June 2020 Edition Vol.11, Issue 6

A Colorectal Cancer Roundtable: Precision Medicine, Immuno-Oncology, and the Management of Adjuvant CRC

When it comes to chemotherapy management for colorectal cancer, the message that emerged from the ASCO 2020 Annual Meeting was clear: less is more.

This message was discussed by a panel of experts that shared their perspectives on key data published in the area of precision medicine, immuno-oncology, and the management of adjuvant colorectal cancer.

The panel was led by Charles H. Weaver, MD, and included Marwan G. Fakih, MD, Professor, Medical Oncology and Therapeutics Research, Judy and Bernard Distinguished Directorship in Clinical Research, Section Head, GI Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA; Daniel Ahn, DO, Director, GI Oncology, Translational Research Working Group and Assistant Professor, Mayo Clinic Hospital, Phoenix, AZ; and John Strickler, MD, Associate Professor, Associate Director Clinical Research – GI Oncology, Duke University Medical Center, Durham, NC.

The following are highlights from the expert panel discussion.

The Increasing Role of Precision Medicine

Dr. Strickler: BRAF V600E mutations occur in approximately 5% to 10% of patients with metastatic colon cancer. These tumors tend to be concentrated on the right side, which is associated with inferior prognosis. All of the patients enrolled in BEACON CRC (n=665) had progressed on 1 or 2 prior regimens in the metastatic setting.1 The primary endpoints were overall survival (OS) and objective response rates.

Median overall survival (OS) was 9.3 months for both the triplet arm (encorafenib, binimetinib and cetuximab) and the doublet arm (encorafenib and cetuximab), while the control arm had an OS of 5.3 months. The confirmed response rate was slightly higher for the triplet versus the doublet arm (26.8% vs. 19.5%), while the control arm had a response rate of just 1.8%.

Both the triplet and the doublet arms showed improved OS compared to the control arm. There was no dramatic difference in survival between the doublet and the triplet arms, but the study was not designed to compare those two arms. Adverse events were fairly similar between all three arms, with perhaps slightly better tolerability in the doublet arm of encorafenib and cetuximab.

We’ve known for a long time that BRAF-mutated colorectal cancer is associated with poor prognosis, aggressive natural history, and resistance, and it’s been shown for several years that anti-BRAF combinations have activity. Once again, these data show the doublet to be a very strong standard of care, but there are still some questions that remain. Are there populations for whom a triplet may be better than a doublet? If so, when should we be giving this? Given its tolerability and response rates, should we bring this therapy into the first-line setting? Finally, what should we do with patients after they progress on this anti-BRAF combination?

Dr. Fakih : The data from BEACON are compelling for the second- and third-line setting, but I don’t think we have enough data to move this combination to the first-line setting. What will be interesting is building on this backbone in the future and potentially investigating combinations of BRAF inhibitors plus an anti-EGFR inhibitor plus systemic chemotherapy in the first-line setting to see if there is potential synergy. Until those data are there, I probably would reserve encorafenib and cetuximab for second-line therapy.

When these patients do progress, there is probably still a role for cytotoxic [drugs] in the third-line setting. If patients never had FOLFIRI, maybe they should get that. Granted, the response rate in that particular setting would be limited, so there’s room for the study of additional investigational agents that may overcome resistance. Clinical trials would also be important for the third-line setting following encorafenib, cetuximab failure.

Dr. Ahn: Given the paucity of data in the first-line setting at this time, I agree that the role for encorafenib and binimetinib is in the refractory setting, but there are plans to study the doublet in a randomized phase 3 study in the first-line setting.

I think most patients with CRC should get the doublet versus triple targeted therapy, but younger patients with a high disease burden who can tolerate the triplet may need that extra 6% to 7% response rate.

In terms of sequencing, I think it matters what patients get in the first-line setting, whether it’s true FOLFOXIRI or FOLFIRI or FOLFOX. Then, they should get targeted therapy in the second line; and in the third line, depending on what they’ve been exposed to prior, we should look at mechanisms of resistance and sequential chemotherapy.

HER2-Positive Metastatic Colorectal Cancer

Dr. Strickler: HER2 amplification occurs in approximately 2% to 3% of patients with metastatic colorectal cancer. Unlike BRAF mutations, these tend to be more concentrated on the left side of the colon and rectal cancers and are associated with RAS wild-type tumors, although they can occur at the same time as RAS mutations.

