Marshall Examines TKIs and Immunotherapy Agents for GI Cancers

John L. Marshall, MD, spoke with a group of physicians during a Targeted Oncology live case-based peer perspectives discussion on the different classes of agents available to treat patients with gastrointestinal cancers.

John L. Marshall, MD

John L. Marshall, MD, spoke with a group of physicians during aTargeted Oncologylive case-based peer perspectives discussion on the different classes of agents available to treat patients with gastrointestinal (GI) cancers. Marshall, chief of the Division of Hematology/Oncology, Medstar Georgetown University Hospital, associate director for clinical care, Georgetown Lombardi Comprehensive Cancer Center, and director of The Ruesch Center for the Cure of Gastrointestinal Cancer, explained the treatment options on the basis of a case study of a patient with colorectal cancer (CRC) and a second patient with hepatocellular carcinoma (HCC).

Case 1

A 53-year-old Caucasian man without a previous colonoscopy presented to his primary care physician, complaining of rectal bleeding and abdominal tenderness. His medical history was notable forhypertension, which was well controlled on a ß-blocker. His mother had died from complications of breast cancer.

He underwent a colonoscopy with biopsy, which showed an ulcerated nonobstructive mass in the descending colon. Pathology results confirmed poorly differentiated adenocarcinoma. Limited molecular testing suggested that he hadRASwild-type andBRAFV600E—mutated disease and microsatellite-stable (MSS) disease. A CT of the chest, abdomen, and pelvis revealed multilobular liver lesions and bilateral pulmonary nodules. He was diagnosed withmetastatic adenocarcinoma of the left colon; T4N0M1.

Targeted Oncology: What are your initial impressions of this case?

Marshall:The biggest thing here is that this is not a resect­able case. You are not going to do a multiteam collaborative resection here. For our endocrinologists, this is 1 of the only cancers for which resection of metastatic disease will, hope­fully, cure somebody. For the patients, sometimes it is only 1 lead. We call that curative therapy, and that has created a new and interesting problem for us all.

Targeted Oncology: When do you typically order next-generation sequencing (NGS) for metastatic CRC?

Marshall:He has had a colonoscopy, so a quick biopsy of his tumor [is done] by the [GI specialist] first, not the primary. Most of those are getting [tested] for microsatellite instability [MSI]. They send them to the lab for this testing but not for the rest. MSI matters, but PD-L1 probably does not for colon [cancer]; lung and gastric cancers, maybe. We know, in this case, theBRAFandRASstatus.

In lung cancer, there is a culture now where you do not start thinking about treating patients until you know theEGFR,ALK,ROS1, and PD-L1 status. You sit on them until you figure it out, but in colon cancer, we still do not have that culture. The first line of the history of present illness in patients with colon cancer should look like breast cancer in the first line. Such-and-such years old; left- or right-sided disease;RAS,BRAF, MSI/MSS, andHER2status—as there isHER2-positive colon cancer—and that is how we should start talking to each other. That is how we are talking to each other about lung and breast cancer. If you think about presentations on breast cancer at ASCO [American Society of Clinical Oncology Annual Meeting], they even have different rooms for triple-negative and for ER-positive disease, whereas we are all together with pancreatic [and other GI malignancies].

By the time you have ordered those 3 or 4 tests, you might as well do the whole thing so you get theNTRK,HER2, and other rare mutations that you may want to target. I do it right away. In this case, though, we know it, although many times we do not. However, all you need to know for stage I, II, and III are MSI-H and MSS. That’s really it.

If we played it out, that this was a right-sided colon cancer; it has different responses than a left-sided tumor. If you have right-sided disease, I do not care if it isBRAF- andRAS-mutated or not, because I am not going to use an EGFR-targeted agent. I might still need to know the results of theBRAFtest, but there are certainly some things on the right that I do not care about as much as I do on the left.

Targeted Oncology:Do you think liquid biopsies could be used in this setting to test for tumor characteristics?

Marshall:I believe—and I think most people in this space feel this way—the baseline test should be with a tissue sample; then, if you want to follow up for resistance, use blood. One thing we all learned is that this is wrong: Cancer is not clonal. The targeted thera­pies have brought this out. You have some cells that areRASand some are not. They kind of come and go. In this way, the liquid biopsy helps us. I think it is not really evolution—I think it is survival of the fittest.

