This past October 20-24, the Annual ESMO (European Society of Medical Oncologists) Congress met in Madrid. In this blog, Maia and Manju cover the most important findings for our community recently presented at this key oncology conference.

The abstracts mentioned can be found by searching the Abstract number or the trial name in ESMO 2023.

PEGASUS

The phase II PEGASUS trial show results of using the Guardant Reveal ctDNA blood test to guide adjuvant treatment of patients with high-risk stage II or stage III colon cancer to reduce toxicity from chemotherapy and improve the response to standard chemotherapy regimens.

In this trial, which included high risk stage II and stage III colon cancer patients, post-surgical treatment if ctDNA (+) was 3 months capecitabine + oxaliplatin or 6 months of capecitabine alone if ctDNA (–). For patients after adjuvant chemotherapy if ctDNA (+) they received folinic acid–5FU–irinotecan (FOLFIRI), de-escalated to capecitabine if ctDNA (–) after capecitabine, or escalated to capecitabine + oxaliplatin if ctDNA (+).

Among 135 patients included in the per-protocol population, 35 (26%) patients had ctDNA (+) after surgery. After 3-month of capecitabine + oxaliplatin, 11/35 (31%) patients converted to ctDNA (–), but 8/11 (73%) eventually relapsed or became ctDNA (+) again. Of 24 patients who received FOLFIRI after capecitabine + oxaliplatin, 13 (54%) remained ctDNA (+) (6 of whom relapsed), and the remaining 11 (46%) converted to ctDNA (–) and continued to be relapse free at the time of analysis (median follow-up 21.2 months).

The study illustrates the benefit of ctDNA-guided treatment and suggests that treatment with FOLFIRI may be useful in post-adjuvant ctDNA (+) patients. (Abstract LBA28)

GALAXY/CIRCULATE-Japan 

In a prospective analysis of 2280 patients with resected stage I-IV CRC, patients with ctDNA (+) at postoperative week 4 had a significantly inferior DFS compared to ctDNA (–) individuals (24-mo DFS: 89% vs.31 %; HR 16.9, p<.0001).

Adjuvant chemotherapy appears to provide no benefit in ctDNA (–) patients (24-mo DFS 88% vs. 90% in the chemotherapy and no chemotherapy groups; HR 1.39, p=0.2). The benefit of adjuvant chemotherapy was evident in ctDNA (+) patients (24-month DFS: 39% vs 16%; HR 3.29, p <0001), particularly with 6 months of treatment.

ctDNA dynamics between 4-12 weeks influenced DFS: the best in continuously ctDNA (–) patients, then in ctDNA clearance (positive to negative), then in ctDNA reemergence (negative to positive), and the worst in continuously ctDNA (+) patients. (Abstract 558MO)

NICHE-3  

In patients with resectable dMMR/ MSI-H colon cancer (stage II-III), the administration of two preoperative (that is, before surgery) doses of nivolumab + relatlimab (anti-LAG3) led to pCR rate of 79% (15 / 19). Pathological responses were observed in all treated patients.

NICHE-3 trial confirmed what it has been seen in previous NICHE trials: immunotherapy works well in early MSI-H colon cancer. (Abstract LBA31)

KRAS G12C inhibitor-centered trials

Two clinical trials with KRAS G12C inhibitors combined with anti-EGFR antibodies confirm activity in KRAS G12C mutant metastatic CRC.

CodeBreak 300: In a phase Ill randomized study, sotorasib + panitumumab (sotorasib: 960 mg or 240 mg daily) was compared to trifluridine/tipiracil or regorafenib (standard of care, control arm) in KRAS G12C-mutated mCRC. Both arms with soto + pani improved the primary endpoint of PFS compared to the control arm. The combination of sotorasib and panitumumab resulted in significantly improved PFS (progression free survival) (5.6 months, for soto-pani 960 mg, vs 2.2 months for control arm), and ORR (objective response rate) was also improved in the experimental arm, with 26% for the higher dose. Overall survival (OS) was not different, but the analysis is still immature. (Abstract LBA10)

KRYSTAL-1 update: The median PFS of adagrasib plus cetuximab was 6.9 months and ORR was 46%. (Abstract 549O)

It is interesting that though both sotorasib and adagrasib are G12C inhibitors, the combination of adagrasib+ cetuximab had better responses in terms of objective response rates (46% versus 26% for sotorasib + panitumumab) as well as PFS (6.9 months for adagrasib + cetuximab versus 5.6 months for sotorasib + panitumumab). It is a bit disappointing that even with combined inhibition of KRAS G12C and EGFR, the response rates and median PFS are not as significant as patients would like. Nevertheless, having more drug combinations is much needed and anything that adds more time for more patients is much welcomed.

