Today, the American Association for Cancer Research (AACR) 2022 Annual Meeting kicks off. As one of the world's largest cancer research events, AACR brings together scientists from around the world oncology basic and clinical research advances.
During the AACR, the Singularity team will share the latest report of the day with you at the Singularity Tumor Exploration. Here are 11 key foundational and clinical developments released today by the AACR.
CT007
PETRA: the second-generation PARP1 selective inhibitor, the first new drug AZD5305 in patients carrying BRCA1/2, PALB2 or RAD51C/D mutations in the first human trial
In patients with advanced breast, ovarian, prostate, or pancreatic cancers who carry blastocyst or somatic BRCA1/2, PALB2, or RAD51C/D mutations, AZD5305 is taken orally once daily until disease progression. Admission criteria include an ECOG PS score of 0-2, hemoglobin ≥ 90 g/L, and previous treatment with PARPi and platinum drugs. The primary study endpoint was safety; secondary study endpoints included: pharmacokinetics (PK) and pharmacodynamics by testing tumor and/or blood sample analysis and assessment of efficacy according to THE RECIST v1.1 criteria, CA125 or PSA. Exploratory analysis includes genomic heterozygosity assessment and ctDNA monitoring.
As of 17 November 2021, 46 patients had taken AZD5305 10-90 mg orally daily (43.5% had received PARPi; median number of treatment lines was 3.5). AZD5305 is well tolerated at all doses before dose-limiting toxicity is reached (table). PK exposure is proportional to dose. Stable blood concentrations were higher than those of the first parpi: 6.3 and 31.9 times higher than the effective concentrations of the first parpi of 10 mg and 90 mg, respectively.
At a dose of 10-40 mg QD, AZD5305 inhibits adenosine ribosylation (PARylation) polyphosphate by≥ 90%, confirming its effective binding to the target. Of the 25 patients, 7 (28%) had objective responses: 5 had a RECIST criteria assessment of PR (3 confirmed) and another 2 responded to PSA50, including platinum-resistant and PARPi-resistant patients. Of the 22 PATIENTs assessed for RECIST, 13 (59%) achieved SD or PR for more than 51 weeks. Of the 13 patients with different doses administered, 7 (54%) (3 in complete remission, 4 in regression>50%) all had a decrease in ctDNA during treatment.
AZD5305 is a highly selective PARP1 inhibitor and trapper with excellent physicochemical properties and a wide therapeutic index. Even after first-generation PARPi treatment, it can still be optimally bound to the target, showing good clinical activity and tolerability.
CT009
Perioperative pambolizumab combined with capecitabine and oxaliplatin and adjunctive pambolizumab therapy for the resection of gastric and gastroesophageal junction (GC/GEJ) adenocarcinoma in Phase II trials
Perioperative treatment is the standard of care for locally advanced (LA) GC/GEJ adenocarcinoma. Although chemoradiation and surgical resection of sequential immune checkpoint inhibitors (ICBs) have significantly improved disease-free survival (DFS) for esophageal cancer, the effectiveness of ICB combined chemotherapy in LA GC/GEJ is unclear.
This is a multicenter, single-arm, phase II clinical trial in which patients with resectable GC/GEJ adenocarcinoma are treated with pambolizumab 200 mg/every 3 weeks in combination with capecitabine 625 mg/㎡ twice daily and oxaliplatin 130 mg/㎡ every 3 weeks (CAPOX). Subjects with AN ECOG PS of 0-1 received 3 cycles of CAPOX plus pambolizumab for 3 cycles before and after surgery, plus an additional cycle of pambolizumab before surgery and 12 months of maintenance therapy after adjuvant immunity therapy. The primary endpoint was the pathological complete response (pCR) rate. The study had 80% efficacy and detected an increase in pCR rate from 3% to 15%, and a unilateral α of 0.05. Secondary endpoints included overall response rate, DFS, and overall survival (OS). This study was registered in ClinicalTrials.gov (NCT02918162).
Between 10 February 2017 and 17 June 2021, 36 patients were enrolled, of which 34 (21 gastric cancers, 13 GEJs) were eligible for efficacy assessment. The median age was 65 years and ecog PS was 1 in 17 (50%) patients. A total of 29 (85%) patients underwent resection. Seven patients achieved pCR (20.6% of assessable patients and 24.1% of resected patients). Another 6 (17.6%) patients were nearing complete response (CR) and 8 (23.5%) showed significant therapeutic effects in pathology review. One patient was considered unsuitable for surgery, two died before surgery, and two patients were found to have metastases during surgery.
