PD-L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non-small cell lung cancer?

PD-L1 and tumor mutation burden (TMB) are the most widely used immunotherapy biomarkers to identify populations who would attain clinical benefit, with the higher values predicting better therapeutic efficacy. This review addresses the predictive values and unresolved challenges of these two biomarkers. PD-1 and PD-L1 inhibitors have induced durable and effective responses in patients with advanced non-small cell lung cancer, confirmed by multiple clinical trials and real-world studies. Different clinical trials, involving both PD-1/PD-L1 inhibitors alone and combination regimens, adopted either PD-L1 or TMB to stratify the patients, although the predictive capabilities of these two biomarkers are different. In the first-line setting, PD-L1 of 50% or more as a cut-off value can help select candidates for pembrolizumab or atezolizumab monotherapy; however, these two biomarkers poorly predict the efficacy of immunotherapy combination regimens as first-line treatments. In the second-line setting, although patients can benefit from nivolumab regardless of PD-L1 expression, both PD-L1 and blood TMB can be used as biomarkers to find patients suitable for atezolizumab. Except for inaccurate predictiveness, there are many unresolved problems with regard to the two biomarkers, such as the lack of standard detection methods, and their susceptibilities to other dynamic changes. The predictive values of TMB and PD-L1 were low in most circumstances; however, PD-L1 expression greater than ≥ 50% can help select appropriate patients for pembrolizumab and atezolizumab, respectively, as first-line monotherapies. Higher PD-L1 or TMB was associated with greater efficacy for atezolizumab as a second-line monotherapy.

Nab-paclitaxel and gemcitabine plus camrelizumab and radiotherapy versus nab-paclitaxel and gemcitabine alone for locally advanced pancreatic adenocarcinoma: a prospective cohort study.

Treatment options specifically for patients with locally advanced pancreatic adenocarcinoma (LAPC) are scare and chemotherapy alone delivers limited efficacy. Immunotherapy and radiotherapy are potential effective treatments for LAPC, and both of them may synergize with chemotherapy. Therefore, in this prospective cohort study, we compared the efficacy and safety of nab-paclitaxel plus gemcitabine combined with anti-programmed cell death (PD-1) immunotherapy and radiotherapy (hereafter, combination treatment) versus nab-paclitaxel plus gemcitabine (chemotherapy alone) in the treatment of LAPC. In the combination group, participants received conventional fractionated radiotherapy with doses ranging from 54 to 63 Gy in 28 fractions, intravenous camrelizumab 200 mg once every 3 weeks, and intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death or unacceptable toxicity. In the chemotherapy group, participants received intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles. From April, 2020 to December, 2021, 96 participants with LAPC were prospectively enrolled with 32 received combination treatment and 64 received chemotherapy alone at a single center. The combination treatment yielded significantly longer median overall-survival (22.3 months vs. 18.6 months, P = 0.031) and progression-free survival (12.0 months vs. 10.5 months, P = 0.043) than chemotherapy alone did. And the incidence of severe adverse events was not significantly different between the combination group and chemotherapy group (P = 0.856). In conclusion, nab-paclitaxel plus gemcitabine combined with anti-PD-1 immunotherapy and radiotherapy was effective and safe for LAPC patients, and it warrants further investigation in larger randomized trials.

Efficacy of radiation plus transarterial chemoembolization and lenvatinib in hepatocellular carcinoma with portal vein tumor thrombus.

