Tweet Chat Recap: Evaluating Treatment Options for Rare Subsets of Colorectal Cancer

Pashtoon M. Kasi, MD, MBBS, MS

Pashtoon M. Kasi, MD, MBBS, MS

In honor of Colorectal Cancer (CRC) Awareness Month,Targeted Oncologywas joined by Pashtoon M. Kasi, MD, MBBS, MS, assistant professor of oncology and senior associate consultant in the Division of Hematology/Oncology at the University of Iowa, Holden Comprehensive Cancer Center, in a tweet chat. Prior to the chat, oncologists and other practicing physicians shared their insights as to what treatment options they would consider for 3 individual cases of CRC.

The 3 cases highlighted a variety of subsets of CRC, including patients with NTRK fusions,BRAFmutations, and HER2 amplifications. Kasi spoke to the recent developments in these different subsets of patients, but he also highlighted the role of liquid biopsy in both the treatment landscape as well as in ongoing clinical trials.

In our first patient case tonight, the majority of our poll selected larotrectinib as the next line of therapy. What are your initial thoughts of this case?@pashtoonkasi#TargetedChatpic.twitter.com/rJqrr6JtCR

— Targeted Oncology (@TargetedOnc)March 31, 2020

The first case highlightsNTRKfusions; this is a rare but important subset of CRC, and they tend to be enriched in patients with microsatellite instability-high (MSI-H) disease, according to Kasi. Immunotherapy is an option for patients with MSI-H cancers, but in this particular case, both single-agent and combination immunotherapy led to progression.

Larotrectinib (Vitrakvi) or entrectinib (Rozlyrek) are viable options in this patient and have been approved in a tumor agnostic fashion, Kasi noted. However, the majority in our poll selected larotrectinib, which Kasi says is likely due to the agent receiving its approval from the FDA first in November 2018 compared with entrectinib, which was approved in August 2019.

Dr. Kasi tweeted, “I have to say I’ve never seen anything like the robust responses to theseNTRK-fusion inhibitors.” He highlighted the quick and rapid responses observed with these agents.

An oncology fellow wrote in asking if the presence ofNTRKfusions are mutually exclusive to other oncogenic drivers, to which Dr. Kasi explained that they tend to be enriched in MSI-H patients and tend to be in RAS/RAFwild-type.

#TargetedChatIn our second patient case, the majority in our poll last week said they would use pembrolizumab, an immune checkpoint inhibitor, as the next line of therapy for this patient. Do you agree with this treatment and why/why not?pic.twitter.com/WoeXcMKY8N

— Targeted Oncology (@TargetedOnc)March 31, 2020

In the second case, Dr. Kasi discussed the role of immunotherapy in a patient withBRAFV600E-mutant MSI-H CRC. While there may be a debate on whether a BRAF inhibitor or immunotherapy would be more appropriate in this setting, Kasi believes most experts would lean towards immunotherapy, which was represented in the poll. The majority voted to use the immune checkpoint inhibitor pembrolizumab (Keytruda).

“It’s intriguing how quality of life (QOL) improves on immunotherapy,” Dr. Kasi tweeted. He sharedimages demonstrating the responsethat has been observed with pembrolizumab.

#TargetedChatIn case #3, the majority in our poll voted to treat with pertuzumab plus trastuzumab as the next line of therapy, although TAS-102 as well as lepatinib plus trastuzumab were also of high interest.@pashtoonkasi#crcsm#colorectalcancerawarenessmonthpic.twitter.com/VpYeyIDhxY

— Targeted Oncology (@TargetedOnc)March 31, 2020

HER2, featured in the third case, is more commonly found as an acquired mechanism of resistance in CRC than it is found at baseline. This demonstrates the importance of retesting patients for HER2, particularly after treatment with a BRAF inhibitor. However, Kasi says liquid biopsy or circulating tumor DNA (ctDNA) may be a more practical method for retesting compared to tissue biopsy for many reasons.

In an interview withTargeted Oncologyfollowing the tweet chat,Kasi highlighted the key takeaways from each case and some important overall advances in the treatment landscape of CRC. He also discussed the use of liquid biopsy for the detection of minimal residual disease (MRD) and the advantages it has over tissue biopsies.

TARGETED ONCOLOGY: In case 1, you mentioned that either larotrectinib or entrectinib would be the next best line of therapy. Could you elaborate on this decision?

Kasi:Both larotrectinib and entrectinib are approved and would be viable options, but larotrectinib received its approval before while entrectinib was approved later. They both are among the first targeted therapy tumor agnostic approvals [in this setting].

TARGETED ONCOLOGY: You mentioned that theNTRKfusion is rare, but when do you recommend testing for this?

Kasi:As we are trying to identify these patients in which we have to find theNTRKfusion because it is a rare but important finding, it seems like it is enriched in the MSI-H population, and it is somewhat mutually exclusive for somebody who has the mutation. For somebody you have tested for MSI-H, you should make sure you check them forNTRKas well.

For somebody who is negative for the BRAF or RAS or other actionable findings, upfront they should ideally have expanded RAS/RAF testing, including HER2 andNTRK, but not every center can do the whole panel upfront for each case. Clinically speaking, if you have an MSI-H patient, you should definitely make sure they have had appropriateNTRKtesting; it is not just 1 test because they could have a different partner of NTRKwhether it is a different genetic aberration because the fusions can occur with different partners. It is very important to make sure that the testing is being done in a more comprehensive way.

TARGETED ONCOLOGY: The second case highlights a patient withBRAFV600e-mutated MSI-H CRC. How does immunotherapy compare with chemotherapy or targeted therapies in this setting?

