John L. Marshall, MD
The importance of molecular profiling in the establishment of a treatment plan for patients with colorectal cancer (CRC) continues to grow. For example, the latest anticancer therapies approved by the FDA for use in CRC—larotrectinib (Vitrakvi) and the checkpoint inhibitor combination of nivolumab (Opdivo)/ipilimumab (Yervoy)—are indicated for patients with specific molecular markers.
With multiple biomarker-directed clinical trials for metastatic CRC (mCRC) expected to produce data within the next few years, experts in gastrointestinal (GI) oncology who took part in a recent OncLive Peer Exchange®
program recommended that clinicians become more proactive about incorporating genomic and immune markers into their decision making.
The experts joined moderator John L. Marshall, MD, for a wideranging discussion on how findings from recent studies, including data presented at the 2019 Gastrointestinal Cancers Symposium, are refining the way clinicians manage advanced CRC, particularly in the perioperative and metastatic settings.
“This is an exciting time in CRC,” Tanios S. Bekaii-Saab, MD, said. “The strides that we’re seeing, the improvements in survival—we are talking about 3, 4, 5 years’ median survival, even in the metastatic setting—are a testament to how far we’ve come.”
Debating EGFR Antibodies for Newly Diagnosed Metastatic Disease
One of the most interesting discoveries about CRC is that tumors arising on the right side of the colon differ markedly from those on the left side, possibly due to immunological differences between the proximal and distal colon.1 Data presented at the symposium confirmed rightsided mCRC as a poor prognostic indicator.1,2
In addition, retrospective analyses of survival outcomes in the CALGB/SWOG 80405, CRYSTAL, and FIRE-3 trials associated the EGFR antibody cetuximab (Erbitux) with greater response rates and survival outcomes in KRAS
wild-type patients who had left-sided tumors.3,4
All 3 trials compared bevacizumab (Avastin) and cetuximab with standard chemotherapy (FOLFIRI [leucovorin (folinic acid), 5-fluorouracil (5-FU), or FOLFOX [leucovorin, 5-FU, and oxaliplatin]) for untreated mCRC.3,4
Marshall described the discovery of left- versus right-sided tumors in CRC as transformative and asked whether it had influenced anyone’s practice. Bekaii-Saab said the data from the CALGB/SWOG 80405 trial were not compelling enough to change his approach for patients with newly diagnosed mCRC because the survival curves show “a little bit of separation… but you still don’t see enough of a separation to subject patients to EGFR inhibitors in the first-line setting.”
Joleen M. Hubbard, MD, expressed the opposite viewpoint: “I actually am a believer in doing the EGFR inhibitor up front for left-sided tumors.” She pointed out that overall survival (OS) in the subset of patients with left-sided mCRC who received cetuximab in CALGB/ SWOG 80405 was approximately 39 months.5
Bekaii-Saab, Christopher Lieu, MD, and Howard S. Hochster, MD, FACP, agreed that they were more likely to use a triplet chemotherapy regimen such as FOLFIRINOX or FOLFOXIRI plus bevacizumab as frontline therapy. (FOLFIRINOX comrpises leucovorin, 5-FU [plus bolus], irinotecan, and oxaliplatin; FOLFOXIRI, 5-FU [without bolus], leucovorin, oxaliplatin, and irinotecan6). Hochster said some of his patients are unable to tolerate the cutaneous toxicity associated with EGFR antibodies.
Everyone agreed they would not use an EGFR antibody in the frontline for patients with right-sided mCRC but might consider it as a third-line option. “For third line and beyond, I think it’s reasonable to expose those patients to an EGFR inhibitor, whether it’s cetuximab or panitumumab [Vectibix],” Bekaii-Saab said.
NTRK Fusion–Positive Tumors
In November 2018, the FDA approved larotrectinib for adults and children with solid tumors that have an NTRK
gene fusion; the drug inhibits TRK proteins encoded by NTRK
The site-agnostic approval was based on results from 3 clinical trials that included 55 patients who had NTRK
-positive metastatic solid tumors encompassing 17 cancer types.8
The study included 4 patients with mCRC. The overall response rate (ORR) per independent review was 75% (95% CI, 61-85) and 80% (95% CI, 67-90) by investigator assessment. At 1 year, 71% of responders still had a response and 55% of patients overall had no progression.8
Bekaii-Saab said that the findings reinforce his belief that “every single patient today with CRC…should get next-generation sequencing or a platform that will include these NTRK
Marshall asked the panelists whether a patient with insufficient tissue should undergo another biopsy given that the prevalence of NTRK
fusion genes in CRC is less than 1%.
“I’d say the answer is yes,” Bekaii-Saab said. “It’s not just NTRK
; if you don’t have tissue for NTRK
, you probably don’t have tissue for human epidermal growth factor receptor 2 and others, so I think you should rebiopsy.” The FDA recently granted priority review to a new drug application for entrectinib, another NTRK
inhibitor, for patients with NTRK
fusion-positive metastatic solid tumors.9
New Immunotherapy Regimens
Also in 2018, the FDA granted accelerated approval to the combination of the CTLA–4 inhibitor ipilimumab, and nivolumab for patients with microsatellite instability–high (MSI-H) or DNA mismatch repair deficient (dMMR) mCRC based on findings from the phase II CheckMate 142 trial.10
The study enrolled 119 patients with previously treated MSI-H/dMMR mCRC.11
The investigator-assessed ORR was 55% (95% CI, 45.2-63.8), and duration of response was not reached. The 1-year progression-free survival (PFS) and OS rates were 71% and 85%, respectively.11
Lieu noted that the FDA previously approved single-agent pembrolizumab (Keytruda), also a PD-1 inhibitor, for MSI-H/dMMR metastatic solid tumors and nivolumab for MSI-H/dMMR mCRC. Response rates to these agents in patients with MSI-H/dMMR CRC ranged from 30% to 50%.12
“The combination [of nivolumab and ipilimumab] buys you a higher response rate compared [with] single-agent therapy alone,” he said.
