18-month Progression-free Survival Rates Research Articles

The efficacy and safety of induction chemotherapy combined with sintilimab followed by concurrent chemoradiotherapy plus sintilimab sequencing maintaining with sintilimab for patients with unresectable locally advanced esophageal squamous cell carcinoma

PurposeTo evaluate the efficacy and safety of induction chemotherapy combined with programmed death protein 1 (PD-1) inhibitor (sintilimab) followed by concurrent chemoradiotherapy (CCRT) plus sintilimab, and subsequent maintenance with sintilimab (IC-ICCRT-IO) for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) in a retrospective study.MethodsData from patients with histologically confirmed, locally advanced, inoperable ESCC who received IC-ICCRT-IO were retrospectively analyzed. Treatment effects were evaluated after 2 cycles of induction therapy and after CCRT by contrast-enhanced CT scans and esophagograms, followed by subsequent evaluations every 3 months post-treatment. The primary endpoints included progression-free survival (PFS) and PFS rates at 6, 12, and 18 months. Secondary endpoints involved overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The influence of the expression level of programmed death ligand-1 (PD-L1) as well as neutrophil-to-lymphocyte ratio (NLR) on efficacy of the IC-ICCRT-IO was analyzed.ResultsIn total, 29 eligible patients were enrolled and analyzed. The median follow-up time was 20.5 months. The median PFS was not reached; the 6-, 12-, and 18-month PFS rates were 100.0%, 93.1%, and 82.8%, respectively. The median OS was not reached, and the 6-, 12-, and 18-month OS rates were all 100.0%. The ORR and DCR were 89.7% and 100.0%. Adverse events (AEs) were manageable, with grade 3 or higher AEs observed in 48.2% of patients, primarily nonimmune-related and clinically manageable. Hematologic toxicity was predominant. Two patients developed grade 3 immune-related rash, and two patients developed grade 3 radiation pneumonitis, all of whom were managed with appropriate symptomatic treatment. No significant differences in survival outcomes were observed with respect to PD-L1 and NLR.ConclusionOur results indicated that the IC-ICCRT-IO regimen for unresectable locally advanced ESCC provided a survival benefit with manageable safety profile. More prospective clinical studies should be warranted.Trial registration2024-04-22, No. QYFY WZLL 28,684, retrospectively registered.

Efficacy and safety of atezolizumab-bevacizumab vs pembrolizumab-lenvatinib in unresectable hepatocellular carcinoma: a retrospective, cohort study.

The relative superiority of atezolizumab-bevacizumab versus pembrolizumab-lenvatinib in treatment of unresectable hepatocellular carcinoma (HCC) remains uncertain. This study aims to compare the efficacy of atezolizumab-bevacizumab and pembrolizumab-lenvatinib in first-line treatments for unresectable HCC. A total of 72 patients receiving pembrolizumab-lenvatinib (PL group) and 92 patients receiving atezolizumab-bevacizumab (AB group) between January 2019 and June 2023 were included in this study. By employing propensity score matching (PSM), we compared the overall survival (OS) and progression-free survival (PFS) between the two groups. After PSM, the 1-, 2-, and 3-year OS rates were 70.4%, 54.5%, and 40.0% in the PL group, and 88.4%, 44.2%, and 44.2% in the AB group, respectively. The 6-, 12-, and 18-month PFS rates were 56.9%, 43.0%, and 32.1% in the PL group, and 74.2%, 40.9%, and 30.7% in the AB group, respectively. No significant differences were observed in both OS (HR, 0.498; 95% CI, 0.217-1.143; P = 0.1) and PFS (HR, 0.913; 95% CI, 0.512-0.1.629; P = 0.758) between the two groups. Through subgroup analysis, we developed a Cirrhosis-Portal vein invasion-ALBI (CPA) score and identified that the AB group exhibited significantly longer OS than the PL group in the CPA high population (HR, 0.219; 95% CI, 0.075-0.637; P = 0.005). The treatment-related adverse events between the PL group and the AB group were comparable. This study suggests that the efficacy of pembrolizumab-lenvatinib and atezolizumab-bevacizumab is comparable in first-line treatment of unresectable HCC, the atezolizumab-bevacizumab combination may confer additional benefits for patients with high CPA scores compared to pembrolizumab-lenvatinib.

Acalabrutinib in Chinese patients with relapsed/refractory chronic lymphocytic leukemia: Primary analysis from an open-label, multicenter phase 1/2 trial.

Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor approved in the United States and Europe for chronic lymphocytic leukemia (CLL) based on phase 3 trials with limited representation of Asian populations. This phase 1/2 trial evaluates acalabrutinib in Chinese adults with relapsed/refractory (R/R) CLL receiving acalabrutinib 100mg twice daily in 28-day cycles until disease progression or treatment discontinuation due to adverse events (AEs) presenting substantial clinical risk. The primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). A total of 60 patients from 20 sites in China received acalabrutinib (median age 62years; median 1 prior therapy line; 21.7% with del(17p) and/or TP53 mutation; 51.7% with unmutated IGHV). Median total treatment duration was 19.4months (range 0.6-28.2) with 53 patients (88.3%) receiving acalabrutinib at data cutoff; median study follow-up was 20.2months. BICR-assessed ORR was 85.0% (95% CI, 73.4-92.9). Median duration of response, progression-free survival (PFS), and overall survival (OS) were not reached. Estimated 12-month and 18-month PFS rates were 91.5% (95% CI, 80.9-96.4) and 78.8% (95% CI, 60.9-89.2); OS rates were both 96.7% (95% CI, 87.3-99.2). AEs of grade ≥ 3 occurred in 25 patients (41.7%), most commonly decreased neutrophil count (13.3%, n = 8), pneumonia (6.7%, n = 4), and upper respiratory tract infection (6.7%, n = 4). AEs led to treatment discontinuation in 2 patients (paraneoplastic pemphigus; rectal neoplasm). This study demonstrated high ORR in acalabrutinib-treated Chinese patients with R/R CLL with no unexpected safety concerns. This trial is registered on ClinicalTrials.gov (NCT03932331).

A single-arm phase II study of platinum doublet induction chemotherapy combined with toripalimab for driver gene-negative advanced NSCLC.

e20565 Background: PD-1/PD-L1 inhibitors combined with platinum doublet chemotherapy have become the standard first-line treatment for driver gene-negative advanced non-small cell lung cancer (NSCLC). However, not all patients can benefit from this treatment. Previous studies have shown that induction chemotherapy can reduce tumor burden, induce tumor immunogenic cell death, and improve the tumor immune microenvironment. Therefore, effective induction chemotherapy may enhance the efficacy of PD-1/PD-L1 immunotherapy. This single-arm, phase II clinical trial aims to evaluate the efficacy and safety of induction chemotherapy followed by immunotherapy (Toripalimab: PD-1 inhibitor) in treatment of driver gene-negative advanced NSCLC. Methods: Eligible patients received platinum doublet chemotherapy for 2-4 cycles (pemetrexed + platinum for adenocarcinoma; paclitaxel or gemcitabine + platinum for squamous cell carcinoma). patients who achieved tumor response (CR/PR/SD) received Toripalimab (240mg Q3W) for 2 years or until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS), which was defined as the duration from the initiation of induced chemotherapy to either tumor progression or death from any cause,and the secondary endpoints were toxicity, overall survival (OS), and clinical tumor response including objective response (defined as complete [CR] or partial response [PR]) and disease control (defined as CR, PR, or stable disease [SD]) during the course of combination treatment with Toripalimab following induction chemotherapy. Results: During the period from February 2020 through October 2023, a total of 19 qualified patients were enrolled in the study. As of December 31. 2023,the median follow-up was 22,9 months (range,15.9 to 30 months).11 patients (57.9%) experienced PFS events and 7 (36.8%) died, mOS were not reached. mPFS was 7.9 mo (95% CI,4.8-15.0months).12-month and 18-month PFS rate were 43% and 35%, respectively. One patient has not received tumor response assessment. Among the remaining 18 pts, 10 patients had a PR,5 patients had SD, and 3 patients had PD. The ORR and DCR were 55.6% and 83.3% respectively.42.1% (8/19) pts experienced immune-related adverse events(irAEs), included immune-related pneumonia (21.1%), rash (10.5%), hypothyroidism (10.5%). 2 pts experienced ≥3 grade irAEs, including grade 3 rash and grade 4 immune-related thrombocytopenia. Conclusions: Induction chemotherapy combined with Toripalimab achieved impressive 12-month and 18-month PFS rates in pts with driver gene-negative advanced NSCLC, along with manageable toxicities. These findings demonstrate the potential of induction chemotherapy could enhance the efficacy of immunotherapy. Clinical trial information: NCT04613804 .

A phase II randomized trial evaluating consolidative nivolumab in locally advanced non-small cell lung cancer post neoadjuvant chemotherapy plus nivolumab and concurrent chemoradiotherapy (GASTO-1091).