Background: We aimed to investigate the efficacy of a novel regimen, external beam radiation (RT) combined with trans arterial chemoembolization (TACE) and lenvatinib (LEN), in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus. Methods: We prospectively observed 102 participants from three tertiary medical centers in China between October 2018 and October 2020, who chose either RT plus TACE and LEN (RT-TACE-LEN) or TACE and LEN (TACE-LEN). LEN (12 mg or 8 mg daily) was administrated orally and continued until progression or intolerable side effects were noted. TACE was given one day after administration of LEN, and RT began within 4 weeks after the first TACE. The median dose/fraction of RT was 50 Gy/25 fractions (range: 45-60 Gy/25 fractions). Overall survival and progression free survival were compared between two groups, and complications were assessed. Results: Both 51 patients received RT-TACE-LEN and TACE-LEN, respectively. Most patients had tumor size> 5 cm (73.8%) and tumor number≥ 2 (69.9%). The overall incidence of toxicities was significantly higher in RT-TACE-LEN group than TACE-LEN group (100% vs. 64.7%, p< 0.001), but incidences of grade 3-4 toxicities were comparable (54.9% vs. 49.0%, p= 0.552). Both median overall survival (22.8 vs. 17.1 months, p= 0.031) and median progression-free survival (12.8 vs. 10.5 months, p= 0.035) were significantly longer after RT-TACE-LEN treatment than TACE-LEN. Conclusions: The addition of RT to TACE and LEN was safe, and might improve clinical outcomes of patients with advanced HCC, which needs conformation from further studies.

Consistency of genotyping data from simultaneously collected plasma circulating tumor DNA and tumor-DNA in lung cancer patients.

BACKGROUND: To clarify the rate of concordance between the results of concurrent sequencing of circulating tumor DNA (ctDNA) and tumor tissue samples based in clinic settings, and to explore potential factors influencing consistency. METHODS: A retrospective analysis of 27 patients with lung cancer who underwent gene sequencing at the Department of Biotherapy of Tianjin Medical University Cancer Hospital from February 2016 to April 2019, was conducted by synchronous sequencing of tumor and plasma DNA samples and the concordance of mutations in nine known driver genes was calculated. RESULTS: The overall concordance, sensitivity, and specificity for sequencing driver genes in plasma samples, were 85.2%, 87.0%, and 75%, respectively, relative to tumor samples. Concordance was 100% in patients with bone metastases, while the rate in those without bone metastases was 69.2%. Moreover, in patients where both the driver gene and TP53 mutations in plasma were detected, the findings of plasma sequencing of the driver gene were identical to those of tumor sequencing (concordance: 100%). CONCLUSIONS: Overall, our data show that circulating tumor DNA (ctDNA) was able to identify 75% of the identical information in driver genes, with higher rates of concordance in lung cancer patients with bone metastases or TP53 mutation-positive plasma samples.

Diagnostic value of ProGRP for small cell lung cancer in different stages.

BACKGROUND: To investigate the roles of gastrin-releasing peptide (ProGRP) in the diagnosis of small cell lung cancer (SCLC). METHODS: We retrospectively analyzed data from 11,206 patients with clinical suspicion of lung cancer from January 1, 2015 to May 31, 2018. ProGRP and neuron-specific enolase (NSE) were detected in peripheral blood, and receiver operating characteristic curve (ROC) was used for analysis. RESULTS: ROC indicated that the cutoff values of ProGRP and NSE were 66 ng/L and 18 µg/L respectively, and the diagnosis efficacy of ProGRP was greater than that of NSE (sensitivity: 86.5% vs. 78.8%; specificity: 96.5% vs. 86.3%, respectively) in the diagnosis of SCLC. Moreover, the median level of ProGRP in SCLC increased with the accompanying stages (P<0.001). Further analysis showed that diagnostic efficacy can be improved by using different cutoff values in different stages, but not stage I and II. The cut-off values of ProGRP in the diagnosis of SCLC in stage I-II, III and IV were 56, 71 and 99 ng/L respectively. In addition, the sensitivity (96.6% vs. 95.8% and 98.3% vs. 94.8%) and concordance rate (χ2 =1,526.9 and 988.7, both P<0.001) of detecting SCLC was improved by using different cutoff values compared with the only criteria of ProGRP being ≥66 ng/L in stage III and IV, but not stage I-II. Additionally in stage III and IV, the concordance rates of ProGRP ≥71 ng/L and ProGRP ≥99 ng/L were also higher than ProGRP ≥300 ng/L (both P<0.001), which was conventionally indicated for SCLC. CONCLUSIONS: ProGRP has significantly higher sensitivity and specificity than NSE in the diagnosis of SCLC. Furthermore, special thresholds for every stage may be more reasonable for the diagnosis of SCLC.