Exploring Precision Medicine Approaches in Colorectal Cancer: Updates From the Gastrointestinal Cancers Symposium

Cathy Eng, MD, FACP, FASCO

Afsaneh Barzi, MD, PhD

Several notable trials in colorectal cancer suggest a shift in treatment management, especially in the length of treatment with immunotherapies. These trials were presented at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium in January.

One of the potentially clinically meaningful trials was an update to the phase 2 GERCOR NIPICOL trial (NCT03350126). GERCOR NIPICOL evaluated the efficacy of 1-year duration of immune checkpoint inhibitors (ICIs) for patients with microsatellite instable (MSI)/deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC).¹

Participants had previously progressed on chemotherapy and received nivolumab (Opdivo) plus ipilimumab (Yervoy) then single-agent nivolumab (n = 57). Thirty-six patients completed 1 year of therapy (FIGURE1). Extended follow-up results to the original data included 1-, 2-, and 3-year progression-free survival (PFS) rates of 75.4%, 70.0%, and 70.0%, respectively. Overall survival (OS) rates at 1, 2, and 3 years were 84.1%, 78.4%, 73.1%, respectively. Follow-up data for 1 year of fixed-duration therapy with ICIs demonstrated durable responses in patients with MSI/dMMR mCRC.¹

“What [the investigators] reported was quite interesting and impressive. I think a very important message is maybe after 1 year of therapy, if the disease has responded or is nonprogressive by imaging, we can maybe stop treatment,” said Afsaneh Barzi, MD, PhD, an associate professor of GI oncology at City of Hope Comprehensive Cancer Center in Duarte, California, and director of employer strategy at AccessHope, in an interview with Targeted Therapies in Oncology™. “In a few patients who had recurrence, [rechallenge] with the same treatment with an ICI demonstrated a benefit. We all know the [safety] profile of an ICI is different from chemotherapy. Although chemotherapy [adverse events] such as nausea and vomiting are transient, [adverse events] of immunotherapy, [such as] hypothyroidism, can last a lifetime. Getting patients off therapy appropriately is important. Another perspective on this is the financial toxicity….If there is a subset of patients who can safely stop this treatment, it not only reduces the chance of physical toxicities experienced by them, but it also reduces the chance of financial toxicities. I thought this abstract was meaningful with positive implications for practice.”

Cathy Eng, MD, FACP, FASCO, the David H. Johnson Chair in Surgical and Medical Oncology, codirector of GI oncology, and coleader of the GI Cancer Research Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, agreed. “It was refreshing to see that maybe just 1 year [of ICI therapy] is enough. [ICIs and duration of use are] just so new in colorectal cancer for our MSI-high patients. It wasn’t a large study, but it was intriguing. It brings to light the question of duration,” she said in an interview with Targeted Therapies in Oncology™.

Another notable trial presented was a phase 1/2 single-arm, single-institution study (NCT04017650) that evaluated patients with treatment-refractory, microsatellite-stable (MSS), BRAF V600E mCRC. Eng said, “BRAF mutation [occurs] in less than 10% of patients and tends to be microsatellite stable; [it is] a very aggressive tumor type.” Patients with MSS, BRAF V600E–positive mCRC may benefi t from combination therapy with encorafenib (Braftovi), cetuximab (Erbitux), and nivolumab therapy, the study results showed.²

Of 26 patients enrolled, 21 were evaluable for response. The overall response rate (ORR) was 45% and disease control rate (DCR) was 95%.2 “We all know that encorafenib and cetuximab [are] the standard of care in BRAF-mutated CRC in the second and subsequent lines of therapy. [The response rate] is significant compared with the response rate of [approximately] 20% in encorafenib and cetuximab,” Barzi said. Safety results included zero dose-limiting toxicities. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 18% (n = 21) and consisted of colitis, maculopapular rash, leukocytosis, and others.²

“This study provides potential treatment for BRAF-mutated cancer, which has very poor prognosis, and this may be the only subset of the MSS colorectal cancer population that would derive some benefi t from the addition of nivolumab to the targeted therapy backbone,” Barzi said. Eng said that the multicenter phase 2 trial to further explore this combination therapy “should be open very soon and that’s encouraging…. The data will be validated in a larger subset in SWOG 2107.”