I have looked at cancer like it is a field of grass, but now I see it as more like a forest. A forest has all kinds of trees, but they are all trees. [These cancers] are all adenocarcinoma, but they are all different. I always think of that more as an evolutionary pressure. Biomarkers somehow drive that.

Case 1 (continued):

The patient was started on FOLFOXIRI (leucovorin, fluorouracil (5-FU), oxaliplatin, and irinotecan) and bevacizumab (Avastin); therapy was well tolerated after management of grade 2 neutropenia.His follow-up scan 2 months later showed a 35% decrease in his liver lesions and the lung lesion. He continued on FOLFOXIRI plus bevacizumab for 4 months and then developed grade 1 neuropathy.

Eventually, he was switched to FOLFIRI (leucovorin, 5-FU, and irinotecan) plus bevacizumab. He did well until 4 months later, when he developed more fatigue and started losing weight. Imaging showed a new 2-cm lung lesion on the right side with pleural expansion and associated pleural effusion. He had an ECOG performance status of 1.

Targeted Oncology:What are the choices of therapy at this point?

Marshall:The trial SWOG S1406 from Scott Kopetz, MD, PhD, [and colleagues] looked at irinotecan and cetuximab [Erbitux] with or without vemurafenib [Zelboraf].1Remember, keeping irino­tecan going is probably a good idea, even if you have had it before. Based on that progression-free survival [PFS] data, the hazard ratio was 0.48, and [that regimen] made it on National Comprehensive Cancer Network [NCCN] guidelines.2That is the new order of the day. Because the drugs were already approved, you do not actually need the FDA to get the drug covered. You need guidelines approved. When the NCCN said this study was good enough, that was enough.

The study going on, the BEACON study, is looking at adding the MEK inhibitor binimetinib [Mektovi] to the BRAF inhibitor encorafenib [Braftovi] plus cetuximab. If we reflect back, we remember when it was bad to beHER2[positive]; now it is good. I am not sure this is going to happen inBRAFyet, but at least you have got a hook. This is why I like to know this early. I want to know if this is an option for my patients. More and more trials are going in this direction. This phase III trial just released positive results in a press release.3

Case 1 (continued):

Thepatient received irinotecan, cetuximab, and vemurafenib. He had a good response for 6 months, and then progressive disease was detected on imaging with multiple new lesions.The patient was started on regorafenib (Stivarga).

Targeted Oncology:What is the optimal dose to start this patient on therapy?

Marshall:This was approved to be administered as 4 pills, or 160 mg daily, based on 1 phase I study. It worked, but we all hated it. It will not work at all in a patient whose performance status is falling, so do not even try it. Start the patient at a dose of 80 mg, then a week later you can increase it. After that first month, most of us stop at about 120 mg. What we are doing is aiming for 160 mg. The problem with this medicine is, once you open it up, it has a 40-day shelf life. We are wasting unused medicine once a month— think about what that costs and what we are throwing out.

The ReDOS study looked at dose-escalation versus a fixed starting dose of regorafenib. The study basically said that if you used the dose escalation-strategy, more people did better. There was an OS [overall survival] advantage and a reduced adverse effect [AE] profile. And although it was not powered for this, you get a higher percentage of patients who get that 6-month tail end of the curve.4I tell my patients that this will not make their cancer shrink, but it will be a break from the infusions for a while. We are better at dosing this now, but if we get 6 months of stable disease, then they know what is coming. They are not expecting more than that. If we get more, we are lucky.

Targeted Oncology: What would you do if this patient exhibited anNTRKfusion on NGS testing?

Marshall:When you have one of these [aberrations], the targeted thera­pies will work well. Many of us will go through an entire career and never find one, but we should look. Just understand, not all tests are the same. Some currently available [commercial assays] only findNTRK1. There are 2 other fusions,NTRK2andNTRK3.

Everyone is catching up to this. I want you to know about this. They are pushing profiling. Larotrectinib [Vitrakvi] was only the second agent to gain a tissue-agnostic approval and the first [inNTRKfusion—positive tumors].