8008 Background: Enhancing clinical outcomes in resectable non-small cell lung cancer (NSCLC) has been associated with neoadjuvant or perioperative administration of nivolumab. However, the efficacy and safety of consolidation nivolumab versus observation following neoadjuvant chemotherapy plus nivolumab, hypofractionated radiotherapy and concurrent chemotherapy (hypo-CCRT) in patients with unresectable stage III NSCLC remain underexplored. Methods: Conducted as a randomized, multi-center, phase 2 trial in patients with unresectable stage IIIA-C NSCLC, this study enrolled individuals aged 18 to 75 with an ECOG performance status of 0 or 1. Neoadjuvant therapy consisted of docetaxel, cisplatin, and nivolumab (360mg every 3 weeks for 2 cycles), followed by hypo-CCRT. Patients without disease progression or G2+ pneumonitis after hypo-CCRT were randomly assigned to receive nivolumab (360 mg every 3 weeks for up to 12 months) or undergo observation. Randomization factors included age, sex, smoking history, and EGFR mutation status. The primary endpoint was progression-free survival (PFS) from randomization, with preplanned analysis results reported herein. The trial is registered with ClinicalTrials.gov, NCT04085250. Results: Between Dec 3rd, 2019, and Aug 18th, 2023, 264 patients underwent neoadjuvant therapy, 242 received hypo-CCRT, and 172 were randomly assigned to nivolumab consolidation (n = 86) or observation (n = 86) post hypo-CCRT. At the January 31, 2024, data cutoff, the median follow-up for all randomized patients was 22.8 months. Nivolumab consolidation exhibited significantly longer PFS compared to observation (median not reached vs. 12.2 months [95% CI 6.2-18.1]; hazard ratio 0.49 [95% CI 0.31-0.79], p = 0.002). The 12-month and 18-month PFS rates were 72.6% and 64.8% in the consolidation group, contrasting with 52.5% and 42.3% in the observation group. Grade 3-4 nonhematological adverse events occurred in 14.0% (37/264) during neoadjuvant therapy and hypo-CCRT. Following randomization, grade 3-5 adverse events occurred in 7.0% (6/86) with consolidation (G3 pneumonitis, 2.3%; G5 pneumonitis, 1.2%; G3 proximal bronchial tree toxicity, 3.5%) and 4.6% (4/86) with observation (G3 pneumonitis, 2.3%; G3 proximal bronchial tree toxicity, 2.3%). Conclusions: Consolidation with nivolumab after neoadjuvant chemotherapy plus nivolumab and hypo-CCRT demonstrates effectiveness and tolerability for patients with unresectable stage III NSCLC. Extended follow-up is essential for confirming these findings. Clinical trial information: NCT04085250 .

Neoadjuvant toripalimab plus chemotherapy followed by concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma (GASTO 1071).

4077 Background: The combination of immune checkpoint inhibitor and concurrent chemoradiotherapy (CCRT) has been under investigation in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC). We explored the efficacy and safety of neoadjuvant toripalimab plus chemotherapy followed by CCRT in patients with locally advanced ESCC. Methods: This phase II, non-randomized, 2-cohort study enrolled patients with unresectable, stage T1-4N0-3M0-1 ESCC (M1 only includes patients with lymph node metastasis in the supraclavicular region). All patients were aged 18–80 years with an Eastern Cooperative Oncology Group performance status of 0–1. Patients in both cohorts received neoadjuvant therapy comprised of paclitaxel-albumin, nedaplatin and toripalimab 240 mg every 3 weeks, for 2 cycles, followed by CCRT (total dose 60Gy in cohort A, 50 Gy in cohort B, combined with oral capecitabine). The primary endpoint was progression-free survival (PFS) from enrollment. The trial is registered with ClinicalTrials.gov, NCT04844385. Results: Between February 26, 2021, and June 20, 2023, a total of 63 patients were enrolled in cohort A (54 men [85.7%]; median [interquartile range] age, 63 [58-65] years; 57 [90.5%] patients had stage III to IVB disease), and 61 patients were enrolled in cohort B (43 men [70.5%]; median [interquartile range] age, 65 [57-69] years; 52 [85.2%] patients had stage III to IVB disease). The objective response rate assessed 2 months after CCRT was 93.7% in cohort A and 93.4% in cohort B. At data cutoff (January 31, 2024), the median (range) follow-up duration was 31.3 (2.5-47.1) months in cohort A, and 17.0 (5.7-38.7) months in cohort B. The 12-month and 18-month PFS rates were 78.3%, 64.4% in cohort A, and 75.7%, 63.6% in cohort B. Median PFS was not reached in either cohort. Locoregional recurrence was observed in 19.0% (12/63) of patients in cohort A, and 24.6% (15/61) of patients in cohort B. Distant metastasis was observed in 12.7% (8/63) of patients in cohort A, and 3.3% (2/61) of patients in cohort B. Grade 3 and 5 pneumonitis occurred in 3.2% (2/63) and 1.6% (1/63) in cohort A, respectively, while no grade 3+ pneumonitis occurred in cohort B. Treatment-related esophageal fistula occurred in 1.6% (1/63) in cohort A and 1.6% (1/61) in cohort B. Conclusions: Neoadjuvant toripalimab plus chemotherapy followed by definitive CCRT demonstrated promising efficacy and acceptable toxicity in patients with locally advanced ESCC. Further study is warranted to confirm this conclusion. Clinical trial information: NCT04844385 .

Real-world osimertinib pretreatment experience in patients with epidermal growth factor receptor T790M mutation-positive locally advanced or metastatic non-small cell lung cancer.

