At the ESMO Annual Meeting 2023, a variety of interesting studies in lower gastrointestinal tumours were presented. In this editorial, we briefly summarise and appraise some of these, providing insights into future perspectives. The only potentially practice-changing study was CodeBreaK 300. This can be considered as the (hopefully first) happy ending of a story that started ∼1 decade ago when, after being long considered undruggable, KRAS has eventually turned into a therapeutic target with the development of KRASG12C inhibitors. Based on the promising results from prior studies, CodeBreaK 300 tested the superiority of combined KRAS and epidermal growth factor receptor (EGFR) inhibition over standard-of-care treatment.1Fakih M.G. Salvatore L. Esaki T. et al.Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C.N Engl J Med. 2023; 389: 2125-2139Crossref PubMed Scopus (12) Google Scholar In this randomised three-arm phase III trial, 160 patients with chemorefractory KRASG12C-mutated colorectal cancer (CRC) were treated with high-dose (960 mg daily) sotorasib plus panitumumab, low-dose (240 mg daily) sotorasib plus panitumumab, or standard treatment according to the investigator's choice (trifluridine/tipiracil or regorafenib). The primary endpoint was progression-free survival (PFS) by blinded independent central review, with a hierarchical testing plan. After a median follow-up of 7.8 months, the statistical hypothesis was met for both experimental arms. The median PFS was 5.6 months in the high-dose sotorasib arm [hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.30-0.80; P = 0.006] and 3.9 months in the low-dose sotorasib arm (HR 0.58, 95% CI 0.36-0.93; P = 0.03), as compared with 2.2 months in the control arm. The objective response rate was 26.4%, 5.7%, and 0%, respectively. The rate of grade ≥3 treatment-related adverse events was higher in the standard arm (43.1%) than in the high-dose (35.8%) and low-dose (30.2%) sotorasib arms. While there was no benefit in overall survival (OS), data were not yet mature at the time of the primary analysis. This trial has the potential to set a new standard of care for chemorefractory KRASG12C-mutated CRC and, based on both the efficacy and safety data, the 960 mg dose should be preferred (consistent with data from lung cancer). Some concerns, however, remain about the use of PFS as the primary endpoint for a study in the refractory setting, and the use of a suboptimal control arm (when CodeBreaK 300 was designed, definitive data on trifluridine/tipiracil plus bevacizumab were not available). With the caveats of an intertrial comparison and the confounding prognostic effect of KRAS mutations, it should be noted that the median PFS in the high-dose sotorasib arm in molecularly selected patients is identical to that previously reported by the investigators of the SUNLIGHT trial in an unselected population.2Prager G.W. Taieb J. Fakih M. et al.Trifluridine–tipiracil and bevacizumab in refractory metastatic colorectal cancer.N Engl J Med. 2023; 388: 1657-1667Crossref PubMed Scopus (38) Google Scholar More work is needed to elucidate and address resistance mechanisms to KRASG12C inhibition. Several trials are ongoing, including a combination of sotorasib plus panitumumab with standard chemotherapy in earlier treatment lines, and an investigation of dual KRASG12C and EGFR blockade using other KRASG12C inhibitors. As a result, the management of patients with KRASG12C-mutated tumours is likely to rapidly evolve in the near future. Further to the recent data from the PROSPECT study,3Schrag D. Shi Q. Weiser M.R. et al.Preoperative treatment of locally advanced rectal cancer.N Engl J Med. 2023; 389: 322-334Crossref PubMed Scopus (63) Google Scholar the investigators of the CONVERT trial addressed the question of omitting neoadjuvant radiotherapy in locally advanced rectal cancer.4Ding P.R. Wang X.Z. Li Y.F. et al.LBA26 neoadjuvant chemotherapy with CAPOX versus chemoradiation for locally advanced rectal cancer with uninvolved mesorectal fascia (CONVERT): final results of a phase III trial.Ann Oncol. 