In the DESTINY-CRC01 trial, all patients had progressed on at least two prior lines of therapy.2 They were treated with trastuzumab deruxtecan (T-DXd) at a dose of 6.4 mg/kg every three weeks. (The approved breast cancer dose is lower due to difficulties with pneumonitis at this dose level.) Patients were treated in one of three cohorts. The data presented here are focused on Cohort A (n=53), which was specifically HER2 IHC 3+ or IHC 2+/FISH positive.

At the data cutoff, all 53 patients were treated in Cohort A, and there was very strong activity. The confirmed response rate was 45%, including one complete response. The disease control rate was also excellent at 83%; median progression-free survival (PFS) was 6.9 months, making these data very impressive.

One of the unique features of T-DXd is that it does have some toxicity. Specifically, five patients had interstitial lung disease, and there were two treatment-related deaths due to interstitial lung disease. Despite the toxicity seen with interstitial lung disease, many patients benefited from this approach. This is yet another study showing excellent activity for an anti-HER2 therapy in patients with HER2-overexpressing metastatic colorectal cancer. What is it going to take to finally have an FDA approval for this patient population? Hopefully, we will get some FDA-approved options, eventually.

Dr. Weaver: How are you thinking about managing these patients now based on these data?

Dr. Ahn : The response rates seen from DESTINY look very similar to the data that Dr. Strickler presented at ESMO 2019 for the combination of tucatinib plus trastuzumab, but it’s worth noting the difference in toxicity profiles. Because trastuzumab deruxtecan is an antibody-drug conjugate, giving additional chemotherapy is a concern, especially in a treatment-refractory patient population where the rate of grade 3 or higher neutropenia was close to 10%.

In this study, patients had received at least two lines of prior therapy, including prior HER2 therapy, but interestingly, we still saw a high response rate in this patient population.

Another thing to highlight is the rate of pneumonitis. This has been consistently seen with this antibody-drug conjugate, especially for patients with a history of chronic interstitial lung disease, or COPD, or asthma. I think that’s something that we have to consider when using this agent.

Now that we have a bevy of options with anti-HER2 agents, the question becomes about sequencing. Given the added toxicities, I’d be more inclined to use agents such as tucatinib and trastuzumab, assuming that they were approved, or pertuzumab and trastuzumab.

Dr. Fakih : I agree. Moving forward, it’s a question of sequencing. Trastuzumab deruxtecan is not without toxicity. There are also GI toxicities and constitutional symptoms, although the grade 3 toxicities are not that common. These are things to keep in mind when treating patients.

Efficacy data from this study also suggest that patients pre-exposed to anti-HER2 targeted agents may still respond to an immunoconjugate, but we do not have the opposite efficacy data (i.e., sequencing with an immunoconjugate followed by a combination of a TKI plus trastuzumab).

Based on the fact that it’s better tolerated, I think I would start with a trastuzumab/pertuzumab combination or with a combination of trastuzumab/tucatinib or trastuzumab/lapatinib, but I don’t think we have any evidence that one is better than the other. Trastuzumab/pertuzumab doesn’t have the TKI toxicities, so that has been more of my preference, personally.

Checkpoint Inhibitors and the Management of Select Patients

Dr. Fakih: Probably the highlight of this meeting has been the plenary session that reported on KEYNOTE-177.3 We’ve known all along that 5% of our patients with microsatellite instability (MSI) who have hyper-mutated tumors are likely to respond to immunotherapy. Nivolumab, pembrolizumab, and the combination of nivolumab and ipilimumab have been endorsed as treatment options for patients with MSI-high metastatic colorectal cancer. However, the use of these immunotherapeutic agents has been endorsed more in the second- and third-line setting (except for patients who are frail and cannot tolerate chemotherapy, where NCCN has also endorsed the use of immunotherapy in the first-line setting).

Finally, we have the anticipated data from KEYNOTE-177. This study was positive in that the PFS was considerably better for pembrolizumab in comparison to chemotherapy. The median PFS was 16.5 months for pembrolizumab versus 8.2 months for chemotherapy. We’re looking at a doubling of the median PFS.

Even more important are the two-year PFS rates. Almost half of the patients (48%) who received pembrolizumab had not progressed at the two-year mark versus only 19% for the systemic chemotherapy. As we’ve seen on prior KEYNOTE trials as well as the prior CHECKMATE trial, once a patient has a response to immunotherapy, that response tends to be very durable.

