Raghav Works Through a CRC Patient Case After First-and Second-Line Therapy Exhaustion


At a recent Targeted Oncology live case-based peer perspectives event, Kanwal P. S. Raghav, MBBS, MD, presented a case scenario of a patient with colorectal cancer who has already gone through first- and second-line treatments. Raghav explained the treatment considerations he would make with similar patients in the clinic and the treatment options available to this patient with CRC in this setting.

Kanwal P. S. Raghav, MBBS, MD

Kanwal P. S. Raghav, MBBS, MD

Kanwal P. S. Raghav, MBBS, MD

At a recentTargeted Oncologylive case-based peer perspectives event, Kanwal P. S. Raghav, MBBS, MD, presented a case scenario of a patient with colorectal cancer (CRC) who has already gone through first- and second-line treatments. Raghav, an assistant professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, explained the treatment considerations he would make with similar patients in the clinic and the treatment options available to this patient with CRC in this setting.


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 for hypertension that was well controlled on a ß-blocker. His mother had died from complications of breast cancer.

The patient underwent a colonoscopy with biopsy. An ulcerated nonobstructive mass was noted in the descending colon. Pathology results confirmed poorly differentiated adenocarcinoma. Limited molecular testing suggested that he had RASwild-type,BRAFV600E—mutated, and microsatellite-stable (MSS) disease;HER2status was not available. A CT of the abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. He was diagnosed withmetastatic adenocarcinoma of the right colon; T4N0M1.

Targeted Oncology:Do you typically order next-generation sequencing (NGS) for metastatic colorectal cancer (CRC)? Do you order a limited versus expanded assay? What is the effect on initiation of first-line treatment?

Raghav:We order expanded testing, and I will, hopefully, be able to argue the point that in other tumor types, it might not be that useful. But in colon cancer, it is very useful. As far as the initiation of first-line treatment is concerned, our go-to treatment for most colon cancers—and again, I’m saying most—is bevaci­zumab [Avastin] and FOLFOX [folinic acid, fluorouracil (5-FU), and oxaliplatin]. It does not matter how your sequencing is. To be fair, I am not hesitant to change the treatment regimen midway if, through the course of his testing, you figure out that the data are showing something different.

Targeted Oncology:What factors do you consider when determining systemic therapy for this patient? Should surgical or liver-directed modalities be considered?

Raghav:I think liver-directed therapy has its value in some patients. A few of the nuances we have seen in our clinical trials is that as you go down the line of therapy and have more and more damage to the liver through oxaliplatin or irinotecan, it tends to cause more adverse effects [AEs] to the liver.

A good thing is to try to get patients on clinical trials as much as possible. Fortunately, there are a lot of clinical trials nowa­days in colon cancer. One could argue about the quality of those trials, but there are still a lot of studies.

Targeted Oncology:What is the significance of hisBRAFmutation?

Raghav:I think thatBRAFtesting is a standard of care for colon cancer for 2 reasons: One, it identifies the prognostic significance of this patient and the aggressiveness of this disease, which is very important. Even if you do not have access to BRAF-directed treatments—which should not be the case, because the NCCN [National Comprehensive Cancer Network] guidelines now have 2 BRAF-directed therapies that are incorporated—or you will not have access to trials, there is still a change in systemic treat­ment that you can implement in these patients.1

ForBRAFV600E-mutant colon cancer, the treatments of choice are the combinations vemurafenib [Zelboraf], cetuximab [Erbitux], and irinotecan or binimetinib [Mektovi], encorafenib [Braftovi], and cetuximab. We have to orderBRAFmutation test­ing. One way of doing it would be to first orderRAS. If it is wild-type, then orderBRAFand go on to subsequent testing. I think that formulation takes away a lot of time.

The SWOG 1406 study was a national study that showed the benefit of adding vemurafenib to irinotecan and cetuximab.2Overall, I thinkBRAFV600E is present in about 8% of patients, but if you test for it in only patients who areRASwild-type, it is as high as 15%.

