Cetuximab and panitumumab are two distinct monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR), and both are widely used in combination with chemotherapy or as ...monotherapy to treat patients with
RAS
wild-type metastatic colorectal cancer. Although often considered interchangeable, the two antibodies have different molecular structures and can behave differently in clinically relevant ways. More specifically, as an immunoglobulin (Ig) G1 isotype mAb, cetuximab can elicit immune functions such as antibody-dependent cell-mediated cytotoxicity involving natural killer cells, T-cell recruitment to the tumor, and T-cell priming via dendritic cell maturation. Panitumumab, an IgG2 isotype mAb, does not possess these immune functions. Furthermore, the two antibodies have different binding sites on the EGFR, as evidenced by mutations on the extracellular domain that can confer resistance to one of the two therapeutics or to both. We consider a comparison of the properties of these two antibodies to represent a gap in the literature. We therefore compiled a detailed, evidence-based educational review of the known molecular, clinical, and functional differences between the two antibodies and concluded that they are distinct therapeutic agents that should be considered individually during treatment planning. Available data for one agent can only partly be extrapolated to the other. Looking to the future, the known immune activity of cetuximab may provide a rationale for this antibody as a combination partner with investigational chemotherapy plus immunotherapy regimens for colorectal cancer.
Background
There is no large real-world data regarding efficacy and safety of immunotherapy in gastric cancer (GC). Although some tumors can grow rapidly after immunotherapy, the patient proportions ...and survival outcomes are unclear in GC.
Methods
A multicenter, prospective observational study was performed to evaluate clinical outcomes including survival time, safety, and tumor behavior of nivolumab treatment for patients with advanced GC. Primary endpoint was overall survival (OS), and secondary endpoints included response rate (RR), disease control rate (DCR), progression-free survival (PFS), tumor growth rate (TGR) at first evaluation, and safety.
Results
Of 501 enrolled patients, 487 were evaluable (median age 70 years, 71% male, performance status 0/1/2 42%/44%/14%, 21% HER2-pos, 42% patients with ascites). Median OS was 5.82 months (95% CI 5.29–7.00) with a 1-year survival rate of 30% and median PFS of 1.84 months (95% CI 1.71–1.97). The DCR was 39.4% and the RR was 14.2% (95% CI 10.3–18.8) in 282 patients with measurable lesions. In 219 patients evaluable for TGR, 20.5% were identified as hyperprogressive disease (HPD). OS from the first evaluation of patients with HPD was shorter compared with non-HPD (HR 1.77, 95% CI 1.25–2.51,
P
= 0.001), but it was not worse than that of patients with progression and non-HPD (HR 1.05, 95% CI 0.72–1.53,
P
= 0.8). A multivariate analysis revealed the presence of peritoneal metastasis was a prognostic factor for OS and PFS.
Conclusions
Our real-world data demonstrated the comparable survival time to a previous clinical trial and revealed the frequency and prognosis of patients with HPD in advanced GC treated with nivolumab.
mutations constitute an important poor prognostic factor in metastatic colorectal cancer (mCRC) and the development of treatments in this context is of great necessity to prolong patient survival. ...Although the association between
mutations and microsatellite instability (MSI) has been known for several years, previous clinical trials have revealed that the former has a limited prognostic impact and that immune checkpoint inhibitors offer a significant survival benefit to mCRC patients with both characteristics. Furthermore, the genomic classification of
mutations according to their molecular functions enables greater understanding of the characteristics of mCRC patients with
mutations, with therapeutic strategies based on this classification made more ideal to improve poor prognosis through the delivery of targeted therapies. Recently, a phase III trial was conducted in previously treated mCRC patients with
V600E-mutated tumors and revealed that the combination therapy approach of
inhibition and anti-epidermal growth factor receptor antibody therapy with or without MEK inhibition was more efficacious than standard chemotherapy alone. This review discusses current treatment strategies and future perspectives in
-mutated mCRC.
Opinion statement
Gastric cancer is a heterogenous cancer, which may be classified into several distinct subtypes based on pathology and epidemiology, each with different initiating pathological ...processes and each possibly having different tumor biology. A classification of gastric cancer should be important to select patients who can benefit from the targeted therapies or to precisely predict prognosis. The Cancer Genome Atlas (TCGA) study collaborated with previous reports regarding subtyping gastric cancer but also proposed a refined classification based on molecular characteristics. The addition of the new molecular classification strategy to a current classical subtyping may be a promising option, particularly stratification by Epstein–Barr virus (EBV) and microsatellite instability (MSI) statuses. According to TCGA study, EBV gastric cancer patients may benefit the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies or phosphoinositide 3-kinase (PI3K) inhibitors which are now being developed. The discoveries of predictive biomarkers should improve patient care and individualized medicine in the management since the targeted therapies may have the potential to change the landscape of gastric cancer treatment, moreover leading to both better understanding of the heterogeneity and better outcomes. Patient enrichment by predictive biomarkers for new treatment strategies will be critical to improve clinical outcomes. Additionally, liquid biopsies will be able to enable us to monitor in real-time molecular escape mechanism, resulting in better treatment strategies.
Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E ...wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge.
This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies MAF of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360).
Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative.
The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.
Purpose
A phase III trial comparing S-1 and docetaxel with S-1 alone as postoperative chemotherapy for pathologically Stage III gastric cancer was conducted and clarified the superiority of the ...doublet in terms of 3-year relapse-free survival as the primary endpoint (67.7% versus 57.4%, hazard ratio HR 0.715, 95% confidence interval CI 0.587–0.871;
p
= 0.0008). This final report analyzed 5-year survival outcomes along with the incidence and pattern of late recurrences.
Patients and methods
Patients with histologically confirmed Stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive adjuvant chemotherapy with either S-1 plus docetaxel or S-1 alone. The same 912 patients who were evaluated for 3-year survival outcomes in the previous report were analyzed.
Results
Five-year overall survival rate of the S-1 plus docetaxel group (67.91%) was significantly superior to that in the S-1 group (60.27%; HR 0.752, 95% CI 0.613–0.922;
p
= 0.0059). The incidence of late recurrence at > 3 years after randomization was similar in both groups (7.3% versus 7.2%). Peritoneal dissemination was the most common pattern of late recurrence. Addition of docetaxel significantly suppressed relapse through the lymphatic (6.8% 95% CI 4.52–9.17 versus 15% 95% CI 11.76–18.30;
p
< 0.0001) and hematogenous (10.2% 95% CI 7.37–12.94 versus 15.7% 95% CI 12.36–19.01;
p
< 0.0137) pathways throughout the 5 years of follow-up.
Conclusion
The survival benefit of postoperative chemotherapy with S-1 and docetaxel in terms of 5-year overall survival rate was confirmed for patients with pathologically Stage III gastric cancer, although late recurrences were not prevented.
Abstract “Neo RAS WT” refers to the loss of RAS mutations (MTs) following first-line treatment in metastatic colorectal cancer (mCRC). We evaluate the incidence and clinicopathological ...characteristics of Neo RAS WT mCRC using next-generation sequencing of plasma circulating tumor DNA. Patients with mCRC enrolled in the GOZILA study initially diagnosed with tissue RAS MT mCRC and received subsequent systemic therapy are eligible. Neo RAS WT is defined as the absence of detectable RAS MT in plasma and assessed in all eligible patients (Group A) and in a subgroup with at least one somatic alteration detected in plasma (Group B). Overall, 478 patients are included. Neo RAS WT prevalence is 19.0% (91/478) in Group A and 9.8% (42/429) in Group B. Absence of liver or lymph node metastasis and tissue RAS MTs other than KRAS exon 2 MTs are significantly associated with Neo RAS WT emergence. Overall, 1/6 and 2/6 patients with Neo RAS WT treated with anti-EGFR monoclonal antibodies (mAbs) show partial response and stable disease for ≥6 months, respectively. Neo RAS WT mCRC is observed at a meaningful prevalence, and anti-EGFR mAb-based therapy may be effective.
In the multimodality treatment strategy for gastric cancer, chemotherapy has an important role in conferring survival benefit. For the last three decades, great progress has been achieved in adjuvant ...and palliative chemotherapy. Powerful combination regimens using doublet or triplet cytotoxic agents have been developed and new molecular targeted drugs, including trastuzumab and ramucirumab, have been introduced in clinical practice. These advances have resulted from the accumulation of many clinical trials. A well-designed phase III trial can change standard treatment; however, such a trial is hard to complete due to its huge cost and need to recruit many patients. Some co-operative groups have actively made efforts at fundraising and patient recruitment, which can make implementation of high-quality and large-scale phase III trials possible. This review summarizes the development of chemotherapy for gastric cancer with focus on co-operative groups around the world, considering effective treatment developments in gastric cancer. We studied 11 active co-operative groups, including six in Europe, two in the United States, and three in Japan, that have completed one or more phase III trials cited in the major guidelines. Each co-operative group had its own characteristics and contributed to the establishment of standard treatment in each region. International collaboration in the development of gastric cancer treatment may be difficult due to regional differences in standards of care, particularly for resectable gastric cancer. Whereas, intergroup collaboration within each region is a reasonable method to effectively develop treatments for resectable and advanced gastric cancer.
PDF