Kasi:The thing about MSI-H patients is that a lot of research suggests these tumors tend to be resistant to chemotherapy. The same thing that makes chemotherapy work so well, which is the high mutational burden, is the same reason immunotherapy works so well in these patients. This is to the point where experts are using the word cure in these MSI-H patients. Most of our patients, if not all of them, do have a response that appears durable and unprecedented, and we see improvement in the performance status right away. Immunotherapy does not have the same baggage or side effects as opposed to chemotherapy. If somebody has an actionable finding such as MSI-H, immunotherapy would be the preferred option in these patients.

In aBRAF-mutated patient who is untreated, the BRAF inhibitors would not be the next step because you have to have some chemotherapy. BRAF inhibitors are approved for the second-line in these patients.

The other thing we do not know, which I mentioned in the tweets, is when you have aBRAFmutation and MSI-H together, which is often the case, most experts would be in favor of using immunotherapy because unlike with targeted therapy, at some point that will stop working. Even the data for BRAF inhibition shows progression-free survival and overall survival were 6 months and 9 months [respectively], so the BRAF inhibitors do stop working. They also have their own baggage of side effects. Immunotherapy as single-agent or in combination would be favored in this case. These patients tend to maintain responses, and I have been pleasantly surprised by the fact that the word cure is being used in these patients because after these patients go to surgery, we don’t find any cancer. This is amazing.

TARGETED ONCOLOGY: What would you like to highlight regarding our third case?

Kasi:The thing about the third case is that there are 2 key concepts. HER2 is 1 of the most recent actionable markers we should be aware of in patients with CRC. The intriguing thing is it is more so an acquired concept as opposed to present at baseline. While you can have it present at baseline, those numbers are small and infrequent, but it does not have an impact. Although not in this case, if somebody was HER2-positive from the get-go, I would not recommend doing anti-EGFR therapy in those patients even though they may be RAS/RAF wild-type because the HER2-positivity is another mechanism of resistance to anti-EGFR drugs. The guidelines are going to be revised to reflect that.

The second key aspect is that it is more of an acquired concept. Supposedly with EGFR [inhibitor] exposure, you can acquire HER2, and that is where the liquid biopsy comes into play. It is not safe, feasible, or tactical to be doing another tissue biopsy again and again to see if someone converted to HER2-positive, but you can rely on liquid biopsy. However, you can always use tissue biopsy as confirmation when that happens. In terms of options, while not FDA-approved yet, there are 2 things I quoted in the tweets.

3️⃣Of note, while not FDA approved, HER2⛔️ are now in@NCCNguidelines. Both HERACLES & MyPathway#clinicaltrialspublished@TheLancet@TheLancetOncolhave led to the consensus.pic.twitter.com/4fFWGuTCe3

— Pashtoon Kasi MD, MS (@pashtoonkasi)March 31, 2020

There is a trastuzumab (Herceptin) plus pertuzumab (Perjeta) study called the My Pathway trial (NCT02091141). The My Pathway had 2 arms, 1 of trastuzumab plus pertuzumab for anyone who was HER2-positive. That showed activity. In another trial, HERACLES (NCT03225937), lapatinib (Tykerb) plus trastuzumab was evaluated for heavily pretreated patients. Some had 4 or 5 lines of therapy, but that trial did not get as much attention as I expected. Sometimes with all the new studies coming out, if drugs offer some stable disease or response, they don’t get as much media attention, but in someone who is as heavily pretreated as these patients were, we are getting some responses with lapatinib or pertuzumab with trastuzumab, so this is still meaningful.

Based on that, the NCCN Guidelines has included both these options. The fact that they are in the guidelines means that you can at least bend the arm of the insurance company and ask them to provide since the NCCN Guidelines have them approved. If you see the responses, it is like a split. There was interest in having that as an option as well [in the tweet chat].

TARGETED ONCOLOGY: To conclude the tweet chat, we discussed some important aspects of liquid biopsy. What is important to highlight here?

Kasi:Under the big umbrella of liquid biopsy, MRD is a new activator for many trials and ongoing research, particularly in patients with CRC. For anyone who is stage II or III, and even stage IV patients, the question is do they have any leftover cancer? That is where these new assays are trying to answer this question. It is important right now that this is in clinical trials; there is not 1 assay that has been approved yet, and there have been no prospective studies to show how much of an impact this makes.

It is important to know, broadly speaking, a tumor informed assay versus a tumor uninformed assay. Tumor informed assays are taking the patient’s tumor and sequencing to design a panel for each patient. That is where it has the advantage because there are no false positives. You could switch it up with what mutations to look for in each patient. In a patient with, say, aBRAF-mutant CRC, we can design a panel to reflect those mutations. We know what to look for so we can dive deeper. That gives us the most sensitivity as well. On the contrary, tumor uninformed assays are being developed where they are relying more on genomic markers. It has the advantage because you do not have to have the tissue in house; it bypasses the step of needing tissue available because it’s a blood test. There is always the risk, however, of false-positives or -negatives. That is where the importance of trials comes into play.

TARGETED ONCOLOGY: You listed a number of clinical trials as well in the chat. Why is it important to have so many clinical trials ongoing in this space?

Kasi:All of a sudden over the last 20 years there has been a flurry in this space with many options, which is a good thing. I like that there are several options because no single test is going to be suitable for all situations, and they all have their pros, cons, strengths and weaknesses. Having more than 1 option in the long run is always a good idea for our patients.

TARGETED ONCOLOGY: What are the key takeaways?

Kasi: