NIPICOL Trial Promising Outcomes With Shorter Duration of Checkpoint Inhibition in Metastatic Colorectal Cancer
Existing discovery and targeted mass spectrometry-based methods used to monitor pTyr networks involve a tradeoff between broad coverage of the pTyr network, reproducibility in target identification across analyses, and accurate quantification. To address these limitations, we developed a targeted approach, termed “SureQuant pTyr,” coupling low input pTyr enrichment with a panel of isotopically labeled, tyrosine phosphorylated internal standard (IS) peptides. Using internal standard guided acquisition, the real-time detection of IS peptides during the analysis initiates the sensitive and selective quantitation of endogenous pTyr targets.
Table 2. Use of concomitant IMMs to manage sTRAEsa.
Complete genomic profiling of periampullary carcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma have differe… With an understanding of immunity in the tumor microenvironment, immunotherapy turns out to be a powerful tool in the clinic to treat many cancers. The strategies applied in cancer immunotherapy mainly include blockade of immune checkpoints, adoptive transfer of engineered cells, such as T cells, natural killer cells, and macrophages, cytokine therapy, cancer vaccines, and oncolytic virotherapy. Many factors, such as product price, off-target side effects, immunosuppressive tumor microenvironment, and cancer cell heterogeneity, affect the treatment efficacy of immunotherapies against cancers. In addition, some treatments, such as chimeric antigen receptor (CAR) T cell therapy, are more effective in treating patients with lymphoma, leukemia, and multiple myeloma rather than solid tumors.
To improve the efficacy of targeted immunotherapy and reduce off-target effects, delivery systems for immunotherapies have been developed in past decades using tools such as nanoparticles, hydrogel m… Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the US. CRC frequently metastasizes to the liver and these patients have a particularly poor prognosis.
Efficacy and Safety Data From the CheckMate-9DW Study
- They induce a durable response in a wide variety of solid tumors, but this response depends on the infiltration of lymphocytes capable of recognizing and killing tumor cells.
- There is growing evidence that the genomic instability in tumours with mismatch-repair deficiency may result in the formation of gene fusions.
- Following FOLFIRINOX (Fluorouracil/Leucovorin/Irinotecan/Oxaliplatin) administration and disease progression, nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) were administered every 3 weeks for four total cycles.
- Next generation sequencing has unveiled many more potentially powerful predictive genomic markers of therapy response.
- Three patients were retreated with nivolumab; two of these had partial responses and were alive and free of progression at 9 and 14 months.
While the mono-chemotherapy provides the same benefit for young and older patients, doublets front-line chemotherapy improves progression-free survival (PFS) but not overall survival (OS) in the elderly. Furthermore, the benefit of the addition of bevacizumab to chemotherapy in older patients has been shown in several clinical trials, while the clinical data for the benefit of anti-epidermal gr… Background Deficiencies in the DNA mismatch repair system cause errors during DNA replication, which in turn give rise to microsatellite instability (MSI). This cohort study aims to investigate the prognostic and predictive value of MSI in mCRC prior to the immune therapy era. Statistical analyses utilized the Kaplan-Meier method, log-rank test, and Cox proportional hazards models. Results The MSS group was well matched to the MSI-H group based on age, gender, location, and chronicity of metastatic diseas…
ICI With Targeted Agents
The tumour microenvironment (TME) has emerged as a key factor in CRC metastasis, including by means of immune evasion—forming a major barrier to effective immuno-oncology. Several approaches are in development that aim to overcome the immunosuppressive environment and boost anti-tumour immunity. Among them are vaccination strategies, cellular transplantation therapies, and targeted treatments. Given the complexity of the system, we argue for rational design of combinatorial therapies and consider the implications of precision medicine in this context. The marked difference in the proportion of dMMR/MSI-H tumours between early and advanced CRC stages points to a strong role of immunoediting in the progression of these tumours. The activation of immunosuppressive pathways linked to PD-1 and CTLA4 protects these tumours from destruction by the immune system and could explain the high efficacy of checkpoint inhibitors in this setting (25).
- Clinicians should closely watch this developing field, consider the option of neoadjuvant chemotherapy for colon cancer patients, and actively seek out opportunities for their patients to participate in ongoing clinical trials to further inform this field in future.
- Patients with MSI‐H/dMMR mCRC have poorer outcomes with chemotherapy than those with microsatellite stable/mismatch repair‐proficient mCRC 6, 7, 8.
- About half of patients are affected by metastasis, with the cancer spreading to e.g., liver, lungs or the peritoneum.
- Median duration of response was not reached; most responses (94%) were ongoing at data cutoff.
- A strong anti-proliferative efficacy with a relatively low direct cytotoxicity, obtainable with oloumicine and roscovitine (selective cyclin-dependent kinases inhibitors) can represent a new expedient for the therapeutic treatment of MMR deficient colorectal cancers.
- This finding supports evaluation of nivolumab combinations in the first-line setting 25.
Extended Data Fig. 3 Examples of central pathology review of response to therapy in baseline and on-study biopsies.
This review focuses on the role of immunotherapy for dMMR CRCs and future directions in the therapy of these tumors. Patients with MSI‐H/dMMR mCRC have poorer outcomes with chemotherapy than those with microsatellite stable/mismatch repair‐proficient mCRC 6, 7, 8. Nivolumab plus low‐dose ipilimumab demonstrated durable responses, high DCR, and high survival rates in previously treated patients with MSI‐H/dMMR mCRC 18. In this safety analysis of previously treated durable clinical benefit with nivolumab plus ipilimumab in dna mismatch repair patients with MSI‐H/dMMR mCRC in CheckMate 142, nivolumab plus low‐dose ipilimumab had a manageable safety profile. The majority of sTRAEs and IMAEs resolved and were manageable using the recommended evidence‐based treatment algorithms for early intervention and treatment.
