Colorectal cancer – personalized medicine for a heterogeneous disease

Prof. Chiara Cremolini, MD, PhD., Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa, Italy

Prof. Chiara Cremolini, MD, PhD.,
Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa, Italy

Metastatic colorectal cancer (mCRC), a major cause of death in the Western world, continuous to have a 5-year survival rate below 15 % [1], with microsatellite stable (MSS) mCRC representing the greatest clinical challenge due to its poorly characterized immune microenvironment and immune response [2]. Although the limited response to immunotherapy has led to the assumption that MSS mCRC is immunologically “cold” [2], strategies to make immunotherapy in proficient mismatch repair (pMMR)/MSS mCRC as efficacious as in microsatellite instable (MSI) high/deficient MMR mCRC, are under evaluation [3 - 6]. Which strategies might become available in the future to enhance the efficacy of immunotherapies in the setting of MSS mCRC?

In the Proffered Paper session – Gastrointestinal tumours, colorectal 1, two phase II trials were presented at the ESMO Congress 2021.The introduction of checkpoint inhibitors provided impressive results in MSI mCRC patients, who comprise only 5 % of mCRC patients [6]. Thus, the AtezoTRIBE and MAYA trial, both conducted in Italy, aimed at making immunotherapy an ­efficacious choice in MSS mCRC, representing the vast majority of mCRC [3, 4].

In the AtezoTRIBE study (NCT03721653) an intensified upfront therapy with FOLFOXIRI plus anti-­angiogenic bevacizumab (bev) plus ­anti-PD-L1 atezolizumab (atezo) was compared to FOLFOXIRI plus bev as first-line treatment of unresectable mCRC patients hypothesizing that the cytotoxic effects of FOLFOXIRI and the immunomodulatory properties of bev may promote the sensitivity to atezo making it an as efficacious treatment approach as in MSS tumors. The primary endpoint was met: the addition of atezo to FOLFOXIRI/bev prolonged the progression free survival (PFS) of mCRC patients resulting in a median PFS of 13.1 months compared with 11.5 months in the control arm (HR 0.69, 80 % CI 0.56-0.85, p=0.012). In the subgroup analysis there was a significant interaction between treatment effect and the MMR status that was determined locally by immunohistochemistry. Although there were only few ­patients in the deficient MMR subgroup, patients in the experimental arm had not yet reached the mPFS at a median follow up of 20.6 months (HR 0.11, 80 % CI 0.04-0.35, p=0.002). In the proficient MMR subgroup there was still a small efficacious advantage upon treatment with atezo (HR 0.78, 80 % CI 0.62-0.97, p=0.071) [3], although probably less relevant from a clinical point of view.

In the MAYA study (NCT03832621) temozolomide, an alkylating agent, was investigated in a subgroup of mCRC patients with pretreated MSS mCRC and O6-methylguanine-DNA methyl-transferase (MGMT) silencing as centrally assessed by immunohistochemistry + pyrosequencing. These patients received temozolomide as priming agent and upon the achievement of stable disease they were exposed to temozolomide + ipilimumab + nivolumab. The primary endpoint was met with an 8 month PFS rate of 36 % [4]. This interesting strategy deserves further investigation in potentially larger studies.

Given the relevant amount of patients unable to receive multiple lines of treatment as a consequence of rapidly progressive and highly aggressive disease, selecting an appropriate first-line therapy is of highest importance [7]. What can be done to increase the proportion of patients with metastatic ­colorectal cancer who receive further lines of treatment rather than just one or two?

I would say that the most important thing is choosing the best upfront therapy since we are all aware of the fact that if we have 100 patients starting their first line therapy we will not have 100 patients starting their second or third line and this number decreases step by step [TRIBE2 study, unpublished data]. The more effective the initial therapy is; the more options we can offer these patients for further lines of treatment.

Indeed, the choice of the first-line therapy is, in my opinion, most relevantly affecting the further lines of treatment of our patients and thus it is the most important choice in the therapeutic route also because in the first-line we have the aim to convert to surgical resectability and thus potentially offer a cure to a subgroup of patients. Summing up, the most important message here is the choice of the first-line therapy ­accompanied with the active management of the treatment which means to pro-actively manage adverse events and to enable patients to adhere to the treatment plan in order to exploit the most of our therapeutic armamentarium.

Research presented at the ESMO Congress 2021 highlights how the treatment armamentarium is expanding while depicting recent success, unmet needs, and fu ture opportunities in moving toward personalized medicine. What is the optimal continuum of
care in 2021 in mCRC in your point of view?

As mentioned previously, I think that choosing the first line therapy is really relevant by a clinical perspective. Today, we have MSI as a molecular marker
and major driver for our choices. For MSI ­tumors, immunotherapy is the standard of care and in my clinical practice this means pembrolizumab [8] while waiting for the results of the combination of the anti-PD-1 antibody nivolumab plus anti-CTL4-antibody ­ipilimumab. In the case of MSS tumors we have 2 groups.

