Transforming growth factor beta (TGFβ) is a pleiotropic cytokine that plays a key role in both physiologic and pathologic conditions, including cancer. Importantly, TGFβ can exhibit both ...tumor-suppressive and oncogenic functions. In normal epithelial cells TGFβ acts as an antiproliferative and differentiating factor, whereas in advanced tumors TGFβ can act as an oncogenic factor by creating an immune-suppressive tumor microenvironment, and inducing cancer cell proliferation, angiogenesis, invasion, tumor progression, and metastatic spread. A wealth of preclinical findings have demonstrated that targeting TGFβ is a promising means of exerting antitumor activity. Based on this rationale, several classes of TGFβ inhibitors have been developed and tested in clinical trials, namely, monoclonal, neutralizing, and bifunctional antibodies; antisense oligonucleotides; TGFβ-related vaccines; and receptor kinase inhibitors. It is now >15 years since the first clinical trial testing an anti-TGFβ agent was engaged. Despite the promising preclinical studies, translation of the basic understanding of the TGFβ oncogenic response into the clinical setting has been slow and challenging. Here, we review the conclusions and status of all the completed and ongoing clinical trials that test compounds that inhibit the TGFβ pathway, and discuss the challenges that have arisen during their clinical development. With none of the TGFβ inhibitors evaluated in clinical trials approved for cancer therapy, clinical development for TGFβ blockade therapy is primarily oriented toward TGFβ inhibitor combinations. Immune checkpoint inhibitors are considered candidates, albeit with efficacy anticipated to be restricted to specific populations. In this context, we describe current efforts in the search for biomarkers for selecting the appropriate cancer patients who are likely to benefit from anti-TGFβ therapies. The knowledge accumulated during the last 15 years of clinical research in the context of the TGFβ pathway is crucial to design better, innovative, and more successful trials.
•TGFβ is a complex cytokine with both antitumor and oncogenic functions.•TGFβ blockade has demonstrated promising antitumor activity in various preclinical models.•The TGFβ pleiotropic role challenges its evaluation as a therapeutic target in clinical trials.•Different anti-TGFβ agents have been developed and tested in clinical trials with diverse and sometimes limited efficacies.•Novel biomarkers are under development to better select patients who may benefit from TGFβ blockade.
Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in ...combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or ‘rechallenge’ in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.
•The epidermal growth factor (EGFR) is a therapeutic option for patients with all RAS WT metastatic colorectal cancer (mCRC).•A better knowledge of the mechanism of primary or acquired resistance to EGFR-therapies can improve patient's selection.•Despite disease progression a subset of mCRC are still sensitive to EGFR inhibition.•Rechallenge strategies with anti-EGFR might represent a promising therapeutic option.
Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK ...pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance.
We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance.
The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models.
These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.
Emerging evidence supports tumor tissue-based comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC). Data on liquid biopsy-based circulating tumor DNA (ctDNA) CGP are scarce ...and mainly retrospective. Prospective comparison between the two tests is not currently available.BACKGROUNDEmerging evidence supports tumor tissue-based comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC). Data on liquid biopsy-based circulating tumor DNA (ctDNA) CGP are scarce and mainly retrospective. Prospective comparison between the two tests is not currently available.The CAPRI 2-GOIM trial investigates efficacy and safety of ctDNA-driven, cetuximab-based, sequence of three treatment lines in patients with RAS/BRAFV600E wild type (WT) mCRC, as determined by local laboratory. Before first-line therapy, CGP is performed with FoundationOne (F1) CDx and F1 Liquid (F1L) CDx (324 genes) on tumor tissue DNA and plasma ctDNA, respectively.METHODSThe CAPRI 2-GOIM trial investigates efficacy and safety of ctDNA-driven, cetuximab-based, sequence of three treatment lines in patients with RAS/BRAFV600E wild type (WT) mCRC, as determined by local laboratory. Before first-line therapy, CGP is performed with FoundationOne (F1) CDx and F1 Liquid (F1L) CDx (324 genes) on tumor tissue DNA and plasma ctDNA, respectively.For 2/207 (0.96%) patients, no ctDNA was detected by F1L CDx. No patient displayed tumor fraction (TF) below 1%, whereas elevated ctDNA (TF≥10%) was detected among 140/205 (68.3%) patients. 