CAIRO 5

Triplet CTx + bev in right-sided/RAS/RAF mutant, and doublet + anti-EGFR in left-sided RAS/RAF-wt mCRC fail to improve OS.

In the randomized phase Ill trial CAIRO5, patients with initially unresectable CRC liver metastases were treated with bevacizumab + FOLFOXIRI or FOLFOX/FOLFIRI (if right-sided and/or RAS/BRAF V600E-mutated - group 1), or with FOLFOX/FOLFIRI + panitumumab or bevacizumab (if left-sided and RAS/BRAF V600E wild-type - group 2).

In group 1, despite previously reported benefit in ORR and PFS with triplet CHT + bev over double CHT + bev, no improvement in OS was seen (mOS: 23.6 vs 24.1 mo; HR 0.92, 95% Cl 0.70-1.20, p=.52).

In group 2, in agreement with the previously reported lack of improvement in PFS (HR 1 .11, 95% Cl 0.48-1.48, p = .46), OS was not different in FOLFOX/FOLFIRI + bevacizumab and FOLFOX/FOLFIRI + panitumumab arms (mOS: 40.4 vs 38.2 mo, respectively; HR 1 .02, 95% Cl 0.72-1.46, p=0.89). ORR was higher with panitumumab than with bevacizumab (80% vs 53%), but R0/1 resection rate was similar (58% vs 58%). It has been hypothesized that comparable OS in both arms may be partially attributed to a high resection rate in the study.

No significant differences in overall survival rates were observed between the different regimens. Therefore, patients can opt for systemic treatment with the least toxicity. (Abstract LBA27)

IDEA/ACCENT

The role of KRAS/ BRAF mutations for early-stage colon cancer was investigated in IDEA/ACCENT pooled analysis

In a pooled analysis of 7 trials evaluating the duration of adjuvant chemotherapy in resected stage Ill CRC, the prognostic impact of MMR status, and KRAS and BRAF V600E mutations were tested.
Five-years recurrence rate was 29% in MSS/pMMR, and 21% in MSl/dMMR cancers.

In MSS/pMMR tumors, KRAS (both codon 12 & 13) and BRAF mutations negatively impacted DFS vs wild-type cancers (HR 1 .41 & 1.58, respectively), OS (HR 1.35 & 2.06), and survival after recurrence (HR 1.25 & 2.87).

In MSI/ dMMR tumors, no impact of KRAS or BRAF mutations on DFS was seen (HR 0.99 & 0.98), however BRAF mutations had a negative effect on OS (HR 1.36), and KRAS and BRAF mutations worsened survival after recurrence (HR 1.52 & 1.99). (Abstract 553O)

ASCOL T 

Patients with Dukes' C (stage III) and high-risk Dukes' B (high-risk stage II) colorectal cancer were randomized to aspirin 200 mg daily or placebo for 3 years after surgery and completion of standard adjuvant therapy.

The primary endpoint of DFS was not improved with aspirin (HR 0.91; 95% Cl 0.73-1.13, p=.38). OS was also similar (HR 0.75, 95% Cl 0.53-1.07, p = .11). The adjuvant role of aspirin appears to be limited. (Abstract LBA29)

Stay Tuned for More! 

Once a month, Maia and Manju spend time unpacking important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the CRC world! 

You can also follow Maia (@sassycell) and Manju (@manjuggm) to stay updated on research and trials and visit ClinicalTrials.gov for more information on trials. 

Clinical trials are critical to finding a cure for colorectal cancer. As an advocacy organization dedicated to supporting and empowering a community of patients, caregivers and families, Fight CRC has partnered with COLONTOWN to deliver a monthly blog series highlighting everything patients need to know about clinical trials and the best treatment options available.  

In this series, we hope to cover promising trials that are enrolling, lessons learned from past research, logistics and resources to joining a clinical trial, and provide relevant and timely updates for our colon and rectal cancer community.

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