Biomarkers Continue to Play a Pivotal Role in Treatment Decisions in Metastatic CRC

The expansion of the treatment armamentarium has emphasized the importance of genetic testing in patients with metastatic colorectal cancer (mCRC), according to Christopher Lieu, MD, who added continued developments in the field have produced additional treatment regimens across patient subsets, based on key genetic markers.

Currently, 15 agents are approved by the FDA for the treatment of mCRC, including 10 biologic or targeted agents designed to treat patients with specific genetic alterations. The quantity of agents at the disposal of physicians underscores the need to tailor treatment to each individual patient, according to Lieu.

“When you have a newly diagnosed patient with mCRC, the genomic information is not only important up front, but it’s certainly important down the line,” Lieu said. “Even now, we’re still looking at [genetic testing] percentages at 60% to 70%, so it’s still not being done early and often enough.”

In a presentation during the 7th Annual School of Gastrointestinal Oncology^®,¹ Lieu, associate director, Clinical Research, director, Gastrointestinal Medical Oncology, University of Colorado Medicine, highlighted optimal treatment options for patients with BRAF V600E mutations, HER2 overexpression, and various biomarkers in mCRC, plus the effects of emerging agents in the space.

Encorafenib/Cetuximab Combo Emerges in BRAF V600E–Mutant mCRC

Multiple clinical trials have pointed to the combination of encorafenib (Braftovi) and cetuximab (Erbitux) as the standard of care in the second line and later in patients with mCRC harboring BRAF V600E mutations, Lieu said.

The phase 3 BEACON CRC trial (NCT02928224) randomized patients with BRAF V600E–mutated mCRC with disease progression after 1 or 2 prior regimens to 1 of 3 arms, where they received either encorafenib and cetuximab; encorafenib, binimetinib (Mektovi), and cetuximab; or FOLFIRI or irinotecan plus cetuximab in the control arm.² The primary end points of overall survival (OS) and overall response rate (ORR) focused on the triplet vs control arms.

At a median follow-up of 12.8 months, the triplet produced a median OS of 9.3 months (95% CI, 8.1-10.8) compared with 5.9 months (95% CI, 5.1-7.1) in the control arm. However, the addition of binimetinib did not increase the OS benefit compared with the doublet therapy, which achieved a median OS of 9.3 months (95% CI, 8.0-11.3).

Notably, instances of grade 3 or higher diarrhea were higher in the triplet and control arms (11% and 10%, respectively) vs the doublet arm (3%). “The doublet therapy, while there are [adverse] effects to it, was fairly well tolerated,” Lieu said.

The phase 1/2 SWOG 2107 trial (NCT04017650) is also exploring a triplet with an encorafenib and cetuximab backbone. In this study, nivolumab (Opdivo) is being added to the combination in patients with microsatellite stable, BRAF V600E–mutated mCRC who had 1 or 2 prior lines of systemic therapy.³

In phase 1, of 22 evaluable patients, the ORR was 50% (95% CI, 28%-72%) and the disease control rate (DCR) was 96% (95% CI, 77%-100%). Phase 2 of the trial will initiate in 2022 and will explore encorafenib and cetuximab with or without nivolumab.

“There is some preclinical evidence suggesting that there’s some T-cell infiltration with this regimen,” Lieu said. “You may be able to activate it with nivolumab. This trial is coming down the pipeline.”

The phase 2 ANCHOR-CRC trial (NCT03693170) also evaluated the encorafenib, binimetinib, and cetuximab triplet, except it was used in the first-line setting for patients with untreated, BRAF V600E–mutated mCRC.⁴ The triplet met its primary end point in ANCHOR-CRC with a confirmed ORR of 47.8% (95% CI, 37.3%-58.5%) and a DCR of 88%.

However, the median progression-free survival (PFS) was 5.8 months (95% CI, 4.6-6.4), and Lieu explained that the result fell short of what clinicians would like to see in this setting.

“We would want to see a PFS that’s higher than this,” Lieu said. “Having said that, [this is] a bad, aggressive disease biology, so 6 months is still comparable to what we might expect.”

Addressing HER2 Overexpression

The overexpression of HER2 in patients with mCRC has become a meaningful marker for deciding therapy, Lieu explained. “When you get [a patient’s] targeted sequencing back and you see wild-type KRAS, NRAS, or BRAF, those are the patients you should be looking for HER2 amplification in,” Lieu said.