At data cut-off, the median follow-up time was 19 months. Of the patients undergoing resection, 4 (13.7%) had disease recurrence and 5 (17.2%) died. The 1-year and 2-year survival rates were 0.91 (0.82-1.0) and 0.80 (0.64-0.99), respectively. Median DFS and OS are not reached. Of the 35 patients treated, 18 (51%) reported treatment-related adverse events (AE) greater than or equal to grade 3. Immune-related AEs greater than or equal to grade 3 were reported in 10 (29%) patients. Three cases of grade 5 AE occurred, 2 may be related to treatment (gastric bleeding and gastric perforation) and 1 case is not related to treatment (cardiac arrest).
In LA GC/GEJ adenocarcinoma, the pCR rate of CAPOX and pambolizumab was 20.6%. The combination was well tolerated, and 85.3% of the patients underwent surgical resection. The trial reached its primary endpoint, supporting further investigation of the regimen as an alternative to patients who could not tolerate three-drug combination chemotherapy. Research is ongoing.
CT010
Phase II study of duvalizumab and helmedumab plus first-line neoadjuvant chemotherapy in patients with advanced ovarian cancer (KGOG 3046/TRU-D)
KGOG 3046 is a phase 2 study evaluating dual immune checkpoint suppression (duvalliumab [D] and trimemizumab [T]) in combination with neoadjuvant chemotherapy (NAC) for advanced preepithelial ovarian cancer (aEOC). The study recruited patients with FIGO STAGE IIIC-IV epithelial ovarian cancer.
Patients were assigned to the following neoadjuvant chemotherapeutic therapy (NACI): the original cohort 1 group (duvalliumab 1500 mg q3w + trimeliumab 75 mg q3w + paclitaxel 175 mg/㎡ + carboplatin AUC 5 [3 cycles]) or the extended cohort 2 group (duvalliumab 1500 mg q3w + trimeliumab 300 mg [1 dose] + original chemotherapy), group 2 started after group 1 was completed.
After neoadjuvant chemotherapy, all patients underwent intermittent tumor cytoreduction (IDS), after which three cycles of dovallizumab (1120 mg) and adjuvant chemotherapy were performed, and maintenance therapy with duvalliumab (1120 mg [for a total of 12 cycles]) was performed.
During treatment, immunological changes in the tumor microenvironment (TME) are explored by performing a series of biopsies. The primary endpoint of the study was 12 months of progression-free survival. After all patients have received intermittent cytoreductive therapy, an interim analysis is performed to evaluate the effects of neoadjuvant chemotherapy.
A total of 45 patients were included in the analysis, including the following numbers: Group 1 (n=23) and Group 2 (n=22). The majority of patients present with high-grade serous carcinoma (91.1%) and stage IV disease (77.8%). After neoadjuvant chemotherapy, the objective response rate was 86.7% (95.7% in the first group, 81.8% in the second group, and 0.17% in the second group) according to the efficacy evaluation criteria for solid tumors (RECIST 1.1). In intermittent tumor cytoreduction, 30 patients (66.7%) were completely resected (73.9% in the first group, 59.1% in the second group, and P=0.353). Fourteen patients (31.1%) had a chemotherapy response score of Grade 3 (39.1% in 1 group, 22.7% in 2 groups, P=0.337), and 5 patients (11.1%) had a pathological response. Rash was the most common adverse event (51.1%), with 3 patients (15.6%) experiencing ≥-3 events but completely relieved symptoms after steroid use.
After neoadjuvant immunotherapy combined with chemotherapy, immunohistochemistry showed interstitial tumor infiltrating lymphocytes (P=0.0335), CD8 (P
These data now highlight the clinical activity and controlled toxicity of the addition of duvalliumab and trimemimumab to neoadjuvant chemotherapy for advanced epithelial ovarian cancer. Data from other translational medicine studies will be presented at the conference.
CT014
Evaluation of the effects of intratumoral bo-112 combined with systemic pambolizumab (Keytruda) in patients with PD-1 immunotherapy resistant melanoma: Final results of the Phase 2 SPOTLIGHT203 clinical trial
The study was a one-arm clinical study (NCT04570332) of intratumoral BO-112 and intravenous paporizumab (Keytruda) in patients with melanoma (skin, extremities, or mucous membranes) and patients who are still undergoing anti-PD-1 therapy and who are still progressing. Patients receive BO-112 for 7 weeks (1 to 2 mg/week) and every 3 weeks (1 to 8 different lesions). Pembolizumab (Keytruda) is applied every 3 weeks with 200 mg. The primary endpoint of the study was that independent reviewers evaluated the overall response rate (ORR) against RECIST 1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and safety assessment. Exploratory objectives include radiological features, itRECIST (Note: response criteria for immunotherapy within solid tumors), and tumor microenvironment assessment. At least 20% of patients responded to the primary endpoint.
On 24 April 2021, 42 patients were enrolled in the group, 43% of whom were women, with a median age of 66 years (27 to 88 years), and the table summarized the baseline characteristics.
Treatment response was assessed in 40 patients, of which 10 (25%) responded to treatment: 3 patients in complete response and 7 patients in partial response. Seventeen patients (44%) were in a stable phase of disease, while the disease control rate reached 68% (18 patients were still receiving treatment). Four patients with an initial lactate dehydrogenase greater than 3 times the upper limit of normal (3xULN) developed disease progression within 8 weeks. The response rates to treatment according to histological distinction are as follows: 66% of the mucous membranes, 28% of the skin, 0% of the extremities. Response rates in patients with BRAF/NRAS mutations are as follows: BRAF mutation 43%, NRAS mutation 31%, and BRAF/NRAS wild type 17%. At least one BO-112-related adverse reaction was monitored in 33 patients (79%), and only 2 patients developed an adverse reaction of grade 3 or higher (grade 4 infusion reaction and grade 3 myalgia). The most common associated adverse reactions are weakness, fever, diarrhea, vomiting, and chills.
The study has reached the primary efficacy endpoint, and the regimen for long-lasting, clinically significant disease control in such patients with melanoma who cannot be treated standardly cannot be used. Initial lactate dehydrogenase greater than 3 times the upper limit of normal and poor prognosis in patients with acromelanoma. This regimen is safe and manageable and does not require interruption of treatment due to associated adverse effects.
CT015
First-line evaluation of the safety and efficacy of TTX-030 (anti-CD39 antibody) combined with chemotherapoimmunotherapy in patients with locally advanced or metastatic gastric cancer/gastroesophageal junction tumor
The extracellular ATPase CD39 is a key rate-limiting enzyme in the adenosine pathway with immunomodulatory effects. TTX-030 is a fully human anti-CD39 antibody that reduces extracellular inhibitory adenosine levels by inhibiting CD39 function to maintain high immunostimulatory ATP concentrations, thereby weakening the immunosuppressive ability of the tumor immune microenvironment. Recent addition of navuliliumab to chemotherapy has become the standard treatment for locally advanced or metastatic gastric cancer, but further improvement is needed.
The TTX-030-002 study (ongoing in the US and Korea) is being expanded to assess the safety and efficacy of first-line combination of TTX-030, budigalimab (PD-1 inhibitor) and FOLFOX chemotherapy in patients with locally advanced or metastatic HER2-negative gastric cancer/gastroesophageal junction tumors. The main objective of the study was to assess safety and tolerability. Secondary endpoints were assessment of overall response rate and progression-free survival by RECIST/iRECIST. Related studies also include the analysis of the expression of CD39 and PD-L1 within tumors.
A total of 44 patients were enrolled, the median age was 61 years (30 to 81 years old), 41% were female, and 57% were Asian. 39% of patients with an ECOG score of 0 and 61% of patients with a score of 1, 70% of patients had gastric adenocarcinoma, and 30% of patients had adenocarcinoma at the gastroesophageal junction.
Safety data as of 19 November 2021 showed that 39 (89%) patients experienced adverse reactions (any level, regardless of relevance) that occurred during at least 1 treatment. Twenty-one (48%) patients experienced at least one adverse reaction (of any level) associated with TTX-030 and five (11%) patients experienced a grade 3/4 adverse reaction associated with TTX-030. The occurrence of grade 5 treatment-related adverse reactions was not monitored. Eleven patients (25%) experienced serious adverse reactions, but were not associated with TTX-030.
The most common adverse reactions (arbitrary level, regardless of correlation) were nausea (52%), neutropenia (39%), decreased appetite (30%), diarrhea (25%) and fatigue (23%). The most common ≥ grade 3 adverse reactions in more than 2 patients (regardless of correlation) were neutropenia (27%), febrile neutropenia (5%), and hypokalemia (5%).
