The Science Leading to Robust Responses in MSI-High Mismatch Repair Deficient mCRC in CheckMate 142

In the phase 2 CheckMate 142 trial, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated continued robust and durable clinical benefit in patients with microsatellite instability-high (MSI-H), mismatch repair deficient (MRD) metastatic colorectal cancer (mCRC), according to 2-year follow-up data presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

In 45 patients, an overall response rate of 69% (95% CI, 53-82) was observed with the combination, including complete responses in 13% of patients (n = 6), partial responses in 56% of patients (n = 26), and stable disease in 16% of patients (n = 7). There was only 1 patient in the study who had progressive disease. The disease control rate in the study was 84% (95% CI, 70.5%-93.5%).

Looking further into the robust responses of the CheckMate 142 patient population, the median time to response was just 2.7 months (range, 1.2-27.7). The median duration of response was not reached but ranged from over 1.4 months to 29.0 months.

The combination of immune checkpoint inhibitors, such as nivolumab and ipilimumab, can be traced back to the early data observed with regorafenib (Stivarga) and TAS-102. These agents by themselves are the standard of care therapies for mCRC. Once efficacy of regorafenib and TAS-102 were demonstrated in combination regimens, oncologists began to see the synergistic possibilities with targeted agents utilizing compounds to treat their patients. Then, after these synergies were confirmed in clinical trials, more combinations went into development.

In an interview with Targeted Oncology, Heinz-Josef Lenz, MD, PhD, discussed the history of immune checkpoint inhibition in the mCRC treatment paradigm. He also touched upon the modern strategies for sequencing the available drugs in the space and how molecular testing guides those treatment decisions.

TARGETED ONCOLOGY: Can you discuss how you sequence the available agents in the treatment paradigm of CRC? Which agents are most prominent in the third-line setting?

Lenz: We have a bit dilemma with the richness of the available agents for CRC. I think the first line is pretty straightforward because they usually use a chemotherapy backbone with a targeted agent, depending on the molecular testing of the tumor. If the test is positive for BRAF, you have the option to use EGFR inhibitors. If it’s mutant, we usually use an anti-VEGF treatment such as bevacizumab (Avastin), and that will determine the choice of the second-line therapy.

In the United States, many of my colleagues start with irinotecan, fluorouracil, folinic acid, oxaliplatin plus bevacizumab or irinotecan, fluorouracil (5-FU), and also folinic acid (leucovorin) plus bevacizumab for wildtype patients. These treatments determine the choice for third-line therapy.

If chemotherapy is used in the first and second line and is no longer effective, the third-line options include regorafenib and TAS-102.

There are newly developed targeted agents such as EGFR inhibitors. Many clinical trials have suggested that when you use an EGFR inhibitor in the first-line setting these treatment showed some effect measured by response or progression-free survival (PFS) of about 6 months, and if you switched an alternative regimen of bevacizumab plus chemotherapy for at least 4 months, there is a possibility that you lose the mechanism of resistance gained EGFR pressure. If this is the case, there are data showing that rechallenging with EGFR inhibitors show response rates between 20% and 30%.The efficacy goes up if you determine with a liquid biopsy that the mechanism of resistance is not present. RAS wildtype and BRAF wildtype, in most cases, are the most fatal mechanisms of resistance.

There are always questions ongoing of when we should use regorafenib or TAS-102 because both drugs haver very similar efficacy data. These data are measured in response, PFS, or overall survival (OS). However, there are significant differences in the toxicity profiles.We also know that we use regorafenib earlier in the lines off treatment, it seemed to increase the efficacy. I think there are more data suggesting that in young patients and patients with better performance status, you should use regorafenib before TAS-102.

We also have data that TAS-102 remains effective after regorafenib failure. That sequence seems to work. The other way around, we have very few data.

The toxicity of regorafenib in clinical trials was a challenge until the re-dose manuscript was published in the Lancet Oncology last year and showed that we don't need to start with the FDA recommended dose of 160 mg. We can start with 80 mg and if patients don’t experience toxicity, we can increase to 120 mg and then go to 160 mg if the patient can tolerate it. This dosing approach actually maintains high efficacy and avoids significant toxicity as well delays in the start treatment. This practice is now being integrated into the National Comprehensive Cancer Network guidelines, and it has been much easier to administer regorafenib and monitor patients while on regorafenib. I still see patients on a weekly basis because the toxicities associated with regorafenib tend to show up in the first 4 weeks.