Osimertinib has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) in clinical trials. However, real-world data on its effectiveness remain scarce. Taiwanese patients with T790M-positive locally advanced or metastatic NSCLC and progressive disease following treatment with at least one EGFR tyrosine kinase inhibitor (TKI) were enrolled from the osimertinib early access program. Of the 419 patients (mean age, 63 years; female, 67%), 53% were heavily pretreated (≥ third-line [3L]), making osimertinib a fourth-line (4L) intervention. The median progression-free survival (PFS) was 10.5 months (95% confidence interval [CI]: 8.95-11.41); the 18-month PFS rate was 26.5%. The median overall survival (OS) was 19.0 months (95% CI: 16.30-20.95); the 24-month OS rate was 40.9%. The objective response rate was 32.46%, and the disease control rate was 86.38%. The median time to treatment discontinuation of osimertinib monotherapy was 11.9 months (95% CI: 10.49-13.11). Subgroup analyses of median PFS and OS in the chemotherapy combination group vs. the osimertinib monotherapy group yielded no difference. Central nervous system (CNS) metastasis, number of prior lines of therapy, and types of initial EGFR-TKIs did not significantly impact outcomes. The median PFS values were 9.0 (95% CI: 5.18-11.34) and 10.9 (95% CI: 9.18-11.90) months with and without CNS metastasis, respectively, and 10.8 (95% CI: 8.59-12.69), 13.6 (95% CI: 10.89-16.3), and 9.2 (95% CI: 7.8-10.62) months for second-line (2L), 3L, and ≥4L therapy, respectively. In patients who received osimertinib as 2L therapy, the median PFS values in response to prior afatinib, erlotinib and gefitinib treatment were 11.2 (95% CI: 4.85-4.79), 10.5 (95% CI: 8.59-20.26) and 8.7 (95% CI: 7.21-16.79) months, respectively. Overall, real-world data from Taiwan support the clinical benefits of osimertinib in EGFR T790M -positive NSCLC.

Long-term survival outcomes and immune checkpoint inhibitor retreatment in patients with advanced cervical cancer treated with camrelizumab plus apatinib in the phase II CLAP study.

Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated long-term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported. In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4-week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing > 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2-year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12-month progression-free survival (PFS) rate was 40.7% (95% confidence interval [CI], 25.2-55.6), with an 18-month PFS rate of 37.8% (95% CI, 22.7-52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3-36.9), and the 24-month OS rate was 47.8% (95% CI, 31.7-62.3). Age > 50 years, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (versus [vs.] < 1), CPS ≥ 10 (vs. < 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio [HR] < 1) and longer OS (HR < 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study. Long-term survival follow-up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first-line platinum-based chemotherapy. No new safety signals were noted with long-term treatment.

Abstract PO4-04-02: Real-world first line use of trastuzumab biosimilar (HLX02), pertuzumab and chemotherapy for Chinese patients with HER2-positive metastatic breast cancer

Abstract Background: HLX02 (Zercepac®) is the first manufactured trastuzumab biosimilar in China. Its similar efficacy, safety, and immunogenicity compared with Herceptin was confirmed in phase III clinical trials in patients with HER2-positive advanced breast cancer. Nevertheless, the real-world evidence of HLX02 combined with pertuzumab and chemotherapy in HER2-positive advanced breast cancer in China is still warranted. Methods: In this real world observational study, patients with HER2-positive advanced breast cancer who received HLX02, pertuzuamb and chemotherapy as first line treatment at Beijing Cancer Hospital from April 2020 to April 2023 were retrospectively and prospectively included. The primary outcome was progression-free survival (PFS), and secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: A total of 55 patients (including one male) were included in this study and analyzed. The median age was 57 (range: 49, 62) years. Nearly one-third of tumors were estrogen receptor-positive (n=20, 36.4%). Thirty patients (54.5%) had newly-diagnosed stage IV disease. Visceral metastasis was reported in 40 patients (72.7%), most commonly observed in liver (n=22, 40%) and lung (n=19, 34.5%). Seven patients received prior anti-HER2 therapy during (neo-) adjuvant therapy (n=7, 12.7%). Taxane was the most commonly administrated chemotherapy regimen (n=51, 92.7%), including 56.4% albumin-bound paclitaxel, 20% liposomal paclitaxel and 18.2% docetaxel. Objective response was observed in 44 patients, leading to an ORR of 80%, and the DCR achieved 100%. HLX02 and pertuzumab was continued as maintenance therapy in 50 patients (90.9%), among which 17 combined with endocrine therapy (30.9%) and 6 combined with oral chemotherapy (10.9%). With a median follow-up of 9.8 months (range: 0.6-38.2). Progressive disease (PD) occurred in 12 of 55 patients (21.8%) and no deaths occurred. The median PFS was 24.8 months (95% confidence interval [CI]: 16.9- not estimated). The 12-month and 18-month PFS rate was 84.0% (95%CI: 72.9-96.9) and 58.8% (95%CI: 41.5 ~ 83.2), respectively. OS cannot be estimated yet due to immature data. HLX02-related diarrhea and infusion-related reaction was reported in 2 (3.6%) and 1 (1.8%) patients, respectively. LVEF values were monitored before and after drug administration, no clinical significant decline in LVEF and cardiac toxicity was observed. Conclusions: The trastuzumab biosimilar HLX02 demonstrated comparable efficacy and safety to Herceptin when combined with pertuzumab and chemotherapy for Chinese patients with HER2-positive advanced breast cancer in real world first-line treatment, which suggested that HLX02 may provide another option of Her2-targeted therapy combined with pertuzumab for Chinese patients. The benefit regarding long-term survival need to be further verified. Table 1. Effectiveness Citation Format: Ruyan Zhang, Guohong Song, Xiaoran Liu, Hui-Ping Li. Real-world first line use of trastuzumab biosimilar (HLX02), pertuzumab and chemotherapy for Chinese patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-02.