1013 genomic variants were identified. F1L CDx found KRAS, NRAS or BRAFV600E alterations in 19 patients, whose tumors were classified as RAS/BRAFV600E WT by local laboratory. Both F1 CDx and F1L CDx were available for 164/205 (80%) patients. Concordance of 61.4% between the two tests was observed. Concordance increased to 72.7% for F1L CDx with TF ≥10%. Concordance for genes potentially involved in anti-epidermal growth factor receptor (EGFR) resistance was found in 137/164 (83%) patients, increasing to 91.5% for F1L CDx with TF ≥10%. A higher number of genomic alterations was detected by F1L CDx compared with F1 CDx, including 6 cases with KRAS and NRAS alterations. Overall, 109/205 (53.2%) patients displayed at least one actionable genomic alteration (I to IIIB), according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT).RESULTSFor 2/207 (0.96%) patients, no ctDNA was detected by F1L CDx. No patient displayed tumor fraction (TF) below 1%, whereas elevated ctDNA (TF≥10%) was detected among 140/205 (68.3%) patients. 1013 genomic variants were identified. F1L CDx found KRAS, NRAS or BRAFV600E alterations in 19 patients, whose tumors were classified as RAS/BRAFV600E WT by local laboratory. Both F1 CDx and F1L CDx were available for 164/205 (80%) patients. Concordance of 61.4% between the two tests was observed. Concordance increased to 72.7% for F1L CDx with TF ≥10%. Concordance for genes potentially involved in anti-epidermal growth factor receptor (EGFR) resistance was found in 137/164 (83%) patients, increasing to 91.5% for F1L CDx with TF ≥10%. A higher number of genomic alterations was detected by F1L CDx compared with F1 CDx, including 6 cases with KRAS and NRAS alterations. Overall, 109/205 (53.2%) patients displayed at least one actionable genomic alteration (I to IIIB), according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT).Baseline liquid biopsy-based CGP is feasible, it has high concordance with tumor tissue-based CGP, it could better recapitulate tumor heterogeneity, and it is clinically informative by identifying additional actionable genomic alterations in approximately half of RAS/BRAFV600E WT mCRC patients.CONCLUSIONBaseline liquid biopsy-based CGP is feasible, it has high concordance with tumor tissue-based CGP, it could better recapitulate tumor heterogeneity, and it is clinically informative by identifying additional actionable genomic alterations in approximately half of RAS/BRAFV600E WT mCRC patients.
RAS mutation is considered one of the most relevant oncogenic drivers in human cancers. Unfortunately, for more than three decades, RAS has been considered an undruggable target. Recently, the ...discovery of selective and potent KRASG12C inhibitors represented a light at the end of the tunnel. Indeed, sotorasib and adagrasib proved clinical activity in patients with refractory metastatic colorectal cancer harboring KRASG12C mutation; however, responses are lower than expected, suggesting the presence of intrinsic resistance. Consequently, novel combinatory strategies to disrupt the RAS signaling pathways are under clinical investigation. This review aims to discuss the current knowledge and novel routes of KRASG12C inhibition in metastatic colorectal cancer.
•KRASG12C mutation occurs in 2%-4% of metastatic colorectal cancer (mCRC).•The presence of KRASG12C mutation is correlated with a dismal response to chemotherapy and poor prognosis.•Selective KRASG12C inhibitors, including sotorasib and adagrasib, showed signals of antitumor activity in mCRC.•Different combinatory strategies are under clinical investigation.
The rechallenge strategy is based on the concept that a subset of patients with RAS wild‐type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) ...inhibition, after progression to an anti‐EGFR based‐therapy. We performed a pooled analysis of two‐phase II prospective trials to determine the role of rechallenge in third‐line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third‐line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression‐free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0–4.9) with median OS (mOS) of 16.9 months (95% CI 11.7–22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7–6.2); mOS was 13.1 months (95% CI 7.3–18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0–5.2); mOS was 18.6 months (95% CI 11.7–25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third‐line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.
Liquid biopsy guides anti‐EGFR rechallenge therapy in CRICKET and CAVE trails.
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