In KEYNOTE-177 the median duration of response on pembrolizumab has not been reached versus 10.6 months for systemic chemotherapy. The response rate was also better (43% vs 33%). Finally, we have very definitive evidence that immunotherapy in the first-line setting considerably betters systemic chemotherapy.

Of note, the curves crossed before immunotherapy clearly showed an improvement in PFS. Early on in the follow up of these patients, systemic chemotherapy was a little bit better in terms of PFS, but after the 6-month mark, we saw a very definitive, major improvement in PFS in favor of the immunotherapy arm.

With respect to toxicity, the immunotherapy arm was also better tolerated (22% of patients receiving pembrolizumab had grade 3 or 4 toxicity versus 66% of patients receiving chemotherapy).

To me, this study is practice changing, but questions still remain. If we’re going to use immunotherapy upfront, what is the best backbone of the immunotherapy? Are these data enough to endorse pembrolizumab as first-line treatment or do we favor using a doublet regimen for our MSI-high patients based on data from the CHECKMATE trial of nivolumab plus ipilimumab?

Finally, given the 29% progressive disease rate with immunotherapy, is there a patient population that should start with chemotherapy first or should immunotherapy be the approach for all MSI-high patients?

Dr. Ahn: The take home from ASCO this year is that less chemotherapy is more. This study is truly a game changer. In the past, it’s been challenging to get immune checkpoint inhibitors in the first-line setting, just based off the FDA approval. Even at the Mayo clinic, a lot of us had to unfortunately start chemotherapy first even though we saw the durable response in the phase 2 study. But, when I see the doubling of PFS and response rates consistent with the phase 2 study, I think using a checkpoint inhibitor in the first line is validated.

In terms of sequencing, my preference is pembrolizumab or any immune checkpoint inhibitor monotherapy first, and if the patient doesn’t seem to be responding, I’ll consider adding an anti-CTLA-4 agent in combination. If they are going to respond, it looks like most patients will respond to just a single immune checkpoint inhibitor and probably don’t need the doublet. But, if they’re not responding, then I would consider adding the doublet at that time.

There are several ongoing studies that will help answer some remaining questions. The COMMIT trial is using a three-arm design to see whether or not chemotherapy should be combined with immune checkpoint inhibitors, and the CHECKMATE phase 3 study is looking at nivolumab versus ipilimumab plus nivolumab versus chemotherapy (investigator’s choice). That will help answer whether chemotherapy should still be considered in the first-line setting, whether an immune checkpoint inhibitor monotherapy is more than adequate, or whether or not the doublet should be considered first. But, at least in my standard practice moving forward, I would just consider immune checkpoint monotherapy, whether it’s pembrolizumab or referencing potentially nivolumab.

Dr. Strickler: This study is a wonderful example of how we can make progress for these patients, and it is practice changing. Clearly, for a sizable number of patients, their lives have been changed in a durable, permanent way by the first-line use of pembrolizumab. I’m so appreciative that we have this option now and that many patients with metastatic colorectal cancer probably won’t ever need to see cytotoxic chemotherapy. It’s truly exciting.

I think the data raise some provocative questions, though. As Dr. Fakih pointed out, in the first 4 months of treatment, patients were less likely to progress on standard cytotoxic chemotherapy. It is only after 4 months that the curves start to converge, and then pembrolizumab clearly establishes its superiority. For patients with highly symptomatic, bulky disease, where there isn’t room for anymore growth, should we potentially give some cytotoxic chemotherapy upfront for immediate debulking before switching over to immunotherapy? It’s a question that we can’t answer from this study.

There are also strong data that ipilimumab and nivolumab are potent in chemotherapy-naïve, treatment-naïve patients. The risks of the added toxicity of dual checkpoint blockade may be worth it for certain highly symptomatic patients with limited time to achieve a response. Of course, this is all theoretical – we don’t have head-to head-trials – but there is a lot of nuance to these data.

For the average patient with MSI-high cancer, though, the right answer is pembrolizumab.

