Objective response rate assessment in oncology: Current situation and future expectations

The tumor objective response rate(ORR)is an important parameter to demonstrate the efficacy of a treatment in oncology.The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials.World Health Organization and Response Evaluation Criteria in Solid Tumors(RECIST)are anatomic response criteria developed mainly for cytotoxic chemotherapy.These criteria are based on the visual assessment of tumor size in morphological images provided by computed tomography(CT)or magnetic resonance imaging.Anatomic response criteria may not be optimal for biologic agents,some disease sites,and some regional therapies.Consequently,modifications of RECIST,Choi criteria and Morphologic response criteria were developed based on the concept of the evaluation of viable tumors.Despite its limitations,RECIST v1.1 is validated in prospective studies,is widely accepted by regulatory agencies and has recently shown good performance for targeted cancer agents.Finally,some alternatives of RECIST were developed as immune-specific response criteria for checkpoint inhibitors.Immune RECIST criteria are based essentially on defining true progressive disease after a confirmatory imaging.Some graphical methods may be useful to show longitudinal change in the tumor burden over time.Tumor tissue is a tridimensional heterogenous mass,and tumor shrinkage is not always symmetrical;thus,metabolic response assessments using positron emission tomography(PET)or PET/CT may reflect the viability of cancer cells or functional changes evolving after anticancer treatments.The metabolic response can show the benefit of a treatment earlier than anatomic shrinkage,possibly preventing delays in drug approval.Computer-assisted automated volumetric assessments,quantitative multimodality imaging in radiology,new tracers in nuclear medicine and finally artificial intelligence have great potential in future evaluations.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor+chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers

BACKGROUND The combination of programmed cell death protein-1(PD-1)inhibitor and che-motherapy is approved as a standard first-or second-line treatment in patients with advanced oesophageal or gastric cancer.However,it is unclear whether this combination is superior to chemotherapy alone.AIM To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer,gastroesophageal junction(GEJ)cancer,or oesophageal carcinoma.METHODS We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer.We employed either random or fixed models to analyze the outcomes of each clinical trial,en-compassing data on overall survival(OS),progression-free survival(PFS),objective response rate,and adverse events(AEs).RESULTS Nine phase 3 clinical trials(7016 advanced oesophageal and gastric cancer patients)met the inclusion criteria.Our meta-analysis demonstrated that the pooled PD-1 inhibitor+chemotherapy group had a significantly longer OS than the chemotherapy-alone group[hazard ratio(HR)=0.76,95%confidence interval(CI):0.71-0.81];the pooled PFS result was consistent with that of OS(HR=0.67,95%CI:0.61-0.74).The count of patients achieving an objective response in the PD-1 inhibitor+chemotherapy group surpassed that of the chemotherapy-alone group[odds ratio(OR)=1.86,95%CI:1.59-2.18].AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group,regardless of whether≥grade 3 only(OR=1.30,95%CI:1.07-1.57)or all AE grades(OR=1.88,95%CI:1.39-2.54)were examined.We performed a subgroup analysis based on the programmed death-ligand 1(PD-L1)combined positive score(CPS)and noted extended OS and PFS durations within the CPS≥1,CPS≥5,and CPS≥10 subgroups of the PD-1 inhibitor+chemotherapy group.CONCLUSION In contrast to chemotherapy alone,the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer,GEJ tumor,or oesophageal cancer.This holds true particularly for individuals with PD-L1 CPS scores of≥5 and≥10.

Intracranial activity of first-line immune checkpoint inhibitors combined with chemotherapy in advanced non-small cell lung cancer

Background:Immune checkpoint inhibitors(ICIs)are increasingly used as first-line therapy for patients with advanced non-small cell lung cancer(NSCLC)harboring no actionable mutations;however,data on their efficacy among patients presenting with intracranial lesions are limited.This study aimed to explore the efficacy and safety of ICIs combined with chemotherapy in advanced NSCLC patients with measurable brain metastasis at initial diagnosis.Methods:Our study retrospectively analyzed clinical data of a total of 211 patients diagnosed with driver gene mutation-negative advanced NSCLC with measurable,asymptomatic brain metastasis at baseline from Hunan Cancer Hospital between January 1,2019 and September 30,2021.The patients were stratified into two groups according to the first-line treatment regimen received:ICI combined with chemotherapy(n=102)or chemotherapy(n=109).Systemic and intracranial objective response rates(ORRs)and progression-free survival(PFS)were analyzed.Adverse events were also compared between the groups.Results:Compared with the chemotherapy-based regimen,the ICI-containing regimen was associated with a significantly higher intracranial(44.1%[45/102]vs.28.4%[31/109],χ^(2)=5.620,P=0.013)and systemic(49.0%[50/102]vs.33.9%[37/109],χ^(2)=4.942,P=0.019)ORRs and longer intracranial(11.0 months vs.7.0 months,P<0.001)and systemic(9.0 months vs.5.0 months,P<0.001)PFS.Multivariable analysis consistently revealed an independent association between receiving ICI plus platinum-based chemotherapy as a first-line regimen and prolonged intracranial PFS(hazard ratio[HR]=0.52,95%confidence interval[CI]:0.37-0.73,P<0.001)and systemic PFS(HR=0.48,95%CI:0.35-0.66,P<0.001).No unexpected serious adverse effects were observed.Conclusion:Our study provides real-world clinical evidence that ICI combined with chemotherapy is a promising first-line treatment option for driver gene mutation-negative advanced NSCLC patients who present with brain metastasis at initial diagnosis.Clinical trial registration:https://www.clinicaltrials.gov/,OMESIA,NCT05129202.