Final database lock results of the phase 2 cohort of lenvatinib + pembrolizumab for progressive disease after a PD-1/PD-L1-containing therapy in metastatic clear cell renal cell carcinoma

Abstract Background Lenvatinib + pembrolizumab is approved for the first-line treatment of advanced renal cell carcinoma (RCC). In the CLEAR trial, the combination showed statistically significant/clinically meaningful improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs sunitinib (Motzer R et al. NEJM. 2021). As immune checkpoint inhibitors (ICIs) have become standards of care as first-line treatment of RCC, an unmet need exists for patients who have disease progression after treatment with ICIs. A phase 1b/2 trial of lenvatinib + pembrolizumab was performed in multiple tumor types enrolling patients who had or had not received prior therapy; the primary analysis of the RCC cohort has been reported previously (Lee C-H et al. Lancet Oncol. 2021). Here, we report the final results of this RCC cohort with an additional 24 months of follow-up. Methods Eligible patients ≥18 years old with measurable disease were treated with lenvatinib 20 mg daily + pembrolizumab 200 mg once every 3 weeks. The primary endpoint (ORR at week 24 [ORRwk24] per immune-related [ir] RECIST by the investigators) has been previously reported (Lee C-H et al. Lancet Oncol. 2021). Secondary endpoints included ORR, duration of response (DOR), PFS (each by the investigators), OS and safety. In the analyses reported herein, efficacy data were grouped by prior therapy patients had received, including ICI-pretreated, treatment-naïve, and previously treated but ICI-naïve. Tumors were assessed by the investigators per irRECIST and RECIST v1.1 (modified to allow assessment of ≤10 target lesions [≤5 per organ]). Results 145 Patients were enrolled, of whom 105 were ICI-pretreated, 23 were treatment-naïve, and 17 were previously treated ICI-naïve. By the final database lock date (August 24, 2022), the median duration of follow-up for OS was 37.7 months (95% CI 35.2–42.7). Efficacy analyses included 104 ICI-pretreated patients and 22 treatment-naïve patients; 1 patient in either group was excluded as they were negative for clear cell disease. Per irRECIST by investigator assessment, ORR was 62.5% for ICI-pretreated patients (median DOR: 14.1 months), 77.3% for treatment-naïve patients (median DOR: 24.2 months), and 52.9% for previously treated ICI-naïve patients (median DOR: 9.0 months) (Table). Notably, 18-month PFS rates were 38.0% for ICI-pretreated patients, 70.5% for treatment-naïve patients, and 36.1% for previously treated ICI-naïve patients (Table). The median OS was 32.1 months for ICI-pretreated patients, 55.8 months for treatment-naïve patients, and 30.3 months for previously treated ICI-naïve patients; 24-month OS rates were &amp;gt;50% in all groups. Additional efficacy data are included in the Table. For those who had their dose of lenvatinib reduced (per recommended algorithms for standard adverse event [AE] management) the median time to first dose reduction was 2.10 months (range 0.1–16.6) for ICI-pretreated patients (n=75), 6.47 months (range 0.3–33.1) for treatment-naïve patients (n=18), and 2.89 months (range 1.0–12.5) for previously treated ICI-naïve patients (n=10). Overall, treatment-related (TR) AEs were reported in 99.3% of all 145 patients; grade ≥3 TRAEs were reported in 66.2%. The most common TRAE was diarrhea (n=88). Treatment-emergent, clinically significant (CS) AEs and AEs of special interest for pembrolizumab (AEOSIs) were reported in 95.2% and 55.9% of patients, respectively. Hypertension was the most common grade ≥3 CSAE (n=37), severe skin reactions were the most common grade ≥3 AEOSI (n=6). The median time to first onset of CSAEs was 0.64 months; the median time to first onset of AEOSIs was 2.07 months. Conclusions Lenvatinib + pembrolizumab demonstrated promising and durable antitumor activity with a manageable safety profile in patients with metastatic RCC, including in those who were ICI-pretreated. To our knowledge, this represents the largest cohort of ICI-pretreated patients with RCC prospectively treated in a clinical trial. CDMRP DOD Funding: no

Concurrent sintilimab with sequential chemoradiotherapy for unresectable, stage III non-small cell lung cancer: a retrospective study.