The approval was based on a small number of patients, so it’s going to be rare that you find one. If you find the golden ticket, you will learn this as fast as you need to learn it. The AEs of [larotrectinib] include dizziness. You get this buzzed kind of feel. It is not a zero-toxicity drug, but it can work well.5

There were a lot of GI cancers in the cohort, and this is a very biomarker-rich cancer. These are common in the salivary glands. Of the total patient population, 22% [in the primary dataset] were salivary tumors.5They have to look in a lot of haystacks to find these needles.

Targeted Oncology:What if the patient hadHER2-amplified disease?

Marshall:About 5% of CRCs will beHER2positive. Almost all of them are in the distal colon, but that does not mean you should not check the proximal colon. We have the pertuzumab [Perjeta] plus trastu­zumab [Herceptin] study [NCT02091141]. You are going to use this in the refractory setting. This is not going to replace your frontline therapy if you came across a patient with these features. I would start a patient on whatever you want and checkHER2expression later. Some people argue that they need to know aboutHER2expression before they give an anti-EGFR therapy because there may be resistance to it. If you put me to the wall and asked, “If they areHER2positive, are you never giving EGFR?” I will give it and try it, but I am not expecting anything. If I have a left-sided, wild-type tumor, I am expecting a lot. It is a good therapy.

Case 2

February 2014

  1. 63-year-old Asian man with chronic hepatitis B virus (HBV) was referred for further imaging studies after routine ultrasound surveillance for HCC produced suspicious findings. Hisα-fetoprotein (FP) level was 540 ng/mL and he had Child-Pugh A class.

His laboratory results were notable for platelets of 230 × 109/L, bilirubin of 1.0 mg/dL, albumin of 3.5 g/dL, no hepatic encephalopathy, and ascites were not present.

  1. CT scan revealed 2 lesions in the right hepatic lobe measuring 2 cm and 5 cm; no extrahepatic disease; no cirrhosis. Biopsy findings showed grade 2 HCC with moderate fibrosis. The patient underwent liver resection with an R0 margin. His AFP was then within normal limits.

August 2016

  1. follow-up imaging showed a new lesion in the liver measuring 2.3 cm. A chest CT showed 3 small lesions (<1 cm) in the left upper lobe of the lung. The patient was started on sorafenib (Nexavar) 400 mg twice daily and tolerated therapy well after management of grade 1 diarrhea.

Targeted Oncology:Is there any evidence for use of adjuvant therapy in patients with HCC?

Marshall:The correct answer is no, there is no adjuvant therapy. That is the right answer even though the temptation is, with all these drugs, that you want to chase it. But there is no evidence for it. The patient followed up and now has a new liver lesion and 3 small lung lesions. Sorafenib 400 mg twice daily was adminis&shy;tered, and he managed pretty well with the AEs. There are now choices in the frontline, and we will talk a little bit about that.

Targeted Oncology: What is the rationale for treating this patient with sorafenib versus lenvatinib (Lenvima)?

Marshall:Everyone fiddles with this a bit. I think the recommendations are starting to fold. The REFLECT trial is the study that compared lenvatinib and sorafenib. This was a 1:1 randomization. There was no difference in OS [13.6 vs 12.3 months; HR, 0.92; 95% CI, 0.79-1.06] between lenvatinib and sorafenib, but there was an advantage in median PFS with lenvatinib [7.4 vs 3.7 months; HR, 0.66; 95% CI, 0.57-0.77;P<.0001]. To most of the liver special&shy;ists, the difference in time to progression [8.9 vs 3.7 months; HR, 0.63; 95% CI, 0.53-0.73;P<.0001] is also significant. If you need a [tumor] response, the argument is in favor of lenvatinib. They are different, but you do not get an OS benefit even though it was approved. Just knowing which one you might start with is based on the response.6

The AEs for lenvatinib are hypertension [42%], diarrhea [39%], and decreased appetite [34%], so you know it is different, but you are used to dealing with these. Discontinuations due to toxicity were slightly higher with lenvatinib. It was found to be noninfe&shy;rior to sorafenib. Those are the data you have to decide from.

Case 2 (continued):

April 2017

  1. patient complained of increasing fatigue. CT scans showed new lesions in the lung nodules. He had an ECOG performance status of 1 and his AFP had increased to >10,000 ng/mL.

Targeted Oncology:What are the treatment options for this patient at this point in the progression of the disease?

