Substantial improvements have been made in the management of metastatic colorectal cancer over the last two decades. The overall survival of patients diagnosed with unresectable metastatic colorectal ...cancer has increased from approximately 1 year during the era of fluoropyrimidine monotherapy to more than 30 months with the integration of multiple cytotoxic agents and targeted therapies. More effective therapeutic combinations have increased the rate of curative-intent surgical resections, resulting in median survival in this subgroup that exceed 5 years. Here we review the landscape of systemic therapies for unresectable metastatic colorectal cancer during the current era of targeted therapies, review the effects of RAS and BRAF mutations on clinical decision making, and reflect on future directions for the treatment of metastatic colorectal cancer.
Purpose of Review
Mutations in kirsten rat sarcoma viral oncogene homolog
(KRAS)
are the most frequently observed genomic alterations in human cancers. No KRAS targeting therapy has been approved ...despite more than three decades of efforts. Encouraging progress has been made in targeting KRAS
G12C
with KRAS
G12C
specific covalent inhibitors in the past few years. Herein, we review the recent breakthroughs in KRAS targeting.
Recent Findings
KRAS
G12C
mutation was found in 14% of non-small cell lung cancer (NSCLC) and 3% of colorectal cancer. Recently, highly potent
KRAS
G12C
specific inhibitors have been developed and demonstrated potent activity in preclinical models. Early results from phase 1 clinical trials with sotorasib and MRTX849 show promising antitumor activity in NSCLC, colorectal cancer and other solid tumors harboring
KRAS
G12C
mutation.
Summary
For the first time, the preclinical success of targeting KRAS has translated into clinical benefits, which holds the potential of transforming clinical management of
KRAS
mutated solid tumors. Additional efforts are needed to identify biomarkers that predict response to KRAS inhibition in patients with
KRAS
G12C
as well as to develop strategies to overcome resistance.
Human epidermal growth factor 2 (HER2) amplification represents a distinct molecular subgroup of colorectal cancers that is associated with anti‐epidermal growth factor receptor resistance and ...sensitivity to dual HER2 targeting. Although clinical trials have reported activity for trastuzumab/pertuzumab and trastuzumab/lapatinib combinations, there are no reports on lapatinib plus trastuzumab activity after resistance to trastuzumab plus pertuzumab. Presented are three cases of HER2 amplified colorectal cancer that developed acquired refractoriness to trastuzumab pertuzumab with subsequent clinical benefit to lapatinib plus trastuzumab, highlighting the potential for HER2 tyrosine kinase inhibition plus trastuzumab in overcoming trastuzumab/pertuzumab resistance.
This brief communication reports on the activity of lapatinib plus trastuzumab after acquired disease resistance to trastuzumab plus pertuzumab in patients with HER2 colorectal cancer. HER2 amplification represents a distinct molecular subgroup of colorectal cancers that is associated with anti‐EGFR resistance and sensitivity to dual HER2 targeting. Three such cases are described.
The treatment of metastatic colorectal cancer has evolved over the last two decades with the FDA approval of several cytotoxic, biological, and targeted agents. In this paper, we review the impact of ...sidedness, RAS, BRAF, HER‐2, and other immune biomarkers on metastatic colorectal cancer treatment selection and sequencing in both the palliative and curative intent settings.
KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours
. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent ...inhibitors that have promising preclinical activity
. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRAS
tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS
tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.
To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC).
ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop ...recommendations for clinical practice.
Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria.
Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti-vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti-epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive
wild-type mCRC; chemotherapy and anti-vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair
wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated
V600E-mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision making are recommended. Qualifying statements with further details related to implementation of guideline recommendations are also included.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. ...MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer.
MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141.
Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20–45). The most common treatment-emergent adverse events were diarrhoea (19 33% of 57 patients), fatigue (18 32% patients), and nausea (17 30% patients). Grade 3–4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three 5% patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths.
Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer.
F Hoffmann-La Roche/Genentech.
Elevated expression of EZH2, the enzymatic subunit of polycomb repressive complex 2 (PRC2), often occurs in cancer. EZH2 expression results in the silencing of genes that suppress tumor formation and ...metastasis through trimethylation of histone H3 at lysine 27 (H3K27me3) at their promoters. However, inhibitors of EZH2 enzymatic activity have not shown the expected efficacy against cancer in clinical trials, suggesting a need for other strategies to address EZH2 overexpression. Here, we show that SUMOylation, a posttranslational modification characterized by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins, enhances EZH2 transcription. Either knockdown of the SUMO-activating enzyme SAE2 or pharmacologic inhibition of SUMOylation resulted in decreased levels of EZH2 mRNA and protein as well as reduced H3K27me3 levels. SUMOylation regulated EZH2 expression by enhancing binding of the E2F1 transcriptional activator to the EZH2 promoter. Inhibition of SUMOylation not only resulted in reduced EZH2 mRNA and protein levels but also increased expression of genes silenced by EZH2, such as E-cadherin, which suppresses epithelial-mesenchymal transition and metastasis. In more than 6,500 patient tumor samples across different cancer types, expression of UBA2 and EZH2 was positively correlated. Taken together, our findings suggest that inhibition of SUMOylation may serve as a potential strategy to address EZH2 overexpression and improve current cancer therapeutic approaches. SIGNIFICANCE: These findings provide important biological insights into the mechanism of EZH2 overexpression in cancers and suggest that inhibiting SUMOylation may improve current cancer therapeutic approaches.
G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C ...inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy.
In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated
G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response.
After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval CI, 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab.
In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.).
We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other ...antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation.
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