HER2 amplification is enriched in KRAS wild-type disease, disrupting the benefit of anti-EGFR therapies for these patients.⁵ Consequently, patients with mCRC and HER2 amplification have demonstrated a shorter median PFS on anti-EGFR therapy of 2.9 months compared with 8.1 months for those with nonamplified disease (P < .001).⁶

Lieu noted that HER2 amplification should not be a hard stop for the use of anti-EGFR therapy, although he said it should give physicians pause. “Particularly in patients who received prior anti-HER2 therapy,” Lieu added.

Anti-HER2 inhibition was explored in the phase 2 HERACLES trial (NCT03225937) and phase 2 My Pathway trial (NCT02091141). In HERACLES, trastuzumab (Herceptin) and lapatinib (Tykerb) were combined in a single-arm study, generating an ORR of 30% (95% CI, 14%-50%) and a median PFS of 21 weeks (95% CI, 16-32) in patients with HER2-amplified mCRC.⁷ My Pathway elicited an ORR of 38% (95% CI, 24%-55%) and a median time to progression of 4.6 months.⁸ Trastuzumab was also utilized in combination with tucatinib (Tukysa) in the phase 2 MOUNTAINEER trial (NCT03043313), where early data produced an ORR of 55%, a median PFS of 6.2 months, and a median OS of 17.3 months.⁹ Final data on MOUNTAINEER are expected to read out later in 2022, Lieu said.

The novel antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu) is also being explored in this space. The agent could provide benefit for patients with HER2-amplified mCRC who had prior treatment with anti-HER2 therapies, according to Lieu. In cohort A of the phase 2 DESTINY-CRC01 trial (NCT03384940), 30.2% of patients received prior anti-HER2 therapies. However, that cohort achieved an ORR of 45.3% with trastuzumab deruxtecan.¹⁰

Notably, treatment with trastuzumab deruxtecan can cause interstitial lung disease (ILD). In DESTINY-CRC01, ILD occurred in 8 patients (9.3%), including 4 instances that were grade 3 or higher.

“The cessation of the [trastuzumab deruxtecan] and the early initiation of steroids is critical,” Lieu said. “Keep in mind, there were 3 stage 5 events [in this study]. This is recoverable, but [physicians] must keep an eye out for it.”

Lieu concluded that anti-HER2 combination therapy is the ideal treatment after first-line progression for patients with HER2-amplified mCRC, although trastuzumab deruxtecan can be an option for patients who have already received anti-HER2 therapies.

Progress in KRAS G12C–Mutant mCRC

Patients with mCRC harboring KRAS G12C mutations have historically been difficult to treat, with this subset of disease considered “undruggable,” according to Lieu. However, recent clinical trials have started to move the needle forward in this space.

For example, sotorasib (Lumakras) elicited a 9.7% ORR, a median PFS of 4.0 months, and a median OS of 10.6 in patients with KRAS G12C–mutated solid tumors in the phase 1/2 CodeBreaK 100 trial (NCT03600883).¹¹

Additionally, adagrasib generated a 22% ORR, a 64% stable disease rate, and an 87% DCR in the phase 1/2 KRYSTAL-1 trial (NCT03785249).¹² Furthermore, KRYSTAL-1 explored the combination of adagrasib and cetuximab, which elicited an ORR of 43%, a stable disease rate of 57%, and a DCR of 100%.

“My hope is that when you see [patients with mCRC harboring KRAS G12C mutations] that you’ll strongly consider getting these patients to clinical trials,” Lieu said. “There should be some amount of benefit [with KRAS G12C inhibitors], particularly in our pretreated patients.”

A Clear Path in MSI-H mCRC

Immunotherapy options utilizing pembrolizumab (Keytruda) or the combination of nivolumab and ipilimumab (Yervoy) have carved out a role in the treatment of patients with microsatellite instability–high (MSI-H) mCRC, Lieu said.

In the phase 3 KEYNOTE-177 trial (NCT02563002), pembrolizumab produced a median PFS of 16.5 months (95% CI, 5.4-38.1) compared with 8.2 months (95% CI, 6.1-10.2) with investigator’s choice chemotherapy.¹³ The median PFS2, defined as the time from randomization to progression on next line of therapy or any cause of death, was 54.0 months (95% CI, 44.4–not reached [NR]) with pembrolizumab vs 24.9 months (95% CI, 16.6-32.6) with chemotherapy. The median OS was NR (95% CI, 49.2-NR) with pembrolizumab vs 36.7 months (95% CI, 27.6-NR) with chemotherapy.

