. pembrolizumab monotherapy
The original study was published in NEJM 2020 which showed a significant PFS benefit
Longer term follow up was presented at ESMO 2023 which showed both a PFS and OS benefit favoring the immunotherapy arm
The 5 year overall survival was 55% with immunotherapy compared to 44% with chemotherapy; a 10% absolute increase in survival
PFS rate at 5 years was 34% compared to 7%, favoring immunotherapy
If patients did respond to immunotherapy, then roughly 70% of those patients had durable response up to 5 years out
Health related quality of life analysis that led to clinically meaningful improvement in the immunotherapy arm compared to chemotherapy
Note: Notice that the overall survival curves favor chemotherapy slightly initially and then cross to favor immunotherapy after the 8 month mark suggesting that patients with higher tumor burden may need chemotherapy first
We also have data for the use of ipilumumab/nivolumab in the front-line setting based on the CHECKMATE 8HW trial which was presented as a late breaking abstract at ASCO GI 2024
Patients were randomized 2:2:1 to receive nivo monotherapy, ipi/nivo, or chemotherapy alone; patients get 4 cycles of combination ipi/nivo followed by nivo monotherapy q4week
The 2 year PFS rate in the ipi/nivo arm was 72% vs. only 14% in the chemotherapy arm
PFS2 was also significantly improved in the ipi/nivo arm compared to chemotherapy though it is unclear how many patients crossed over to immunotherapy which would significantly impact that results
At the data cut off about 20% of patients were still on treatment in the ipi/nivo arm
Longer term follow up is needed and nivo monotherapy data will also be helpful but results of this study are very promising and combination immunotherapy should be considered for fit patients with metastatic MSI-high disease
If our patient has a BRAF V600E mutation found on NGS, how do we approach management these patients?
Currently first line therapy is still either FOLFOX or FOLFIRI with or without bevacizumab and 5-FU maintenance as we discussed in detail last week
It’s important to know that roughly 5-8% of metastatic patients have BRAF mutated disease and about a third of patients with MSI-high tumors will also have a BRAF mutation
These patients also tend to have right sided tumors and have a poor prognosis with tumors that behave aggressively
BRAF inhibitor monotherapy did not work well with low response rates (roughly 5%) in early phase studies for these patients
There was a pivotal paper published in 2012 in Nature that showed BRAF inhibition led to overactivation of the MAPK pathway through EGFR signaling and that dual inhibition with both BRAF and EGFR inhibitors were effective
There was a phase 1b study looking at the BRAF inhibitor encorafenib combined with cetuximab which showed response rates of roughly 20% in heavily pretreated patients
We then had the pivotal phase III BEACON trial that lead to the approval of encorafenib + cetuximab in the second line setting
Patients had all received either one or two prior treatments
They were randomized 1:1:1 to encorafenib + cetuximab, encorafenib + binimetinib (the MEK inhibitor), or investigators choice (irinotecan monotherapy + cetuximab or FOLFIRI + cetuximab)
Median OS improved from roughly 6 months to 9 months with encorafenib + cetuximab compared to chemotherapy arm
There was a response rate of 20% which mirrors the phase 1b results
There was no additional benefit of adding binimetinib with identical overall survival results
Is there a role for upfront more intensive regimens in patients?
TRIBE-2 was a study looking at FOLFOXIRI vs. Standard FOLFOX followed by FOLFIRI
Patients were randomized to FOLFOXIRI + bevacizumab followed by 5-FU + bev maintenance and then retreatment with FOLFOXIRI at progression followed by maintenance vs. FOLFOX + bevacizumab followed by 5-FU + bev maintenance and then switch to FOLFIRI followed by maintenance
There were 38% of patients with right sided primary site and 10% of patients with BRAF mutation with a majority have synchronous metastatic disease reflecting a higher risk group of patients
Outcomes:
Median OS was improved from 22 months to 27 months favoring the FOLFOXIRI arm
Median PFS2 was also improved from 16 months to 19 months
There were significantly higher Grade 3 and 4 events in the FOLFOXIRI arm including neuropathy, diarrhea, stomatitis, and neutropenia
Roughly 20% of patients compared to 5% had grade 3 or 4 diarrhea
There were 8 treatment related deaths with FOLFOXIRI and 4 treatment related deaths in the control arm so patient selection is critical
This led to approval in the front line but reserved for younger, fit patients and really should be considered for those with high risk disease features
What about patient with HER2+ metastatic colorectal cancer. What therapies are utilized for these patients?
Check out our breast cancer series for more nuanced discussion on HER2 positivity and the mechanism of action for HER2 directed therapies in the early stage and metastatic HER2 episodes
HER2 positivity was defined as HER2 3+ by IHC or HER2 2+ by IHC and positive by FISH
There was earlier data looking at combination of trastuzumab + pertuzumab in a basket trial of multiple tumor types that showed a response rate of roughly 30% of patients with metastatic colorectal cancer
Most recently, the phase II MOUNTAINEER study was published which looked at trastuzumab + tucatinib for patients with chemotherapy refractory metastatic colorectal cancer
A total of 117 patients were enrolled and there was a randomization to the doublet therapy or tucatinib alone
The objective response rate was 38% and there were 3 patients with CR which led to the approval of this combination in later lines
Long term follow up is still pending
We also have data on the use of the antibody drug conjugate trastuzumab deruxtecan
There was a phase II study called DESTINY-CRC01
There were 73 patients with any HER2 positivity included
Patients were included if they were HER2 positive or if they were HER2 low (HER2 2+ by IHC with negative FISH or HER2 1+ by IHC)
Outcomes:
The ORR in HER2 positive patients was almost 50% with median PFS of 7 months
The ORR was 0% in patients with HER2 low tumors
References:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201568/: Large pooled analysis showing incidence of MSI status in patients with metastatic colorectal cancer
https://ascopubs.org/doi/10.1200/JCO.19.02107: KEYNOTE164 showing efficacy of pembrolizumab as effective therapy in MSI-H patients in second line setting
https://ascopubs.org/doi/10.1200/JCO.21.01015: CHECKMATE 142 showing efficacy of ipi/nivo in second line setting
https://www.nejm.org/doi/full/10.1056/NEJMoa2017699: KEYNOTE 177 study showing efficacy of pembrolizumab in first line setting
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00197-8/abstract: Longer term follow up data on KEYNOTE 177
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00064-4/abstract: Quality of life data from KEYNOTE 177
https://ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.LBA768: CHECKMATE 8HW showing efficacy of ipi/nivo in first line setting
https://pubmed.ncbi.nlm.nih.gov/26460303/: Early study investigating BRAF inhibitor monotherapy
https://www.nature.com/articles/nature10868: Nature paper showing dual blockade is more effective with BRAF mutations
https://pubmed.ncbi.nlm.nih.gov/28363909/: Phase Ib study showing efficacy of BRAF/EGFR dual blockade
https://ascopubs.org/doi/10.1200/JCO.20.02088?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed: BEACON III study showing efficacy of cetuximab + encorafenib
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30862-9/abstract: TRIBE-2 study showing efficacy of FOLFOXIRI in younger, fit population
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00150-X/abstract: MOUNTINEER Study for trastuzumab + tucatinib
https://www.nature.com/articles/s41467-023-38032-4: Efficacy of trastuzumab deruxtecan
The crew behind the magic:
Show outline: Ronak Mistry
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Ronak Mistry
Social media management: Ronak Mistry
We are proud to partner with HemOnc.org!
Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org
mCRC patient checklist:
Limited vs. metastatic disease?
Left vs. right sided primary?
MSI status
HER2 status
BRAF status
RAS status
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