2023; 34: S1267-S1268Abstract Full Text Full Text PDF Google Scholar This was a randomised noninferiority phase III trial from China, where 589 patients with stage II or III rectal cancer (without mesorectal fascia involvement or T4b tumours) were treated with either four cycles of neoadjuvant oxaliplatin and capecitabine (CAPOX) followed by surgery and four cycles of adjuvant CAPOX or conventional long-course chemoradiotherapy (LC-CRT) followed by surgery and six cycles of adjuvant CAPOX. Salvage LC-CRT in the experimental arm was considered only for local progressive disease. The primary endpoint was 3-year loco-regional recurrence-free survival (with a noninferiority boundary, defined as the upper limit of the 95% CI of the HR, set at 1.6). While this was a formally negative trial (HR 1.08, 95% CI 0.46-2.54), not confirming the noninferiority of neoadjuvant chemotherapy alone compared with chemoradiotherapy, the rate of loco-regional recurrence-free survival was 97.4% in the control arm and 96.3% in the experimental arm. Further, comparable results were observed for disease-free survival and OS at 3 years (87.9% versus 89.2%; HR 0.88, 95% CI 0.54-1.44, and 94.1% versus 95%; HR 0.86, 95% CI 0.42-1.76, respectively). Regarding long-term toxicity, a significantly lower rate of grade 2 adverse events was reported in favour of the chemotherapy-only arm (71% versus 47%; HR 1.30, 95% CI 1.08-1.54; P = 0.007). Overall, these results suggest that in patients with higher-risk tumours than those recruited in the PROSPECT trial, omitting neoadjuvant radiotherapy may be safe (or associated with an acceptable risk of increased locoregional recurrence). Notably, this contention is supported by the findings from the FOWARC trial (recently updated at the 2023 ASCO Annual Meeting) showing similar outcomes with or without neoadjuvant radiotherapy in an even higher-risk population. Despite the increasing interest in de-escalation neoadjuvant strategies, treatment intensification in locally advanced rectal cancer remains the subject of active investigation. In this regard, the investigators of the UNION trial tested the addition of an anti-programmed cell death protein 1 (anti-PD-1) antibody to total neoadjuvant therapy.5Zhang T. Tao K. Lin Z. et al.LBA25 Neoadjuvant short-course radiotherapy followed by camrelizumab plus chemotherapy versus long-course chemoradiotherapy followed by chemotherapy in locally advanced rectal cancer: a randomized phase III trial (UNION).Ann Oncol. 2023; 34: S1266-S1267Abstract Full Text Full Text PDF Google Scholar In this study, 231 patients with stage II or III rectal cancer (the majority of which had high-risk features) were randomly assigned to LC-CRT followed by two cycles of CAPOX, surgery and six cycles of adjuvant CAPOX or short-course radiotherapy followed by two cycles of CAPOX plus camrelizumab, surgery and six cycles of adjuvant CAPOX plus camrelizumab (the latter being continued for up to nine cycles beyond CAPOX). The primary endpoint of the study was pathological complete response (pCR). This was 39.8% in the former and 15.3% in the latter arm (odds ratio 3.7, 95% CI 2.0-6.9; P < 0.001). Adding camrelizumab to consolidation chemotherapy increased the risk of neither grade ≥3 treatment-related adverse events nor surgical complications. The results from this trial are certainly interesting. Nevertheless, it remains to be confirmed whether the improved pCR with camrelizumab would translate into better long-term survival outcomes. Further, some caveats should be considered such as the short duration of consolidation chemotherapy (not in line with established regimens of total neoadjuvant therapy), and the different radiotherapy schedule between arms (although LC-CRT could have favoured tumour regression in the control arm). In early-stage colon cancer, neoadjuvant therapy has recently gained traction. However, one of the key hurdles to the routine implementation of this approach is the lack of robust prognostic/predictive biomarkers and the resulting high risk of overtreatment, as compared with upfront surgery plus or minus adjuvant chemotherapy based on pathological risk factors. Further to the recent publication of the main study results,6Morton D. Seymour M. Magill L. et al.Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial.J Clin Oncol. 