Validity data as of December 2, 2021 show that the median time for this study was 139 (8 to 375) days. Of the 38 patients whose efficacy could be evaluated, 23 had a partial response or better response (21 had a partial response and 2 had a complete response, with an overall response rate of 61%), 12 had stable disease, and 3 had disease progression. Of the 38 patients with assessable efficacy, 36 had a known PD-L1 plus positive score (CPS): the response rate was 4/10 (CPS
Preliminary findings suggest that the combination of TTX-030, budigalimab, and FOLFOX chemotherapy in patients with locally advanced or metastatic gastric cancer/gastroesophageal junction tumors has shown promising efficacy and manageable safety, regardless of the CPS score. To our knowledge, this is the first study of anti-CD39 antibodies combined with chemotherapy for the treatment of stomach cancer. The final findings will update clinical and biomarker study data.
CT034
Phase II clinical trial of SCC244 in patients with non-small cell lung cancer (NSCLC) (GLORY trial)
It has been reported that 3-4% of patients with non-small cell lung cancer (NSCLC) have an exon-jumping mutation of interstitial epithelial transforming factor No. 14 (METex14) and become a new target for the treatment of NSCLC. Cometinib (SCC244) is a highly selective, potent oral mesenchymal epithelial transforming factor (MET) inhibitor.
Lu Shun's team at Shanghai Chest Hospital reported for the first time the results of the single-arm, II clinical trial (GLORY trial) of SCC244 in NSCLC patients with METex14 mutation. The GLORY trial is an open-label, international, multicenter, single-arm Phase II clinical trial to evaluate the efficacy and safety of SCC244 in patients with locally advanced or metastatic NSCLC who carry METex14 mutations (central laboratory confirmation) and fail after first- or second-line drug system therapy, or who do not meet or refuse chemotherapy after adequate evaluation.
For a 21-day treatment cycle, 300 mg of SCC244 is taken orally once a day (QD) until the disease progresses or intolerable toxicity develops. Tumors are assessed every 6 weeks for the first 8 treatment cycles and every 9 weeks thereafter. The primary endpoints were the objective response rate (ORR) assessed by the Blinded Independent Review Committee (BIRC) according to RECIST 1.1, and the secondary endpoints included investigator-assessed (INV) ORR, response duration (DoR), reaction time (TTR), and safety. Post-mortem analysis was conducted to explore intracranial antineoplastic activity.
As of 6 May 2021, 73 patients from 163 patients from 42 regions were screened and treated at a dose of 300 mg QD. Of these, 69 were laboratory-confirmed as METex14 mutations. Of the 69 patients, the overall ORR was 60.9% (95% CI: 48.4%-72.4%) of patients who had not been treated and those who had previously received treatment had ORRs of 66.7% (95% CI: 50.5-80.4) and 51.9% (95% CI: 31.9-71.3), respectively, as assessed by BIRC. The median DoR was 8.2 months (95% confidence interval: 4.8, NE), the median progression-free survival (PFS) was 7.6 months (95% confidence interval: 4.2, NE), and tumor responses were still ongoing in 30 of the 42 responders. Responded quickly, with a median TTR of 1.4 months (1.2-4.2). Eight of the 10 patients with brain metastases showed a partial response. Five patients with brain metastases were selected as target lesions, and after INV evaluation, there was an intracranial response, and the median for intracranial tumor reduction was 57% (34% to 71%).
The most common (20%) treatment-related adverse events (TRAEs) were peripheral edema, headache, nausea, loss of appetite, hypoproteinemia, elevated alanine transaminases (ALT), and vomiting. The incidence of grade 3 TRAEs was 43.8%, and 6.8% of patients had interruption of treatment due to TRAEs, the most common of which was peripheral edema (4.1%).
This clinical trial data shows that SCC244 has a high and stable efficacy in patients with meTex14 mutation of different treatment lines in non-small cell lung cancer patients with good intracranial anti-tumor activity. Good safety and controllable toxicity. The data support that SCC244 can be an important option for targeted therapy in patients with METex14 non-small cell lung cancer.
CT038
Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for broad-phase SCLC: a Phase 3 clinical trial
Clinical treatment options for extensive small cell lung cancer (ES-SCLC) are limited and the prognosis is poor. Recently, immunotherapy has shown strong clinical efficacy in ES-SCLC. In this double-blind Phase 3 clinical trial, Ying Cheng's team at Jilin Cancer Hospital evaluated the clinical efficacy of the novel anti-PD-L1 antibody Adebrelimab (SHR-1316) combined with standard chemotherapy (chemo) as a first-line treatment for ES-SCLC.
Patients with ES-SCLC who had not undergone systemic therapy were randomized on a 1:1 basis and received 4-6 cycles of treatment, one group received Adebrelimab (20 mg/kg, intravenously, d1, q3w) + carboplatin (AUC 5, d1, q3w) + etoposide (20 mg/kg, intravenously, d1, q3w) and the other group received placebo + carboplatin (AUC 5, d1, q3w) + etoposide (20 mg/kg, intravenously, D1, Q3W) treatment, followed by adebellimumab or placebo maintenance therapy. The primary endpoint was overall survival (OS).
462 patients were randomized and treated (Adebrelimab + chemotherapy group 230; placebo + chemotherapy group 232). As of 8 October 2021, the median follow-up was 13.5 months (all patients; 22.5 months for survivors). OS was significantly prolonged (median OS 15.3 months [95% CI 13.2-17.5] vs 12.8 months [95% CI 11.3-13.7] compared with placebo+chemotherapy, hazard ratio HR=0.72, [95% CI 0.58-0.90], unilateral p=0.0017) compared with placebo+, and OS rates were 62.9% in the Adebrelimab+ chemotherapy and placebo+chemotherapy groups at 12 months, respectively. and 52.0%, 31.3% and 17.2% at 24 months, respectively.
The Independent Review Committee (IRC) assessed progression-free survival (PFS) of 5.8 months (95% CI 5.6-6.9) and 5.6 months (95% CI 5.5-5.7) in the Adebrelimab+ chemotherapy group and placebo+chemotherapy group, respectively, with PFS rates of 49.4% and 37.3% at 6 months and PFS rates of 19.7% and 5.9% at 12 months, respectively.
The objective response rate (ORR) and duration of response (DoR) in the Adebrelimab+ chemotherapy group were also superior to those in the placebo+chemotherapy group. The incidence of grade 3 treatment-related adverse events in the Adebrelimab+ chemotherapy group and the placebo+ chemotherapy group were 85.7% and 84.9%, respectively, and the most common adverse event (incidence ≥5%) in both groups was hematologic toxicity.
The addition of Adebrelimab to chemotherapy significantly improves OS and is an acceptable safety profile, and data from this trial support that the combination regimen can be used as a new first-line treatment option for ES-SCLC.
CT538
Efficacy of Tepotinib in combination with gefitinib in patients with EGFR mutation-positive non-small cell lung cancer with MET amplification: INSIGHT final analysis
The main analysis of the INSIGHT trial showed (NCT01982955; median follow-up time: 21.8 months) that Tepotinib (a potent, highly selective, once-daily [QD] MET inhibitor) in combination with gefitinib in patients with EGFR mutations positive and resistant to EGFR therapy due to MET amplification was more effective than chemotherapy (CTX) (Wu et al., Lancet Respir Med). 2020）。 The AACR conference reports the final results of INSIGHT 's analysis (data deadline: September 3, 2021; median follow-up time: 57.5 months).
NSCLC patients with EGFR mutation positivity (T790M negative) and resistant to anti-EGFR therapy (MET gene copy number (GCN) ≥5 and/or MET: CEP7 ≥2 and/or MET IHC 2+/3+) were randomly divided into Thepotinib 500 mg (active fraction 450 mg) + gefitinib 250 mg [QD] and cyclophosphamide (CTX) 250 mg. The primary endpoint was progression-free survival (PFS).
19/55 randomized subjects (34.5%) had MET amplification (GCN≥5, n=18; MET:CEP7≥2,n=13; Met IHC 3+, n=17), median age 60.4 years, 68.4% of patients never smoked, and previously used EGFR inhibitors such as gefitinib (57.9%), afatinib (21.1%), erlotinib (10.5%), and exetinib (10.5%). The median course of treatment for Tepotinib + gefitinib was 11.3 months (1.1 to 56.5), of which 6 cases (31.6%) were > 1 year and 3 cases (15.8%) were > 4 years old. Two patients continued to receive treatment outside the study.