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

Raghav:I would use bevacizumab plus FOLFOXIRI [folinic acid, 5-FU, oxaliplatin, and irinotecan] in these patients in the first line. I think BRAF-directed therapy is effective, but the data and the NCCN endorsement are for the second-line setting. The data for the bevacizumab combination come from the TRIBE study.

TRIBE was a study of bevacizumab plus FOLFOXIRI versus bevacizumab plus FOLFIRI [folinic acid, 5-FU, and irinotecan].3Response rates went up from 53.1% to 65.1% [with FOLFIRI and FOLFOXIRI, respectively]. PFS [progression-free survival], which was the primary endpoint, went up to 12.1 months from 9.7 months [HR, 0.75; 95% CI, 0.62-0.90;P= .003]. And OS [overall survival] went up by about 5 months [HR, 0.79; 95% CI, 0.63- 1.00;P= .054].

Overall, the bevacizumab combination was good, but the prob­lem was that the AEs were also there. Neutropenia occurred more in the FOLFOXIRI group [50% vs 20.5%].

I think the patients that should receive bevacizumab plus FOLFOXIRI are those who are likely to progress through their first-line treatment. In the TRIBE study, 78.6% of patients in that control arm of FOLFIRI went to a second-line treatment, which is not what we see in general practice. Most of our patients will go through 2 lines of therapy. When they did the subgroup anal­ysis, they found that individuals withBRAFmutations had more benefit, and I use this mostly inBRAF-mutant patients.

This is not a regimen for everyone, but clinicians should keep it in the back of their minds that this is a very good regimen for some patients. [For] somebody who has lots of liver disease, progression on FOLFOX, and/or liver failure and has never had FOLFIRI, you might as well use it. I think the survival benefit in this trial was because of those patients that could never get a second-line treatment. If they get both lines of treatment, that’s great. But if they cannot, then I think that this is a good regimen to try.

Case (continued):

The patient was started on FOLFOXIRI and bevacizumab; therapy was well tolerated after management of grade 2 neutropenia. A follow-up scan 2 months later showed a 35% decrease in his liver lesions and the lung lesion.

  1. continued on FOLFOXIRI plus bevacizumab for 4 months and then developed grade 1 neuropathy. Eventually, he was switched to FOLFIRI plus bevacizumab.
  2. 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 left side with pleural expansion and associated pleural effusion. He had an ECOG performance status of 1.

Targeted Oncology:What are the choices for therapy after trying FOLFIRI plus bevacizumab?

Raghav:Fortunately, we now have 2 options. The SWOG 1406 trial tested the combination cetuximab plus irinotecan, which would have been the standard of care for this patient, versus vemurafenib plus cetuximab and irinotecan. The median PFS was 4.3 months in the experimental arm versus 2 months [HR, 0.48; 95% CI, 0.31- 0.75;P= .001]. The 2 months in the control arm tells you how bad these patients are.

The response rate increased from 4% to 16%, so you more than doubled the response rate. However, there was no OS benefit, because the study allowed crossover. All the patients got vemurafenib plus cetuximab and irinotecan and then progressed on this.

The BEACON study is more interesting. This is one of the few studies that had a safety lead-in, so the only published data [involve] about 30 to 40 patients. The response rate of this regimen is about 48%.4You do not get that response rate with first-line chemotherapy inBRAF-mutant patients. The PFS was about 8 months. PFS with first-line chemotherapy is about 10 months, and the OS is about 15 months. This is just the initial phase. The randomized phase is not done, but just because of these data, this now has a breakthrough therapy designation from the FDA5and is also now part of the NCCN guidelines.1One-year OS was 62.1%, the median OS was about 15.5 months. This is exceptionally good. If you see any of theBRAFtrials, they never look like that.

One could argue [about] what is the standard of care. I would say it is a clinical trial. But if you do not have a clinical trial, you could use TAS-102 [Lonsurf] or regorafenib [Stivarga].

Case (continued):

The patient received irinotecan, panitumumab (Vectibix), and vemurafenib (Zelboraf). Following a good response for 6 months, progressive disease was detected on imaging with multiple new lesions.The patient was started on regorafenib.

Targeted Oncology:If you were to start this patient on regorafenib, at what dosage would you start?