Immune Checkpoint Inhibitors

The role of ICIs in CRC is currently being explored in different patient populations. Dostarlimab (Jemperli), a PD-1 inhibitor with benefit in dMMR advanced solid tumors after prior therapy, was evaluated in an open-label, multicenter, single-arm, phase 1 trial (NCT02715284).³ A subgroup of cohort F included patients with dMMR/MSI-high CRC or patients with POLε-mutated CRC. Confirmed ORR was 36.2% in patients with CRC (n = 69). TRAEs in the dMMR nonendometrial solid tumor cohort F occurred in 68.1% of patients (n = 141). The most common TRAE grade 3 or higher was increased lipase (1.4%). No new safety concerns were noted with dostarlimab in cohort F, and efficacy results were consistent with non-CRC populations.³

Another trial (SPRINT; NCT04256707) evaluating the use of immunotherapy in CRC was the open-label phase 1/2 trial in MSS, RAS-mutated, pretreated, advanced, or mCRC, which investigated the use of selinexor (Xpovio) with pembrolizumab (Keytruda).⁴ Selinexor selectively inhibits nuclear export and has demonstrated activity in KRAS mutation in combination with PD-1/PD-L1 inhibition. In patients with RAS-mutated CRC, the best overall response was stable disease in 62% (n = 13). Stable disease was achieved as the best overall response in 25% of RAS wild-type (WT) CRC (n = 12). Median PFS was longer in patients with CRC with RAS mutations (3.0 months) compared with patients with RAS WT mutations (1.4 months; P = .04). Common treatment-emergent AEs included nausea, vomiting, fatigue, decreased appetite, and diarrhea.⁴

Also presented at the symposium were some notable negative trials. Regorafenib (Stivarga) combined with pembrolizumab (Keytruda) was evaluated in patients with MSS CRC in a multicenter phase 1/2 trial (NCT03657641).⁵ Liver metastases were identifi ed in 78% of patients at baseline (n = 73), and their median PFS was 2.0 months and median OS was 10.9 months. Median PFS in patients with nonliver metastatic disease was 4.3 months (n = 16). Common grade 3 toxicities were rash, hand-foot syndrome, and hypertension.⁵

“The study was considered positive if the prespecified median PFS of 2.85 months was achieved; this benchmark is a significant improvement over the PFS of single-agent regorafenib. Unfortunately the study failed to show improvement in PFS,” Barzi said. “However, I think in every negative study there are lessons to be learned. The potential lessons of this study are, No. 1, we do not want to use the combination of regorafenib with ICIs in [patients with MSS CRC] outside of trials because we don’t have evidence of any efficacy…from this trial and a number of other trials already presented. No. 2 is that in the overall study population, this [treatment] was not effective, but a post hoc analysis identified 2 groups of patients with potential benefit—those who received prior radiation therapy and those who had nonliver metastases. We have an extensive biomarker analysis that’s planned, and we are hopeful that in the future we can record biomarkers or unique clinical characteristics that identify the subset of patients who may benefi t from this treatment.”

Another negative trial was in patients with KRAS WT mCRC, a multicenter, single-arm, Simon 2-stage phase 2 trial (NCT03446157) that evaluated cetuximab and palbociclib (Ibrance) in patients with at least 2 prior treatment regimens.⁶ Results from cohort B demonstrated a 4-month DCR of 20% (n = 10). However, enrollment was stopped based on the DCR not meeting prespecified criteria from the fi rst stage. Enrollment for cohort A with patients who were anti–EGFR naïve is ongoing.⁶

“We’ve had a lot of negative studies in CRC and yes, it looks disappointing,” Barzi said. “We should look at it as our learning opportunity and hopefully [we] are putting all of these lessons into action.…I believe all of what we have and will learn are propelling us toward new treatments, new paradigms, and new ways to treat patients with CRC.”