Compared with CTX, Tepotinib plus gefitinib significantly improved progression-free survival (HR 0.13; 95% CI 0.04, 0.43), overall survival (HR 0.10; 95% CI 0.02, 0.36), objective response rate, and duration of response (see table). Treatment≥-related grade 3 adverse reactions occurred in 7 patients (58.3%) in the Tepotinib + gefitinib group and 5 patients in the CTX group (71.4%).
In META IHC 3+ patients (n=34, including 17 patients with MET amplification), Tepotinib + gefitinib also significantly improved PFS (HR 0.35; 95% CI 0.17, 0.74) and OS (HR 0.44; 95% CI 0.23, 0.84) compared with CTX.
Compared with CTX, Tepotinib in combination with gefitinib significantly improved PFS and OS in patients with EGFR mutation-positive NSCLC with MET amplification. INSIGHT 2 Tepotinib + osimertinib is also being evaluated for efficacy in such patients.
CT555
Efficacy of pambolizumab versus chemotherapy in PD-L1-positive patients with non-small cell lung cancer in China: results of 4-year follow-up data from keynote-042 China study
In the global Phase 3 clinical study of KEYNOTE-042, pambolizumab therapy significantly prolonged the overall survival of patients with untreated advanced/metastatic non-small cell lung cancer (PD-L1 TPS [tumor ratio score] ≥1%, without EGFR/ALK mutations) compared with chemotherapy. For the Chinese patients in the study, pambrolizumab treatment extended overall survival compared with chemotherapy in patients with PD-L1 TPS ≥50% (HR 0.63, 95CI% 0.43-0.94), TPS ≥20% (HR 0.66, 95CI% 0.47-0.92), TPS ≥1% (HR 0.67, 95CI% 0.50-0.89).
Wu Yilong's team at Guangdong Provincial People's Hospital continued to follow up the Chinese patients in the Keynote-042 study for 14 months, reporting the latest patient efficacy and safety results at this AACR meeting. Participants in the Keynote-042 global study (NCT02220894) and the Chinese Extended Cohort (NCT03850444) were randomized to the permabrilizumab treatment group (200 mg, Q3W, ≤35 cycles) or chemotherapy group (paclitaxel/pemetrexel + carboplatin, follow-up optional pemetrexed maintenance therapy (non-scaly NSCLC only)) on a 1:1 ratio, with primary endpoints of PD-L1 TPS ≥50%, ≥20%, and ≥1% Overall survival in patients. Eligible patients may undergo a second cycle of treatment after completing 35 cycles of pambolizumab therapy. The significance level (alpha) was not set for the China Extended Queue analysis.
A total of 262 patients with PD-L1 TPS ≥1% were included in the study, including 128 patients in the pambolizumab treatment group (pembro group) and 134 patients in the chemotherapy group (chemo group). The median time for patients from enrolment to data collection (28 April 2021) was 47.2 months (39.8-56.1 months).
Compared with chemotherapy, pabolizumab therapy extended overall survival in patients with PD-L1 TPS ≥50% (HR 0.66, 95CI% 0.45-0.95), ≥20% (HR 0.68, 95CI% 0.49-0.93), and ≥1% (HR 0.67, 95CI% 0.51-0.89). In the PEMBRO and Chemo groups, 19.5% and 68.8% of patients, respectively, experienced treatment-related grade 3-5 adverse reactions. In 22 patients who completed 35 cycles of pambolizumab therapy, the total effective rate was 81.8% (95% CI 59.7% to 94.8%), and the estimated survival rate after randomization was 69.1% at 4 years (see table above for detailed data). At the end of data collection, 79 patients in each group began follow-up treatment, of which 4 patients started a second course of pambolizumab therapy.
This study shows that, similar to the Keynote-042 study, in patients with advanced/metastatic PD-L1-positive non-small cell lung cancer in China (without EGFR/ALK mutation), through nearly 4 years of follow-up, pambolizumab as a first-line treatment can prolong patient survival and produce long-lasting therapeutic effects, and pambolizumab monotherapy can become the standard of treatment for this type of patient.
LB511
The combination of HA and TMB acts as a pan-cancer biomarker for patients receiving terelizumab therapy
451 patients were treated with different doses of terelitizumab. To assess gene expression (HTG EdgeSeq Precision Immunology Oncology Panel) and genomic mapping (FoundationOne CDX) of baseline tumor tissues. TMB-H is defined as ≥10 mutations/Mb, and gene overextending (HA) is defined as the minimum copy number increment >5. The correlation between progression-free survival (PFS) and overall survival (OS) was examined using the COX proportional risk model.