Raghav:Doing a dose escalation is no problem. In the ReDOS trial, the group that did an escalation [80 mg/day; weekly dose escalation if no significant drug-related toxicities, up to 160 mg/day] had an improved OS [over 160 mg/day starting dose]. This dosing schedule was much better tolerated, which is understandable, and the PFS and OS were superior compared with 160 mg. The study gives you data to support escalating treatments and not use the FDA-approved 160 mg [right away]. All of us who use regorafenib know that at 160 mg, the patient would have to be like Superman to tolerate that dose.6

Targeted Oncology:What if the patient exhibited anNTRKfusion on NGS testing?

Raghav:NTRKfusions are extremely rare. I have seen only 1NTRKfusion ever in the past 5 years, and that includes every tumor type that I see. For these patients, we can use larotrectinib [Vitrakvi]; and that response rate was close to 80%, and many of those durations of response have not even been reached.7This is like a miracle drug for most patients [with that gene mutation]. The only problem is that we do not do this as sepa­rate testing; if you check for fusions, you have to check them separately. Fortunately, if you do an NGS platform, they give you the information for fusions also. The advantage of doing the NGS panel now for colon cancer is that it will give youRAS[and]BRAFand if perchance a patient has anNTRKfusion, it will give you that also.

Targeted Oncology:What if the patient exhibited aHER2amplification?

Raghav:Then there is the question ofHER2amplification. I am the national primary investigator on SWOG 1613, which is the randomized trial forHER2-amplified metastatic CRC [NCT03365882]. The value of testingHER2amplification is that it is found in just 4% of all colon cancers, but it is not found inRAS-mutant colon cancers. Most of the time, it is found only inRASandBRAFwild-type patients.

If the patient hasRAS—wild-type andBRAF—wild-type disease, then you perform HER2 testing only with immu­nohistochemistry [IHC]. And if you have 2-plus, you do the next test, which is FISH [fluorescence in situ hybridization]. The value of this is 2-fold. For 1 thing, this is a big negative predictor biomarker for anti-EGFR efficacy. In our analysis, we looked at PFS on anti-EGFR plus chemotherapy in the second-line setting.HER2-amplified patients have a PFS of less than 3 months, whereas nonamplified patients have a PFS of 9 months. We test routinely forHER2amplification before subjecting anyone to anti-EGFR. Since the data are immature and retrospective, I will not be bold enough to say that you should never give anyone withHER2-amplification an anti-EGFR agent, but I would definitely say [you should] consider them for a clinical trial.

In SWOG 1613, patients get trastuzumab [Herceptin] plus pertuzumab [Perjeta] or cetuximab plus irinotecan. You have good responses with this regimen. One of my colleagues put a patient on this study and had a pathologic complete response and unresectable liver disease that converted to resectable liver disease. One of our patients has been on this trial for a year now and has been experiencing no AEs.


  1. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer, version 1.2019. nccn. org/professionals/physician_gls/pdf/colon.pdf. Published March 15, 2019. Accessed June 4, 2019.
  2. Kopetz K, McDonough SL, Lenz H-J, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406).J Clin Oncol.2017;35(suppl 15; abstr 3505). doi: 10.1200/ JCO.2017.35.15_suppl.3505.
  3. Loupakis F, Cremolini C, Masi G. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.N Engl J Med. 2014;371(17):1609-1618. doi: 10.1056/ NEJMoa1403108.
  4. Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC).J Clin Oncol.2019;37(suppl 4; abstr 688). doi: 10.1200/JCO.2019.37.4_suppl.688.
  5. Array Biopharma receives FDA breakthrough therapy designation for Braftovi in combination with Mektovi and cetuximab for BRAFV600E-mutant metastatic colorectal cancer [news release]. Boulder, CO: Array BioPharma Inc; August 7, 2019. http:// investor.arraybiopharma.com/news-releases/news-release-details/array-biopharma-receives-fda-breakthrough-therapy-designation. Accessed June 4, 2019.
  6. Bekaii-Saab TS, Ou F-S, Anderson DM, et al. Regorafenib dose optimization study (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.
  7. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA website. fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0. Published Updated December 14, 2018. Accessed June 4, 2019.
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