Concurrent programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors with sequential chemoradiotherapy (SCRT) have been reported in only a limited number of studies involving patients with unresectable stage III non-small-cell lung cancer (NSCLC). A retrospective study was conducted to systematically analyze the efficacy and safety of the emerging therapy among Chinese patients. We included patients with unresectable, stage III NSCLC who received concurrent sintilimab with chemotherapy or chemotherapy alone for 3-6 cycles, followed by radical radiotherapy at the First Hospital of Jilin University from Dec 15, 2019, to Jul 15, 2022. The primary end point was the objective response rate (ORR). The secondary end points included progression-free survival (PFS), overall survival (OS), 12-month and 18-month PFS rates, the duration of response (DoR), and safety. The retrospective study involved 77 patients, of which 49 receiving concurrent sintilimab with SCRT were assigned to cohort A, and 28 receiving SCRT alone were assigned to cohort B. The ORR was significantly higher in cohort A (79.6%, 95% CI 65.7-89.8) than in cohort B (35.7%, 95% CI 18.6-55.9) (p<0.001). Median PFS was significantly longer in cohort A than in cohort B (NR [95% CI 21.4-NR] vs. 16.0 months [13.0-22.5]; HR 0.375, 95% CI 0.192-0.735; p=0.003). The PFS rates at 12 and 18 months were 84.8% (95% CI 75.0-95.9) and 71.3% (95% CI 58.7-86.7) in cohort A and 75.0% (95% CI 60.6-92.9) and 38.3% (95% CI 23.7-61.7) in cohort B, respectively. Grade 3 or 4 adverse events (AEs) were reported in 19 patients (38.8%) and seven patients (25.0%) in two cohorts, respectively. Grade 3 or 4 pneumonitis or immune-mediated pneumonitis, radiation pneumonitis, and pneumonia occurred in five (10.2%), four (8.2%), and two (4.1%) cohort A patients, and zero, two (7.1%), and two (7.1%) cohort B patients, respectively. Only cohort A reported AE leading to death in one (2.0%) patient (immune-mediated pneumonitis). Concurrent sintilimab with SCRT resulted in a significantly better ORR and longer PFS than SCRT alone, with manageable safety profiles in Chinese patients with unresectable stage III NSCLC.

Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis.

Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor-1 (PD-1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD-1 inhibitor on the advanced HCC beyond oligometastasis. In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD-1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD-1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression-free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM). The 6-, 12- and 24-month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30-0.66; p < .001). The 6-, 12- and 18-month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33-0.63; p < .001) between the two collections. Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD-1 inhibitor led to significant improvements in survival.

Proteomic Discovery of Plasma Protein Biomarkers and Development of Models Predicting Prognosis of High-Grade Serous Ovarian Carcinoma

Ovarian cancer is one of the most lethal female cancers. For accurate prognosis prediction, this study aimed to investigate novel, blood-based prognostic biomarkers for high-grade serous ovarian carcinoma (HGSOC) using mass spectrometry–based proteomics methods. We conducted label-free liquid chromatography–tandem mass spectrometry using frozen plasma samples obtained from patients with newly diagnosed HGSOC (n = 20). Based on progression-free survival (PFS), the samples were divided into two groups: good (PFS ≥18 months) and poor prognosis groups (PFS <18 months). Proteomic profiles were compared between the two groups. Referring to proteomics data that we previously obtained using frozen cancer tissues from chemotherapy-naïve patients with HGSOC, overlapping protein biomarkers were selected as candidate biomarkers. Biomarkers were validated using an independent set of HGSOC plasma samples (n = 202) via enzyme-linked immunosorbent assay (ELISA). To construct models predicting the 18-month PFS rate, we performed stepwise selection based on the area under the receiver operating characteristic curve (AUC) with 5-fold cross-validation. Analysis of differentially expressed proteins in plasma samples revealed that 35 and 61 proteins were upregulated in the good and poor prognosis groups, respectively. Through hierarchical clustering and bioinformatic analyses, GSN, VCAN, SND1, SIGLEC14, CD163, and PRMT1 were selected as candidate biomarkers and were subjected to ELISA. In multivariate analysis, plasma GSN was identified as an independent poor prognostic biomarker for PFS (adjusted hazard ratio, 1.556; 95% confidence interval, 1.073–2.256; p = 0.020). By combining clinical factors and ELISA results, we constructed several models to predict the 18-month PFS rate. A model consisting of four predictors (FIGO stage, residual tumor after surgery, and plasma levels of GSN and VCAN) showed the best predictive performance (mean validated AUC, 0.779). The newly developed model was converted to a nomogram for clinical use. Our study results provided insights into protein biomarkers, which might offer clues for developing therapeutic targets.