TAS-102 has less toxicities, so we can use that in patients with poorer performance status

without any problem of impact on quality of life or dose-limiting toxicity. There is an interesting adverse event associated with TAS-102, which is neutropenia. A recent publication in the Annals of Oncology showed that the neutropenia is a significant predictor of efficacy outcomes.

Overall, I think we have some particular measurements that tell us how you use and how you sequence regorafenib and TAS-102.

TARGETED ONCOLOGY: Based on the research surrounding regorafenib, what is a key takeaway regarding this drug?

Lenz: Beyond the standard of care using single-agent regorafenib or single-agent TAS-102, there are very exciting developments using combinations in the third-line setting. One of the most exciting clinical trials presented at ASCO 2019 was the regorafenib plus nivolumab trial in gastric and colon cancer. The data in patients with microsatellite stable disease showed very promising response rates of 26% in colon cancer and 44% in gastric cancer. It was impressive to me that in gastric cancer patients who failed with 1 checkpoint inhibitor responded again to checkpoint inhibition with regorafenib, indicating that you can overcome resistance to an immune checkpoint therapy, which is a very important mechanism of action. This provides better understanding that the significance that anti-VEGF and immune checkpoint inhibitors are a very important new combination which should be further explored.

These combinations led to multiple clinical trials combining many VEGF tyrosine kinase inhibitors with immune checkpoint inhibitors. I think this is only the beginning of developing a better understanding of combinations using pathway synergisms.

There are also promising developments in combinations of TAS-02 with bevacizumab. The recent data published in the Lancet Oncology showed very significant improvements in PFS and OS with this combination. I have been using this combination increasingly in my practice because it's well tolerated and has a very for promising efficacy profile. It does need to be further evaluated in larger clinical trials.

The take home message is that in the future, we may more effective combination treatments in the third-line setting. We will have an improved armamentarium against CRC.

TARGETED ONCOLOGY: One study you touched on was the HERCULES trial. Can you discuss the types of response observed with trastuzumab plus lapatinib in that study with patients with KRAS-mutant metastatic disease?

Lenz: In third-line mCRC settinig, more and more we are relying on the molecular subtyping of this disease because we know CRC is not 1 disease. There is the RAS mutation, and we already have a specific treatment for BRAF mutations. There is also a subgroup that not as interesting, which is the subgroup of patients with HER2-overexpressed and/or amplification.

There are now a number of clinical trials of frontline combinations showing very promising efficacy in this patient population. The first trial was the HERCULES trial, which showed a response rate of 36%. A response rate like this is unheard of in the first-line setting and even higher than most response rate seen in the second-line setting. Interestingly, in this disease, we no longer use chemotherapy. It is all targeted agents, showing that when we select patients correctly, we can have high efficacy and very little toxicity.

These data led to a development of many different HER2-targeted agents, potentially improving the efficacy of HER2 inhibition, including antibodies like CW25. This antibody binds to have different HER2 epitopes and can be effective, even in trastuzumab failures.

The other compound is the antibody drug conjugate. With these agents, we don’t even known what level of overexpression in necessary to demonstrate the effect because it just binds to the receptor and delivers a lethal load of the cytotoxic agent.

Multiple trials in different diseases on trastuzumab resistant showed response rates from 30% to 50%, indicating that targeting this pathway is encouraging, and we now have 3 different ways to target and drug this pathway. It is important for my colleagues to know that you need to look for HER2 overexpression and amplification.

The rate of these overexpressions amplifications is higher in patients who received EGFR inhibitors because one of the mechanism of resistance is up regulation off HER2 and HER3, which is seen in up to 10% off left-sided colon cancers treated with EGFR inhibitor. Oncologists should watch out for these patients by monitoring them in real-time watch out for these patients, which you can monitor in real time with the use of liquid biopsy.

TARGETED ONCOLOGY: How is ctDNA currently being using to monitor responses and resistance in patients with CRC.

Lenz: This is a technology which will change our paradigm and how we treat patients in the future. It allows us to do molecular monitoring in real-time and identify the molecular make up of the tumor at the time of treatment. Also, it allows us to catch the dynamics and changes of molecular characteristics under treatment pressure and identify the escape mechanism for the ongoing treatment on a molecular level.

It’s not only about understanding the biologics of why treatments fail but also to be see potential new targets we can treat or use in order to make better treatment decisions for our patients. I think this is becoming more standard in academic centers.

_Reference:

_{Lenz HJ, ZAgonel V, Cutsem EV, et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Two-year clinical update. J Clin Oncol. 2020:38 (suppl; abstr 4040). doi: 10.1200/JCO.2020.38.15_suppl.4040}