2023; 41: 1541-1552Crossref PubMed Scopus (70) Google Scholar the investigators of the phase III FOxTROT trial presented the findings from an extended biomarker analysis of the embedded phase II study testing the addition of panitumumab to neoadjuvant FOLFOX.7Seligmann J. Morton D. Seymour M. et al.552O FOxTROT: results of embedded phase II evaluating the addition of panitumumab (pan) to neo-adjuvant FOLFOX for patients (pts) with KRAS-wt colon cancer (CC) with extended biomarker panel.Ann Oncol. 2023; 34: S412Abstract Full Text Full Text PDF Google Scholar Among 169 patients with ≥cT3 RAS/BRAF wild-type tumours, combining EGFR blockade with 6 weeks of neoadjuvant chemotherapy led to a numerically better 3-year recurrence-free survival (88.1% versus 79.2%; HR 0.51, 95% CI 0.24-1.10; P = 0.09). When the same analysis was carried out in patients with RAS/BRAF wild-type tumours and high levels of amphiregulin/epiregulin, a statistically significant advantage was observed for the panitumumab arm (HR 0.29, 95% CI 0.09-0.99; P = 0.047). However, a treatment-by-biomarker interaction was not found (P = 0.33). Given the small numbers, the retrospective design and the lack of statistical significance, these results remain hypothesis generating. The road to the implementation of neoadjuvant therapy for early-stage colon cancer appears less bumpy for immune checkpoint inhibitors and patients with mismatch repair-deficient tumours. Building on the impressive results from the first two NICHE studies,8Chalabi M. Verschoor Y.L. Van Den Berg J. et al.LBA7 neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: the NICHE-2 study.Ann Oncol. 2022; 33: S1389Abstract Full Text Full Text PDF Google Scholar Verschoor et al9Verschoor Y.L. Van Den Berg J. Balduzzi S. et al.LBA31 neoadjuvant nivolumab plus relatlimab (anti-LAG3) in locally advanced MMR-deficient colon cancers: the NICHE-3 study.Ann Oncol. 2023; 34: S1270Abstract Full Text Full Text PDF Google Scholar reported the preliminary findings from NICHE-3. In this single-arm phase II trial, 19 patients with stage II or III mismatch repair-deficient colon cancer were treated with two administrations of nivolumab plus relatlimab (an anti-lymphocyte activation gene 3 [LAG-3] inhibitor), with surgery being performed at 8 weeks. The rate of pCR was 79%, while major and overall pathological responses were observed in 89% and 100% of patients, respectively. Although these data compare favourably with those previously reported by the same group with the combination of nivolumab and ipilimumab, it is not possible to draw any conclusion regarding the comparison between anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) and anti-LAG-3 agents as the preferred companion drugs to combine with PD-1 inhibitors. Further, many questions remain unanswered such as the actual need for the combination versus single-agent therapy, and the optimal duration of treatment. Finally, given the potential of immunotherapy in this setting, studies are needed to address the question of the feasibility of an organ-sparing approach in a colon cancer population. After decades of studies suggesting an association between the regular use of aspirin and a reduced risk of CRC incidence and mortality, results from the first randomised study in an adjuvant setting were finally presented. ASCOLT was a double-blind randomised phase III trial of aspirin 200 mg daily versus placebo for 3 years in 1,587 patients who had completed standard therapy for Dukes C or high-risk Dukes B CRC.10Chia J.W.K. Segelov E. Deng Y. et al.LBA29 aspirin after standard adjuvant therapy for colorectal cancers (ASCOLT): an international, phase III, randomised, placebo-controlled trial.Ann Oncol. 2023; 34: S1269Abstract Full Text Full Text PDF Google Scholar After a follow-up of 5 years, the investigators failed to show a benefit in either disease-free survival (primary endpoint, HR 0.91, 95% CI 0.73-1.13; P = 0.38) or OS (HR 0.75, 95% CI 0.53-1.07; P = 0.11). Although these data do not support the use of aspirin in this setting, results from other randomised trials with different designs with regard to the dose or duration of aspirin, and molecular selection of the patient population (based on PI3KCA mutation) are awaited before drawing definitive conclusions. None declared.
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