A Phase 2 Study of Pembrolizumab (MK-3475) after Autologous Stem Cell Transplantation in Patients with T-Cell Non-Hodgkin Lymphoma

Introduction Peripheral T cell lymphomas (PTCL) are a heterogenous group of diseases that carry a poor prognosis except for ALK+ anaplastic large cell lymphoma (ALCL). Autologous stem cell transplantation (ASCT) in first remission is considered standard of care at most institutions to improve progression free survival (PFS). Despite this, more than 50% of patients will relapse after ASCT. PD-1 blockade has been studied as a treatment modality for PTCL. A phase 1b study evaluated nivolumab in PTCL and showed an ORR of 40% (Lesokhin et al., 2016). Another phase 2 study using single agent pembrolizumab in relapsed and refractory PTCL showed an ORR of 33% (Barta et al.,2019). In this current study, we explored the efficacy of PD-1 blockade as consolidation therapy after ASCT for patients with PTCL in first remission. Methods We conducted a phase II, multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab given after ASCT for several lymphoma subtypes. Arm C enrolled patients with PTCL in 1st remission. The expected 18-month PFS rate after ASCT in chemosensitive T-NHL is ~40-50%. We hypothesized that consolidation treatment with pembrolizumab would improve the 18-month PFS rate to 70%. For the sample size of 21, we would consider the treatment promising if at least 13 patients remained alive and progression-free at 18 months post-ASCT. Pembrolizumab 200 mg IV was administered every 3 weeks up to 8 cycles starting, when possible, within 21 days of post-ASCT discharge. Secondary end points included overall survival (OS), response rate to pembrolizumab in those with measurable disease after ASCT and safety. Treatment response was assessed with PET and CT scans at weeks 10 and 22, and at 12 and 18 months post-ASCT. If radiographic progression was documented at week 10, continued treatment was allowed if the patient was tolerating treatment. Results Twenty-one patients were enrolled between January 2017 and July 2020. The median age was 58 (range 33-73). The most common histology was PTCL NOS (52%). Other histologies included: angioimmunoblastic T-cell lymphoma (19%), extranodal NK/T-cell lymphoma, nasal type (14%), ALK- ALCL (10%) and monomorphic epitheliotropic intestinal T-cell lymphoma (5%). The median number of prior therapies was 1. Prior to ASCT, 90% of the patients were in complete metabolic response (CMR). At post-ASCT baseline, 95% of patients were in CMR. 14 of the 21 patients completed the planned 8 cycles of treatment. Reasons for discontinuing treatment were toxicity (4), progressive disease (PD) (1), withdrawal of consent (1) and COVID-19 (1). Among all subjects, 13 of 21 (62%) were progression-free at 18-months post-ASCT meeting the primary endpoint. Of the remaining 8 patients, 3 had PD and 5 were lost to follow-up with 3/5 patients in CMR (up to months 4, 12 and 12). The one patient with AITL who had stable disease upon study entry achieved a CR after treatment with pembrolizumab. With a median follow-up of 34.8 months, the median PFS was 30.1 months (95% CI: 21.3 - NR) and median OS was 38.7 months. All patients who received at least one dose of study treatment were included in the toxicity assessment (n = 21). Seventeen patients experienced at least one toxicity while on study including grade 1 (n = 5/21; 24), grade 2 (n = 8/21; 38) and grade 3 (n = 3/21; 14). The most common toxicities of any grade were nausea (n = 5/21; 24%), alkaline phosphatase increase (n = 4/21; 19%), diarrhea (n = 4/21; 19%), abdominal pain (n = 3/21; 14%), hypothyroidism (n = 3/21; 14%), alanine aminotransferase (ALT) increase (n = 2/21; 10%), anemia (n = 2/21; 10%), arthralgia (n = 2/21; 10%), and aspartate aminotransferase (AST) increase (n = 2/21; 10%). The most common grade 3 toxicities were abdominal pain (n = 1/21), colitis (n = 1/21), diarrhea (n = 1/21), ALT increase (n = 2/21), AST increase (n = 1/21) and headache (n = 1/21). One patient experienced grade 4 respiratory failure which was unrelated to study treatment. No other grade 4 toxicities or grade 5 toxicities occurred. Conclusion Consolidation therapy after ASCT with pembrolizumab is feasible and led to a favorable PFS, meeting the study's primary endpoint. This is the first study to show a possible role for PD-1 blockade as consolidation therapy in PTCL. Since sensitivity to this therapy is likely variable across PTCL histologic or molecular subtypes, further studies might define a subpopulation most likely to benefit from this approach and justify a larger confirmatory study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chemo-radiotherapy plus durvalumab for loco-regional relapse of resected NSCLC