Management of Adjuvant Colorectal Cancer

Dr. Ahn: Another abstract that was presented at ASCO was the updated OS and disease-free survival (DFS) results from the IDEA collaboration,4 which randomized patients to 3 versus 6 months of adjuvant chemotherapy (FOLFOX or CAPOX by physician choice). First published in 2018, the study did not meet its primary endpoint of non-inferiority,5 but it did show a 12% difference in DFS. Pre-planned subgroup analysis also showed that in low-risk patients, 3 months of adjuvant chemotherapy appeared to be non-inferior to 6 months of adjuvant chemotherapy. This was especially seen with CAPOX, where it tended to favor 3 versus 6 months.

Even though the study was technically negative, a lot of practitioners began to adopt the 3-month regimen of chemotherapy in favor of CAPOX. At this year’s ASCO, updated results, again, failed to meet the primary endpoint, but 5-year OS by chemotherapy showed a benefit favoring 3 months versus 6 months of CAPOX. In FOLFOX, there appeared to be very minimal difference (only 1.2%) but favoring 6 months of FOLFOX. Analysis of DFS showed similar results, favoring 3 versus 6 months of CAPOX and the longer course of FOLFOX.

Interesting, toxicity results showed a 3- to 6-fold increase in the degree of neuropathy in patients who received 6 months of chemotherapy, whether they received CAPOX or FOLFOX.

In my practice, I tend to give 3 months of CAPOX for those that are low risk, and for high-risk patients who have either T4 or N2 disease, I consider giving 3 months of CAPOX followed by 3 months of capecitabine to minimize neurotoxicity. With the ongoing COVID-19 pandemic, this approach could also save up to four office visits per month compared with the FOLFOX regimen.

Dr. Fakih: When the DFS data were reported, we adopted 3 months of capecitabine and oxaliplatin in the management of our adjuvant patients. I think there’s always been some concern regarding the higher-risk patient, but if we look at the initial DFS data, there was only a 0.4% difference in 3 versus 6 months of CAPOX in high-risk disease.

The updated data also attenuated the potential harm of 3 months of FOLFOX. In high-risk patients there was a 4% difference in DFS, while updated data showed only a 2% difference in OS in favor of 6 months versus 3 months of FOLFOX.

At the end of the day, I don’t want to subject my patients to additional neuropathy, so I’m still using 3 months with CAPOX. It’s also reassuring that if I can’t use capecitabine (if a patient has renal dysfunction or an ileostomy, for example), I can still use 3 months of FOLFOX in low-risk patients. For high-risk patients, I will still use 6 months of FOLFOX.

Dr. Strickler: This update largely confirms the study’s previous results. In general, and certainly for our lower-risk patients, 3 months is just as good as 6 months, so there’s no reason to subject the patient to the long-term risk of serious neuropathy. The DFS and the OS benefit just isn’t there, specifically for patients getting capecitabine and oxaliplatin.

The decision is a bit more challenging for patients who are not candidates for capecitabine and oxaliplatin. Do we feel like this 2% difference in OS is enough to subject a patient to the long-term risk of neuropathy by going out to 6 months for FOLFOX?

Ideally, we would give 3 just months of CAPOX, but not every patient can take CAPOX. It’s something that we will be weighing with our patients, but it’s great to have these choices. I think it’s wonderful, particularly in the COVID era, that we can get away with 3 months, and we can look patients in the eyes and say, “Your outcomes will be identical, and your long-term risk and neuropathy is lower if you get capecitabine and oxaliplatin.” This confirmatory study is very helpful to our daily practice.


References

  1. Kopetz S, Grothey A, Cutsem EV, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E metastatic colorectal cancer: Updated survival results from a randomized, 3-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Journal of Clinical Oncology 38, no. 4_suppl (February 01, 2020) 8-8.
  2. Siena S, Bartolomeo MD, Raghav K, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 4000-4000.
  3. Andre T, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. Journal of Clinical Oncology 38, no. 18_suppl. Published online June 01, 2020.
  4. Sobrero AF, Andre T, Meyerhardt JA, et al. Overall survival (OS) and long-term disease-free survival (DFS) of 3 versus 6 months of adjuvant (adj) oxaliplatin and fluoropyrimidine-based therapy for patients (pts) with stage III colon cancer (CC): Final results from the IDEA (International Duration Evaluation of Adj chemotherapy) collaboration. Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 4004-4004.
  5. André T, Vernerey D, Mineur L, et al. 3 Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial. J Clin Oncol . 2018 May 20;36(15):1469-1477.

 

 

 

 

 

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