Marshall:He gets fatigue, progression, and AFP levels going through the roof. You have cabozantinib [Cabometyx], pembrolizumab [Keytruda], nivolumab [Opdivo], and regorafenib. Immunotherapies are emerging; in the right patients, they seem to be working. Cabozantinib is now approved in HCC.

Ramucirumab [Cyramza], for me, would be low on the list compared with some of these other drugs that are out there. It does not mean it is wrong for this patient. Some patients will also go through more than just second- and third-line therapy.

The RESORCE trial led to the regorafenib approval. Patients had to be on sorafenib and had to have tolerated it, and they were randomized 2:1 to best supportive care plus regorafenib or placebo. The OS was improved with regorafenib [10.6 months] against the placebo [7.8 months]. But if you think about it, this is just sort of a continuation of therapy. It is randomized discontinuation on some level, but these numbers were actually better than frontline sorafenib, which surprised everybody. Going to regorafenib in the second line seemed like a pretty good option for these patients.7

Targeted Oncology: What are the immunotherapy options for this patient?

Marshall:In the CheckMate 040 trial, you had nivolumab in patients with advanced HCC with or without HBV or hepatitis C virus [HCV]. We were nervous to put patients on immunotherapy if they were positive for hepatitis virus. It turned out to be OK. There was a 20% response rate in the total cohort, 20% in HCV, and 14% in HBV. Basically, the punchline of these data is that there is not a lot of difference [depending on the] kind of HCC you had or the instigator of your HCC. You did about the same across the board. Not a home run, but when it works, it can work very nicely. There is a long duration of response like we are used to in immunotherapy.8

With the KEYNOTE-224 data in pembrolizumab, response rates are OK [objective response rate, 17% (95% CI, 11%-26%); disease control rate, 62% (95% CI, 52%-71%)].9A lot of combi&shy;nation studies are going on now, and we have almost put all our patients on combination studies in HCC. These [efficacy data] are getting better and better with pembrolizumab. I have had only a couple of patients where I can say they had pseudoprogression. It was with adenocarcinoma on a study.

The cabozantinib data in the CELESTIAL trial was also posi&shy;tive, and advanced HCC is intolerant to it.10These are the data that got this approved. Now, all of a sudden, you have all sorts of choices: tyrosine kinase inhibitors and immunotherapy.


  1. Kopetz S, McDonough SL, Lenz H-J, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406).J Clin Oncol.2017;35(suppl 15; abstr 3505). doi: 10.1200/ JCO.2017.35.15_suppl.3505.
  2. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer, version 2019. National Comprehensive Cancer Network website. physician_gls/pdf/colon_blocks.pdf. Published June 17, 2019. Accessed June 18, 2019.
  3. Array Biopharma announces Braftovi + Mektovi + Cetuximab meet primary endpoints of ORR and OS in phase 3 BEACON CRC trial interim analysis for the treatment of BRAF(V600E)-mutant metastatic colorectal cancer [news release]. Boulder, CO: Array BioPharma Inc.; May 21, 2019. investor.arraybiopharma. com/news-releases/news-release-details/array-biopharma-announces-braftovi-mektovi-cetuximab-meet. Accessed June 18, 2019.
  4. Bekaii-Saab T, Ou F-S, Anderson DM, et al. Regorafenib dose optimization (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study.J Clin Oncol. 2018;36(suppl 4; abstr 611). doi: 10.1200/JCO.2018.36.4_suppl.611.
  5. Lassen UN, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach.Ann Oncol. 2018;29(suppl 8; abstr 409O). doi: 10.1093/annonc/mdy279.397.
  6. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treat&shy;ment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet. 2018;391(10126):1163-1173. doi: 10.1016/ S0140-6736(18)30207-1.
  7. Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2016;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
  8. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion study.Lancet. 2017;389(10088):2492- 2502. doi: 10.1016/S0140-6736(17)31046-2.
  9. Zhu AX, Finn RS, Edeline J, et al; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.Lancet Oncol. 2018;19(7):940-952. doi: 10.1016/S1470-2045(18)30351-6.
  10. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the randomized phase III CELESTIAL trial.J Clin Oncol. 2018;36(suppl 4; abstr 207). doi: 1200/JCO.2018.36.4_suppl.207.