Backgroundtumor recurrence after NSCLC surgical resection is the most common cause of treatment failure that sharply reduces the patient’s life expectancy. The optimal treatment strategy for loco-regional recurrences developing after surgical resection in patients with non–small-cell lung cancer (NSCLC) is not established yet.This report aims to describe the pattern of relapse, PFS, and OS in patients treated with radio-chemotherapy and durvalumab for loco-regional relapse after surgery.Methods We conducted a multicenter, retrospective study including subjects who underwent surgical resection for NSCLC and were treated with Pacific protocol after loco-regional relapse.ResultsTwenty-four patients met the inclusion criteria. At the time of diagnosis mean age was 65 years (range 47–78), the majority being male (58.3%). The 12-month progression-free survival rate was 68.7%, the 18-month progression-free survival rate was 45.8%, and the 24-month progression-free survival rate was 34.3%. There were three deaths: the 12-month survival rate was 91%, and the 18-month survival rate was 82.8%.ConclusionsIn this article, we propose a treatment strategy that might prolong post recurrence survival in patients with good performance status experiencing loco-regional relapse after surgery.

A phase 1/2 study of onatasertib, a dual TORC1/2 inhibitor, combined with the PD-1 antibody toripalimab in patients with advanced solid tumors (TORCH-2).

2610 Background: Pre-clinical studies suggest synergistic activity of the combination of inhibitors of mTOR with a PD-1 antibody in solid tumors. Here we report initial results of a phase 1/2 open-label, dose escalation and expansion trial of the oral TORC1/2 inhibitor, onatasertib (ATG-008) in combination with toripalimab (tori), a PD-1 monoclonal antibody, in patients (pts) with advanced solid tumors (NCT04337463). Methods: This study consists of two phases: dose escalation and dose expansion. The primary objective in the dose escalation phase was to evaluate safety and tolerability of onatasertib combined with tori, followed by a dose expansion phase to assess antitumor efficacy and verify the safety and tolerability profile of the combination therapy. Primary endpoints included maximum tolerated dose (MTD), recommended phase II dose (RP2D) and efficacy of the combination. Other endpoints included pharmacokinetics, and exploratory biomarkers of drug activity. Prior check point (anti-PD-1, anti-PD-L1, CTLA-4), mTOR and/or PI3K/AKT/mTOR inhibitor therapy was excluded, regardless of PD-L1 expression. Onatasertib was administered orally once a day (QD) at three dose levels (15, 20 and 30mg) in combination with tori at the approved dose of 240 mg, once every 21 days (Q3W). Efficacy assessments are reported based on RECIST1.1 criteria. Results: As of Dec 20, 2021 cut-off, 28 advanced solid tumor pts were enrolled in the study with 10 pts in the dose escalation phase and 18 pts in the dose expansion phase. Median age was 52 years. Baseline ECOG scores were 0 (4 pts) and 1 (24 pts) with a median of 2 prior lines therapy (0-7), 21 pts had stage IV disease. No dose-limiting toxicities were reported in dose escalation phase. The study did not reach MTD. All pts had ≥ 1 TEAEs; 19 (67.9%) pts had grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAEs included lymphocyte count decreased (21.4%), rash (14.3%) and hyperglycemia (10.7%). AEs lead to discontinuation in 2 pts (7.1%). The RP2D for onatasertib was determined to be 15-20 mg in combination with the recommended dose of tori. Among the 21 efficacy evaluable (EE) pts, the ORR was 28.6% (6 pts, 5 confirmed) and DCR was 71.4% (15 pts). In 5 EE pts with cervical cancer, 1 complete response (CR) and 3 partial responses (PR) were observed (all confirmed). One cervical cancer pt with negative PD-L1 expression achieved CR and remains on treatment after 580 days. Two other PRs were seen (one nasopharyngeal carcinoma, one ovarian carcinoma). Median progression free survival (PFS) in the whole cohort was 3.52 months and 18-month PFS rate was 31.2%. Conclusions: Onatasertib in combination with tori is tolerable with encouraging response rates and disease stabilisation in subjects with advanced solid tumors, especially in cervical cancer. Expansion enrolment for cervical cancer is ongoing and updated information will be presented. Clinical trial information: NCT04337463.

Updated Results from CARTITUDE-1: Phase 1b/2Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Patients With Relapsed/Refractory Multiple Myeloma

Updated Results from CARTITUDE-1: Phase 1b/2Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Patients With Relapsed/Refractory Multiple Myeloma

Extended Characterization of Newly Diagnosed Multiple Myeloma (NDMM) Patients with In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy in the Community-Based United States (US) MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation

Extended Characterization of Newly Diagnosed Multiple Myeloma (NDMM) Patients with In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy in the Community-Based United States (US) MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation

Daratumumab, Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: Pooled Analysis of Octans and Alcyone

Daratumumab, Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: Pooled Analysis of Octans and Alcyone

Pomalidomide and Dexamethasone with or without Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Updated Analysis of the Phase 3 Apollo Study

Pomalidomide and Dexamethasone with or without Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Updated Analysis of the Phase 3 Apollo Study