The overall objective response rate was 13.3% (95% CI: 10.3, 16.8), the median PFS was 2.1 months (95% CI: 2.1, 2.7), and the median OS was 10.3 months (95% CI: 8.5, 11.6). An improvement in clinical efficacy was observed in patients with TMB-H (n =43, accounting for 16.2% of patients with TMB-evaluable), and in PTS without the HA gene, the efficacy was further enhanced (TMB-H/HA-). The tumor microenvironment (TME) of this population exhibited higher cytotoxic T cell activity and interferon signaling, with less HA in the RTK-RAS-PI3K pathway. These results were validated in a separate PD-(L)1 inhibitor monotherapy pan-cancer cohort (n=837): TMB-H/HA-(n=139) had a longer OS than TMB-H/HA+(n=89) (median OS was 34 and 15 months, respectively, P=0.07).
The combined detection of TMB and HA predicts the clinical effect of terelizumab in the treatment of various solid tumors. This combined algorithm may be used to identify patients most likely to benefit from PD-(L)1 inhibitor therapy to provide new insights.
LB512
RATIONALE-304: Clinical prognosis of tumor mutation burden (TMB) versus tislelizumab (TIS) + chemotherapy (chemo) versus chemotherapy alone in first-line treatment for advanced nonsquamous non-small cell lung cancer (nsq-NSCLC).
In a preliminary analysis of RATIONALE-304 (NCT03663205), terelizumab (TIS) plus platinum chemotherapy significantly improved the clinical prognosis of early-stage NSQ-NSCLC compared with chemotherapy alone (median progression-free survival [PFS] assessed by the Independent Review Committee [IRC] was 9.7 vs. 7.6 months, HR=0.645, p=0.0044). Lu Shun's team at Shanghai Chest Hospital reported biomarker analysis of baseline tissue and blood TMB (tTMB and bTMB, respectively).
Patients with NSQ-NSCLC were randomly divided into TIS+ platinum + pemetrexed group and platinum + pemetrexed group in a 2:1 ratio. TMB scores for baseline tumor and blood samples were assessed by OncoScreen Plus. The relationship between tTMB and Spearman's rating of bTMB was evaluated. The PFS (primary endpoint) determined by the Independent Review Committee was assessed within the subgroup of TMB status definition using the Cox proportional risk model, using disease staging and PD-L1 expression as stratification factors. Interactive p-value
Of the 325 patients treated with no EGFR-sensitive mutations in the RATIONALE-304 study, 177 (54.5%) had assessable tTMB and 107 (32.9%) had assessable bTMB. The medians tTMB and bTMB were 7.2 and 3.1mut/Mb, respectively. The correlation between tTMB and bTMB is acceptable (r=0.71, p versus patients with low TMB, in patients with high TMB, the addition of TIS to chemotherapy can prolong the benefit of PFS (see table above). Interaction analysis showed that neither tTMB nor bTMB significantly differentiated the benefits of treatment-specific PFS (interaction p-value > 0.05; see table above).
In this retrospective analysis, tTMB and bTMB were not significantly associated with the benefits of PFS, indicating that tTMB and bTMB had limited clinical utility in TIS+ chemotherapy as the first-line treatment of advanced nsq-NSCLC.
bibliography:
CT007：https://www.abstractsonline.com/pp8/#!/10517/presentation/20149
CT009：https://www.abstractsonline.com/pp8/#!/10517/presentation/20151
CT010：https://www.abstractsonline.com/pp8/#!/10517/presentation/20152
CT014：https://www.abstractsonline.com/pp8/#!/10517/presentation/20156
CT015：https://www.abstractsonline.com/pp8/#!/10517/presentation/20157
CT034：https://www.abstractsonline.com/pp8/#!/10517/presentation/20172
CT038：https://www.abstractsonline.com/pp8/#!/10517/presentation/20384
CT538：https://www.abstractsonline.com/pp8/#!/10517/presentation/20277
CT555：https://www.abstractsonline.com/pp8/#!/10517/presentation/20294
LB511：https://www.abstractsonline.com/pp8/#!/10517/presentation/19966
LB512：https://www.abstractsonline.com/pp8/#!/10517/presentation/19967
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