Prognostic impact of early tumor shrinkage and depth of response in patients with microsatellite instability-high metastatic colorectal cancer receiving immune checkpoint inhibitors

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The event of pseudoprogression is rare in patients with MSI-high metastatic colorectal cancer receiving immune checkpoint inhibitors. In this response to the Letter to the Editor by Colle et al, we highlight that the timing of disease re-assessment may influence the incidence of pseudoprogression, with early assessments being associated with higher incidence. Such dynamics should be considered when interpreting the efficacy of treatment.

Section: Dear Editormentioning

confidence: 88%

Author response to Colleet al

Fucà

Corti

Pietrantonio

2021

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“… 16 17 Also, patients with Response Evaluation Criteria in Solid Tumors(RECIST) very good partial responses≥50% or complete responses are usually cured, even if the best tumor response may be achieved after several months of treatment. 18 …”

Section: Discussionmentioning

confidence: 99%

“…Evaluation Criteria in Solid Tumors(RECIST) very good partial responses≥50% or complete responses are usually cured, even if the best tumor response may be achieved after several months of treatment. 18 Here we have used a multivariable mixture cure model to develop a tool for predicting the 12-month PFS probability of patients with MSI-high mCRC receiving ICIs. The timepoint for PFS prediction was chosen based on the observation that the greater proportion of PFS events occurred within 1 year, in order to allow predictions as early as possible, therefore, with specific focus on patients with low chance of being cured; this consideration is particularly true for the two groups with the worst prognosis, as appears from the PFS curves stratified according to the EFP quartiles (probability <24%, online supplemental figure 3).…”

Section: Open Accessmentioning

confidence: 99%

Nomogram to predict the outcomes of patients with microsatellite instability-high metastatic colorectal cancer receiving immune checkpoint inhibitors

Pietrantonio

Corti

Infante

et al. 2021

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BackgroundThe efficacy of immune checkpoint inhibitors (ICIs) in patients with microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC) is unprecedented. A relevant proportion of subjects achieving durable disease control may be considered potentially ‘cured’, as opposed to patients experiencing primary ICI refractoriness or short-term clinical benefit. We developed and externally validated a nomogram to estimate the progression-free survival (PFS) and the time-independent event-free probability (EFP) in patients with MSI-high mCRC receiving ICIs.MethodsThe PFS and EFP were estimated using a cure model fitted on a developing set of 163 patients and validated on a set of 146 patients with MSI-high mCRC receiving anti-programmed death (ligand)1 (PD-(L)1) ± anticytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. A total of 23 putative prognostic factors were chosen and then selected using a random survival forest (RSF). The model performance in estimating PFS probability was evaluated by assessing calibration (internally—developing set and externally—validating set) and quantifying the discriminative ability (Harrell C index).ResultsRFS selected five variables: ICI type (anti-PD-(L)1 monotherapy vs anti-CTLA-4 combo), ECOG PS (0 vs >0), neutrophil-to-lymphocyte ratio (≤3 vs >3), platelet count, and prior treatment lines. As both in the developing and validation series most PFS events occurred within 12 months, this was chosen as cut-point for PFS prediction. The combination of the selected variables allowed estimation of the 12-month PFS (focused on patients with low chance of being cured) and the EFP (focused on patients likely to be event-free at a certain point of their follow-up). ICI type was significantly associated with disease control, as patients receiving the anti-CTLA-4-combination experienced the best outcomes. The calibration of PFS predictions was good both in the developing and validating sets. The median value of the EFP (46%) allowed segregation of two prognostic groups in both the developing (PFS HR=3.73, 95% CI 2.25 to 6.18; p<0.0001) and validating (PFS HR=1.86, 95% CI 1.07 to 3.23; p=0.0269) sets.ConclusionsA nomogram based on five easily assessable variables including ICI treatment was built to estimate the outcomes of patients with MSI-high mCRC, with the potential to assist clinicians in their clinical practice. The web-based system ‘MSI mCRC Cure’ was released.

“…2 We are surprised that no cases were reported in their study. 1 PSPDs were described under ICI in patients treated for MSI/dMMR mCRC, more frequently with anti-PD1 alone compare to anti-PD1+antiCTL-4. 3 4 In a cohort of 123 patients treated with anti-PD1±antiCTL-4 for MSI/dMMR mCRC, we reported 12 patients with PSPD, representing 10% of the cohort.…”

Section: Dear Editormentioning

confidence: 99%

Letter to the Editor from Colleet al

Colle¹,

Thewis²,

Menu³

2021

In their article, Fucà et al highlight that early tumor shrinkage and depth of response predict the prognosis of patients with metastatic colorectal cancer (mCRC) microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) treated by immune checkpoint inhibitors (ICI). We are surprised that no cases of pseudoprogression (PSPD) were reported in their study. PSPDs were described under ICI in patients treated for MSI/dMMR mCRC. In a cohort of 123 patients treated with anti-PD1±antiCTL-4 for MSI/dMMR mCRC, we reported 12 patients with PSPD, representing 10% of the cohort. Of 12 patients with PSPD, 8 secondary achieved an objective response and were alive and free of progression at the data lock. Conversely, in Fucà’s article, no PSDP was observed and the patients with primary radiological progression (21.7%) had a poor overall survival. These differences between the two series could be probably explained by the following points. First, Fucà et al use RECIST 1.1 criteria for radiological evaluation. Second, the first imaging was done after 8–9 weeks of treatment in Fucà’s article, which may be late to detect PSPD. In conclusion, if the first evaluation is made during the first 3 months of treatment, using iRECIST criteria seems mandatory to avoid stopping treatment prematurely, especially in patients receiving anti-PD1 alone.