Phase II clinical trial using camrelizumab combined with apatinib and chemotherapy as the first-line treatment of advanced esophageal squamous cell carcinoma

Background:Effective therapeutic options are limited for patients with advanced esophageal squamous cell carcinoma(ESCC).The incorporation of an immune checkpoint inhibitor and a molecular anti-angiogenic agent into the commonly adopted chemotherapy may produce synergistic effects.Therefore,we aimed to investigate the efficacy and safety of camrelizumab plus apatinib combined with chemotherapy as the first-line treatment of advanced ESCC.Methods:In this single-arm prospective phase II trial,patients with unresectable locally advanced or recurrent/metastatic ESCC received camrelizumab 200 mg,liposomal paclitaxel 150 mg/m2,and nedaplatin 50 mg/m2 on day 1,and apatinib 250 mg on days 1-14.The treatments were repeated every 14 days for up to 9 cycles,followed by maintenance therapy with camrelizumab and apatinib.The primary endpoint was objective response rate(ORR)according to the Response Evaluation Criteria in Solid Tumors(version 1.1).Secondary endpoints included disease control rate(DCR),progression-free survival(PFS),overall survival(OS),and safety.Results:We enrolled 30 patients between August 7,2018 and February 23,2019.The median follow-up was 24.98 months(95%confidence interval[CI]:23.05-26.16 months).The centrally assessed ORR was 80.0%(95%CI:61.4%-92.3%),with a median duration of response of 9.77 months(range:1.54 to 24.82+months).The DCR reached 96.7%(95%CI:82.8%-99.9%).The median PFS was 6.85 months(95%CI:4.46-14.20 months),and the median OS was 19.43 months(95%CI:9.93 months–not reached).The most common grade 3-4 treatmentrelated adverse events(AEs)were leukopenia(83.3%),neutropenia(60.0%),and increased aspartate aminotransferase level(26.7%).Treatment-related serious AEs included febrile neutropenia,leukopenia,and anorexia in one patient(3.3%),and single cases of increased blood bilirubin level(3.3%)and toxic epidermal necrolysis(3.3%).No treatment-related deaths occurred.Conclusions:Camrelizumab plus apatinib combined with liposomal paclitaxel and nedaplatin as first-line treatment demonstrated feasible anti-tumor activity and manageable safety in patients with advanced ESCC.Randomized trials to evaluate this new combination strategy are warranted.Trial registration:This trial was registered on July 27,2018,at ClinicalTrials.gov(identifier:NCT03603756).

Irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer(ESWN 01):a prospective randomized,multicenter,open-labeled phase 3 trial

Background:The benefit of systemic treatments in esophageal squamous cell carcinoma(ESCC)which has pro-gressed after chemotherapy is still uncertain and optimal regimens based on randomized trials have not yet been established.We aimed to compare the efficacy of irinotecan plus S-1 with S-1 monotherapy in recurrent or metastatic ESCC patients who had resistance to platinum-or taxane-based chemotherapy.Methods:We conducted a prospective randomized,multicenter,open-label,phase 3 trial in 15 centers across China.Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC,and were randomly assigned(ratio,1:1)to receive either irinotecan plus S-1(intravenous infusion of irinotecan[160 mg/m2]on day 1 and oral S-1[80-120 mg]on days 1-10,repeated every 14 days)or oral S-1 monotherapy(80-120 mg/day on days 1-14,repeated every 21 days)using a central computerized minimization procedure.The primary endpoint was progression-free survival(PFS).Results:Between December 23,2014 and July 25,2016,we screened 148 patients and randomly assigned 123 patients to receive either irinotecan plus S-1 regimen(n=61)or S-1 monotherapy(n=62).After a median follow-up of 29.2 months(95%confidence interval[CI]17.5-40.9 months),the median PFS was significantly longer in the irinotecan plus S-1 group than in the S-1 monotherapy group(3.8 months[95%CI 2.9-4.3 months]vs.1.7 months[95%CI 1.4-2.7 months],hazard ratio=0.58,95%CI 0.38-0.86,P=0.006).The objective response rates were 24.6%in the irinotecan plus S-1 group and 9.7%in the S-1 monotherapy group(P=0.002).The patients in the irinotecan plus S-1 group presented with increased rates of grade 3-4 leukopenia(16.4%vs.0%),neutropenia(14.8%vs.1.6%),and nausea(4.9%vs.0%).No significant difference in grade 3-4 diarrhea and no treatment-related deaths were observed in both groups.Conclusions: The combination of irinotecan with S-1 was similarly tolerable but significantly prolonged PFS compared to S-1 monotherapy as a second- or third-line treatment in patients with recurrent or metastatic ESCC.