Lieu said that approximately 4% of patients with mCRC have the MSI-H/dMMR phenotype, 11 which is associated with a high tumor mutational burden. He recommended testing patients for MSI-H/dMMR early. “Testing for MSI does not even require sequencing. It’s an immunohistochemistry [IHC] test that can be done on any biopsy,” Hochster said. Most most clinicians follow up a positive IHC test with polymerase chain reaction testing to look at fragment length, he said. Because approximately 60% of patients with MSI-H CRC have Lynch syndrome, he suggested having family members assessed.
CheckMate 142 included a cohort of 74 patients who received nivolumab monotherapy, and Bekaii-Saab said a comparison of the waterfall plots for the single-agent and dual immune checkpoint inhibitor (ICI) cohorts suggested to him that most patients probably do not benefit from the addition of ipilimumab.
Hubbard said she is unlikely to use the combination unless she sees a strong rationale for doing so, such as an MSI-H patient who really needs a response.
Hochster said although he found the high ORR and prolonged PFS with the combination persuasive. He said while he does not underestimate the risk of toxicity with ICIs, he felt the dosing schedule for the dual ICI regimen used in CheckMate 142 did not greatly increase toxicity compared with nivolumab monotherapy.
The panelists strongly agreed that it would be inappropriate to use ICIs—alone or combined—in patients with microsatellite- stable CRC.
Optimizing Dosing for Regorafenib
Although the multikinase inhibitor regorafenib (Stivarga) has been available for mCRC since 2012,12
dose reductions or interruptions are frequently required to manage hand-foot skin reactions, fatigue, and hypertension.13,14
Bekaii-Saab was the lead investigator for the phase II ReDOS trial, which evaluated a dose-escalation strategy to reduce toxicity in 123 patients starting regorafenib.14
He said the investigational arm started at 80 mg/day and escalated the dose by 40 mg/day each week as tolerated up to a maximum of 160 mg/day, which is the standard regorafenib dose. The control arm received 160 mg/day.
The primary endpoint was the difference between the groups in the proportion of patients able to initiate the third treatment cycle.14
“We were hoping for 15% improvement with a dose-escalation strategy versus the standard 160 mg/day dose, and we actually got 16%,” Bekaii-Saab said. In the dose-escalation arm, 43% of evaluable patients (n = 116) made it to the third cycle compared with 24% of patients in the standard-dosing arm (1-sided P
“The most intriguing finding was actually a survival advantage,” he said. Publication of the findings are pending, but Bekaii-Saab said the updated data show a 4-month survival advantage for the dose-escalation strategy.
Hubbard said, “We’ve been doing this at the Mayo Clinic for a long time, and it works quite well.” Hochster said although the goal is always to reach 160 mg/day, many patients are unable to escalate beyond 120 mg/day, which he said is acceptable.
Bekaii-Saab said the findings are likely to result in a change to the label for Stivarga and have already been incorporated in the National Comprehensive Cancer Network guidelines for CRC.
- Ulanja MB, Rishi M, Beutler BD, et al. Colon cancer sidedness, presentation, and survival at different stages. J Oncol. 2019;2019:4315032. doi: 10.1155/2019/4315032.
- Mendis SR, Lee B, Lee M, et al. Left- versus right-side metastatic colorectal cancer: teasing out clinicopathologic drivers of disparity in survival. J Clin Oncol. 2019;37(suppl 4):623. doi: 10.1200/JCO.2019.37.4_suppl.623.
- Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1°) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34(suppl 15; abstr 3504). doi: 10.1200/JCO.2016.34.15_suppl.3504.
- Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017;3(2):194-201. doi: 10.1001/jamaoncol.2016.3797.
- Dacuma M. Primary tumor location predictive of treatment response in patients with metastatic colorectal cancer. Keck Medicine of University of Southern California website. cancer.keckmedicine.org/primary-tumor-location-predictive-of-treatment-response-in-patients-with-metastatic-colorectal-cancer. Accessed May 7, 2019.
- Nipp RD, Ryan DP. Should FOLFOXIRI plus bevacizumab be the standard first-line therapy in metastatic colorectal cancer? Oncologist. 2015;20(3):236-238. doi: 10.1634/theoncologist.2014-0495.
- Vitrakvi [prescribing information]. Stamford CT: Loxo Oncology, Inc; 2018. FDA website. www.accessdata.fda.gov/drugsatfda_docs/label/2018/210861s000lbl.pdf.
- Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.
- FDA grants priority review to Roche's personalised medicine entrectinib [media release]. Basel, Switzerland: Roche; February 19, 2019. roche.com/media/releases/med-cor-2019-02-19b.htm. Accessed May 6, 2019.
- FDA grants accelerated approval to ipilimumab for MSI-H or dMMR metastatic colorectal cancer. FDA website. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ipilimumab-msi-h-or-dmmr-metastatic-colorectal-cancer. Published July 10, 2018. Updated July 11, 2018. Accessed May 6, 2019.
- Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779. doi: 10.1200/jco.2017.76.9901.
- Overman MJ, Ernstoff MS, Morse MA. Where we stand with immunotherapy in colorectal cancer: deficient mismatch repair, proficient mismatch repair, and toxicity management. Am Soc Clin Oncol Educ Book. 2018;38:239-247. doi: 10.1200/edbk_200821.
- Goel G. Evolution of regorafenib from bench to bedside in colorectal cancer: is it an attractive option or merely a "me too" drug? Cancer Manag Res. 2018;10:425-437. doi: 10.2147/CMAR.S88825.
- 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.