Those who are fit and potential candidates for a combination regimen will benefit the most from a chemotherapy doublet plus an anti-EGFR-based treatment in the case of left sided RAS and BRAF wild-type mCRC. Here, we will soon see results from the intensification of the chemotherapy backbone and
its effect in molecularly selected patients in combination with anti-EGFR (TRIPLETE study). The triplet plus ­anti-EGFR is in my opinion not the ­standard of care yet but has potential to become in the near future once we have understood how relevant the magnitude of benefit is that may be provided by more intensified regimens.

All other patients (right sided and/or RAS or BRAF mutant) are candidates for chemotherapy + bevacizumab. In BRAF mutant mCRC the added value of FOLFOXIRI has not been confirmed ­differently than in initial experiences while for others (right-side and/or RAS mutant) this is for sure a choice for relatively young patients with an ECOG performance status of 0 and good general condition. On the other hand, for ­patients that are unfit for a combination, I think the major standard is capecitabine plus bevacizumab [9] but again anti-EGFR may have a place also in combination with 5FU/LV as monotherapy especially in well selected patients with (left-sided) RAS/BRAF wild type tumors [10].

Since there is no marker available to predict progressive disease thus avoiding CT scans during maintenance or follow-up after the end of the induction therapy in mCRC you and your colleagues tried to investigate whether the increase of CEA from nadir could predict a progression [11]. Could you highlight the results of the pooled analysis of TRIBE and TRIBE2 studies?

This is an interesting idea that came from one of my collaborators Roberto Moretto. He reflected about the fact that when a patient has completed the induction therapy and has achieved the best response the CT scan at the end of the induction therapy identifies whether he/she is a candidate either for surgery or maintenance. This is a frequent treatment strategy for depotentiating the ­intensity of chemotherapy while maintaining disease control as longest as possible. In this phase, he asked whether CT scans need to be performed or if CEA level would be enough to ­predict disease progression. Thanks to the data collected from TRIBE and TRIBE2 study, we found out that having an increase in CEA levels has an accurate predication in terms of disease progression so that we could offer CT scans to patients with a CEA increase more than 10 ng/ml, only, thus sparing ­patients CT scans every 2 months and still being able to predict disease progression. This means if we detect a high CEA level, a higher CEA level compared to nadir (the lowest value of CEA after baseline), we will ask the patient to perform a CT scan in order to see if a disease progression has occurred and in this is the case we would suggest switching to another line of therapy, otherwise maintenance therapy (or treatment holi­day) can be continued. Clearly, in my opinion, these results are not totally practice changing but I think in patients where surgery is no longer a treatment option, we can decide not to go for such a strict monitoring in terms of CT scans but instead use CEA levels, if informative/accurate enough to predict disease progression [11].


  1. Siegel RL, et al. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12. Erratum in: CA Cancer J Clin. 2021 Jul;71(4):359.
  2. Zaborowski AM, et al. The therapeutic and prognostic implications of immunobiology in colorectal cancer: a review. Br J Cancer. 2021 Jul 23. doi: 10.1038/s41416-021-01475-x. Epub ahead of print.
  3. Cremolini C, et al. LBA20 – FOLFOXIRI plus bevacizumab (bev) plus atezolizumab (atezo) versus FOLFOXIRI plus bev as first-line treatment of unresectable metastatic colorectal cancer (mCRC) patients: Results of the phase II randomized AtezoTRIBE study by GONO. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346.
  4. Pietrantonio F, et al. 383O – MAYA trial: Temozolomide (TMZ) priming followed by combination with low-dose ipilimumab and nivolumab in patients with microsatellite stable (MSS), MGMT silenced metastatic colorectal cancer (mCRC). Annals of Oncology (2021) 32 (suppl_5): S530-S582.
  5. André T, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218.
  6. Marmorino F, et al. Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge. Cancers (Basel). 2020 Aug 17;12(8):2317.
  7. Moretto R, et al. Exploring clinical and gene expression markers of benefit from FOLFOXIRI/bevacizumab in patients with BRAF-mutated metastatic colorectal cancer: Subgroup analyses of the TRIBE2 study. Eur J Cancer. 2021 Aug; 153:16-26.
  8. KEYTRUDA® (pembrolizumab) prescribing information, 19/10/2021 – EMEA/H/C/003820 – II/0099
  9. Cunningham D, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1077-1085.
  10. Lonardi S, et al. First-line FOLFOX plus panitumumab versus 5FU plus panitumumab in RAS-BRAF wild-type metastatic colorectal cancer elderly patients: The PANDA study.
    J Clin Oncol 38: 2020 (suppl; abstr 4002)
  11. Moretto R, et al. CEA increase as a marker of disease progression after first-line induction therapy in metastatic colorectal cancer patients. A pooled analysis of TRIBE and TRIBE2 studies. Br J Cancer. 2021 Sep;125(6):839-845.

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