In the current analysis, we further explored the safety profile of nivolumab plus low‐dose ipilimumab in previously treated patients with MSI‐H/dMMR mCRC. STRAEs were managed using protocol‐specified algorithms that directed continuation, symptomatic treatment, IMM treatment, delay, or discontinuation of therapy based on sTRAE grade and category 20. Together, these data suggest that sTRAEs in the GI tract may not be related to recognition of shared tumor antigens. Overall, the sTRAEs were mostly low grade and resolved in the majority of patients with the use of established management algorithms, including concomitant IMM. This comparatively lower resolution rate was attributed to the continuing need for hormone replacement therapy. The majority of patients who had a dose delay because of a sTRAE resumed therapy (25 of 29 patients).
After reviewing dMMR prognostic value, immune checkpoints as major targets for dMMR carcinomas will be highlighted. Following, BRAF V600E prognostic impact will be reviewed and therapeutic strategies with the combination of cytotoxic agents and especially the combinations of BRAF and MAPK inhibitors will be discussed. Nivolumab is a PD-1 inhibitor approved for the use in treatment of multiple tumor types (such as melanoma, non-small-cell lung cancer, renal cell carcinoma, urothelial cancer and Hodgkin’s lymphoma). In July 2017, the US FDA granted accelerated approval of this agent for the treatment of metastatic colorectal cancer patients whose tumor harbors deficient mismatch repair, or microsatellite-instability high and have progressed on conventional chemotherapy. In this review, we will discuss the use, efficacy, and safety of this agent in microsatellite-instability high metastatic colorectal cancer.
Cancer at Nature Portfolio
Limited studies have evaluated the antitumor efficacy of immune checkpoint inhibitors in patients after the appearance of immune‐related AEs. We previously demonstrated that patients who discontinued treatment because of a study drug‐related AE had an ORR and DCR that were comparable to rates in patients continuing treatment 18. In the current analysis, patients who discontinued treatment because of any sTRAE had survival rates that were comparable to the overall population. Some preclinical and clinical evidence suggests that concomitant treatment with corticosteroids to manage immune‐related AEs may compromise the antitumor response 25, 26, 27.
The DCR was numerically higher in patients with sTRAEs compared with those without sTRAEs (90% vs. 67%, respectively; Table 3). The 12‐month PFS rates (77% vs. 63%) and OS rates (93% vs. 75%) were also numerically higher in patients with sTRAEs compared with patients who did not have sTRAEs, respectively. Kaplan‐Meier plots of PFS and OS suggested that patients in both groups had comparable survival rates across all sTRAE grades (Fig. 3A, 3B; supplemental online Fig. 1A, 1B). Patients with sTRAEs who were and were not treated with IMMs had comparable ORR and DCR (ORR, 52% vs. 57% and DCR, 84% vs. 75%, respectively). The 12‐month PFS and OS rates were also comparable between patients with sTRAEs who were and were not treated with IMMs (PFS, 70% vs. 72% and OS, 87% vs. 82%, respectively).
To address resistance to ICIs driven by oncogenic signaling pathways, strategies to boost antitumor immunity include inhibitors of mitogen-activated protein kinase, PI3K, and WNT signaling combined with ICIs. Binimetinib is an MEK inhibitor that increases MHC class I expression, increases TILs, and downregulates multiple immunosuppressive cytokines in preclinical models. In a phase III study known as IMblaze 370, however, the combination of binimetinib and atezolizumab failed to show an OS benefit versus regorafenib in chemorefractory mCRC patients. Tumors that activate the antitumor immune response because of increased TMB and antigenicity are most likely to benefit from ICIs. Even with sufficient antigenicity, however, sensitivity to ICIs can be antagonized by defects in factors regulating antitumor immunity including the mutational landscape, IFN signaling pathway function, expression of antigen-presenting molecules, and immune-evasive oncogenic signaling. These factors influence the priming, activation, and recruitment of T cells to the TME, which are necessary for an immune response in context of ICI blockade.
The ongoing COMMIT study in dMMR mCRCs will determine whether immunotherapy plus chemotherapy is superior to single-agent anti–PD-L1 therapy. Other studies exploring the role of ICIs in combination with chemotherapy and biologics are summarized in Table 2. Efficacy was maintained in patients with sTRAEs, with an ORR of 57%, which was comparable to patients without sTRAEs (52%; Table 3).
At the same time, germline multigene panel testing by next-generation sequencing (NGS) technology has become the new gold standard for molecular genetics. K.L.K., Z.E., S.H.-L., W.E.C., J.A.S., G.K.I., A.I., J.H., A.S.B., N.I.K., J. Markowitz, G.N., S.K., G.C.D., U.S., T.R., B.N.M. and A.R. The search for reliable predictors is ongoing and detailed reviews of potential biomarkers for immunotherapy of colorectal cancer are available (40, 41). Tumour mutation burden (TMB) was a better biomarker for the efficacy of immunotherapy than the absence of an MMR-related protein. Although the great majority of dMMR/MSI-H tumours had high TMB, some dMMR/MSI-H tumours with low TMB have been identified, and they exhibited resistance to therapy with checkpoint inhibitors (28, 29). Almost half the patients had received at least three prior lines of chemotherapy; 18% had BRAF V600E mutations, and 56% had Lynch syndrome–related cancer.