In the phase 2 CheckMate142 trial (NCT02060188), the combination of nivolumab and ipilimumab produced an ORR of 69%, plus a 24-month PFS rate of 74% and a 24-month OS rate of 79%.¹⁴

“Most people are choosing to use pembrolizumab, but nivolumab and ipilimumab do remain an option [in patients with MSI-H mCRC,” Lieu said.

Treatment Sequencing in the Refractory Setting

Past data have shown starting a drug at a lower dose and increasing it over time can lead to increased tolerability, and the phase 2 ReDOS trial (NCT02368886) explored that strategy with regorafenib (Stivarga), with the goal of seeing whether more patients would finish 2 cycles of treatment on an escalating dose compared with patients on the standard dose.¹⁵

At the end of cycle 2 at 8 weeks, 43% of patients on an escalating dose of regorafenib finished both cycles compared with 24% on the standard dose (P = .0281).

“This is how we dose regorafenib. The tolerance is better, and it’s nice that we have a study that shows that,” Lieu said.

Regorafenib, trifluridine/tipiracil (TAS-102; Lonsurf), and TAS-102 plus bevacizumab (Avastin) can all be utilized in the refractory setting, Lieu said, and there have been early data on the use of circulating tumor DNA (ctDNA) to determine whether patients can be rechallenged with anti-EGFR therapies. The phase 2 CHRONOS trial (NCT03227926) demonstrated a 30% ORR with the use of panitumumab (Vectibix).¹⁶ However, Lieu noted those responses were not durable, and more studies need to be conducted regarding this approach.

References

1. Lieu C. Novel targeted therapies in refractory mCRC: a target rich environment? Presented at: 7th Annual School of Gastrointestinal Oncology® (SOGO®). March 26, 2022; Washington, D.C.
2. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632-1643. doi:10.1056/NEJMoa1908075
3. Morris VK, Parseghian CM, Escano M, et al. Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAFV600E metastatic colorectal cancer. J Clin Oncol. 2022;40(suppl 4):12. doi:10.1200/JCO.2022.40.4_suppl.012
4. Van Cutsem E, Tabernero J, Taieb J, et al. ANCHOR CRC: results from a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E–mutant metastatic colorectal cancer. Presented at: ESMO World Congress on Gastrointestinal Cancer 2021; June 30-July 3, 2021.
5. Bertotti A, Migliardi G, Galimi F, et al. A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011;1(6):508-523. doi:10.1158/2159-8290.CD-11-0109
6. Raghav KPS, Overman MJ, Yu R, et al. HER2 amplification as a negative predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. J Clin Oncol. 2016;34(suppl 15):3517. doi:10.1200/JCO.2016.34.15_suppl.3517
7. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(6):738-746. doi:10.1016/S1470-2045(16)00150-9
8. Hurwitz H, Raghav KPS, Burris HA, et al. Pertuzumab + trastuzumab for HER2-amplified/overexpressed metastatic colorectal cancer (mCRC): interim data from MyPathway. J Clin Oncol. 2017;35(suppl 4):676. doi:10.1200/JCO.2017.35.4_suppl.676
9. Strickler JH, Zemla T, Ou FS, et al. Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): initial results from the MOUNTAINEER trial. Ann Oncol. 2019;30(suppl 5):v200. doi:10.1093/annonc/mdz246.005
10. Yoshino T, Di Bartolomeo M, Raghav KPS, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2021;39(suppl 15):3505. doi:10.1200/JCO.2021.39.15_suppl.3505
11. Fakih MG, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022;23(1):115-124. doi:10.1016/S1470-2045(21)00605-7
12. Weiss J, Yaeger RD, Johnson ML, et al. KRYSTAL-1: adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
13. Andre T, Shiu KK, Kim TW, et al. Final overall survival for the phase III KN177 study: pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). J Clin Oncol. 2021;39(suppl 15):3500. doi:10.1200/JCO.2021.39.15_suppl.3500
14. Lenz HJ, Lonardi S, Zagonel V, et al. Subgroup analyses of patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) treated with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line (1L) therapy: two-year clinical update. J Clin Oncol. 2021;39(suppl 3):58. doi:10.1200/JCO.2021.39.3_suppl.58
15. Bekaii-Saab TS, Ou FS, 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)611. doi:10.1200/JCO.2018.36.4_suppl.611
16. Sartore-Bianchi A, Pietrantonio F, Lonardi S, et al. Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: the CHRONOS trial. J Clin Oncol. 2021;39(suppl 15):3506. doi:10.1200/JCO.2021.39.15_suppl.3506