Another genomic alteration being explored in CRC is ERBB2/3. ⁷ A real-world exploratory analysis of prevalence of ERBB2/3 alterations using next-generation sequencing (NGS) was assessed using 7688 deidentified records from patients with CRC.⁷ Results demonstrated 5% of tumors consisted of ERBB2/3 alterations. ERBB2 amplification occurred in 1.9% of tumors (n = 143) whereas 1.3% of tumors were ERBB2 mutated (n = 97) and 0.9% of tumors were ERBB3 mutated (n = 72). Tumors with ERBB2/3 alterations were associated with MSI high (P < .001) and tumor mutational burden (TMB) high (P < .001), compared with ERBB2/3 WT. Cooccurring mutations in ERBB2/3 alterations compared with ERBB2/3 WT were significant and may be further explored to guide the development of HER2-targeted therapies.⁷

“It looks like the [overall] progress in [research in] CRC is a slow one in that we’re not identifying new therapies [compared with other solid tumors],” Barzi said. “However, we must take a step back and look at it a different way, and that is that CRC is a disease that is fairly chemotherapy sensitive… thus it is hard to identify therapies that can beat the very effective chemotherapy that exists for this disease. In oncology, I don’t think we should always look for new therapies. Optimization of current therapies is actually one of the important things that we should focus on or work on in the field, and we are seeing some of that optimization in recent years.”

Looking to the future of treatment on CRC, Eng said, “We are trying to become more intelligent with how we approach our patients with sequencing, impact on quality of life, looking at new tools such as circulating tumor DNA in our [patients with early-stage cancer] and the risk of recurrence, which impacts how patients undergo surveillance. Additionally, we need to do a better job with clinical trial enrollment. We cannot get any new drug advances unless patients participate in clinical trials.”

REFERENCES

1. Cohen R, Meurisse A, Pudlarz T, et al. One-year duration of nivolumab plus ipilimumab in patients (pts) with microsatellite instability-high/mismatch repair-defi cient (MSI/dMMR) metastatic colorectal cancer (mCRC): long-term follow-up of the GERCOR NIPICOL phase II study. J Clin Oncol. 2022;40(suppl 4):13. doi:10.1200/JCO.2022.40.4_suppl.013

2. 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

3. Andre T, De Braud FG, Jimenez-Rodriguez B, et al. Antitumor activity and safety of dostarlimab monotherapy in patients with mismatch repair defi cient non-endometrial solid tumors: a post-hoc subgroup analysis of patients with colorectal cancer. J Clin Oncol. 2022;40(suppl 4):201. doi:10.1200/JCO.2022.40.4_suppl.201

4. Golan T, Kutiel TS, Gottfried M, et al. Open-label phase 1/2 study evaluating the tolerability and antitumor activity of selinexor and pembrolizumab in colorectal cancer. J Clin Oncol. 2022;40(suppl 4):110. doi:10.1200/JCO.2022.40.4_suppl.110

5. Barzi A, Azad NS, Yang Y, et al. Phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite stable colorectal cancer (MSSCRC). J Clin Oncol. 2022;40(suppl 4):15. doi:10.1200/JCO.2022.40.4_suppl.015

6. Sorah JD, Moore DT, Reilley M, et al. Phase II single-arm study of palbociclib and cetuximab rechallenge in KRAS/NRAS/BRAF wild-type (KRAS WT) metastatic colorectal cancer (mCRC) patients (pts). J Clin Oncol. 2022;40(suppl 4):88. doi:10.1200/JCO.2022.40.4_suppl.088

7. Tie J, El-Refai SM, Yoshino T, et al. Genomic landscape of ERBB2/3 alterations in colorectal cancer: Comutations, immuno-oncology biomarkers, and consensus molecular subtype. J Clin Oncol. 2022;40(suppl 4):176. doi:10.1200/JCO.2022.40.4_suppl.176