Any-grade Treatment-related Adverse Events Research Articles

Capmatinib plus nazartinib in patients with EGFR-mutated non–small cell lung cancer

PurposeThis phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non–small cell lung cancer (NSCLC). MethodsIn phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200–400 mg bid plus nazartinib 50–150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1–3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0–2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M−; any MET); group 4 (with food; 0–2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1–3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. ResultsThe RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET− (n = 42), T790M+ (n = 29), and T790M− (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). ConclusionCapmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. Clinical trial registrationClinicalTrials.gov NCT02335944

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial.

Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Interim results from a prospective multicenter phase II trial of stratified treatment of localized cervical esophageal squamous cell carcinoma induced by neoadjuvant immunotherapy plus chemotherapy (SCENIC trial).

e16089 Background: Definitive concurrent chemoradiotherapy (dCRT) is the standard treatment for cervical esophageal squamous cell cancer (CESCC). However, salvage esophagectomy poses significant technical challenges in dCRT failures, and optimizing patient selection for dCRT remains an unsolved concern. In this context, we propose a stratified screening strategy by incorporating induction immunochemotherapy, aiming to identify suitable candidates for organ-sparing dCRT and timely surgical treatment. Methods: This prospective multicenter interventional phase II study (ChiCTR2200057732) enrolled patients with clinical stage T2-4NanyM0 (AJCC TNM 8th) resectable CESCC. Eligible participants received induction therapy of intravenous PD-1 inhibitor tislelizumab (200mg, day 1) plus nab-paclitaxel (100 mg/m2, day 1,8,15) and carboplatin (area under curve of 5 mg/mL/min, day 1) of each 21-days cycle, for two cycles. Treatment response was evaluated 4 weeks after the completion of induction therapy, according to the criteria of the CROC trial: Grade 1, remarkable response (RR); Grade 2, limited partial response (LPR); and Grade 3, poor response (POR). Stratified patients would receive different follow-up treatments: dCRT was administered to RR patients, and radical surgery was performed in LPR and POR patients. Tislelizumab was maintained after dCRT in RR patients, and the postoperative adjuvant therapy was dependent on the doctors in the surgery groups. The primary endpoint was the 2-year event-free survival with a planned enrollment of 36 patients in this study. Results: From Jul 2022 to Jan 2024, 28 patients were enrolled. Of these, 22 patients completed the full two-cycle induction therapy and response evaluation. The response after induction immunochemotherapy were RR in 50.0% (11/22), LPR in 31.8% (7/22), and POR in 18.2% (4/22). All of the RR population underwent subsequent dCRT. Among 11 non-RR patients, only 7 cases received esophagectomy, other 4 selected dCRT according to their will. Up to Jan 2024, the median follow-up was 11.0 months (3.5-17.7), all of the RR patients with dCRT were in disease-free survival, 1 LPR and 1 POR patients received dCRT had progression in the primary lesion, and 4 patients underwent surgery had locoregional or distant recurrences. Overall, 24 patients (96%) had any-grade treatment-related adverse events with the most common being leukocytopenia. Four patients (16%) had adverse events of grade 3 or worse, and no treatment-related death occurred. Conclusions: The 1-year survival of RR followed by dCRT appears promising compared to historical data. The strategy of induction immunochemotherapy showed effective in identifying candidates suitable for dCRT in patients with resectable CESCC. Enrollment is ongoing. Clinical trial information: ChiCTR2200057732.

A phase Ib/IIa trial to evaluate the safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced NSCLC.

8533 Background: The combination of immune checkpoint inhibitors with chemotherapy has become the first-line treatment for advanced non-squamous NSCLC with negative driver genes, but not for driver gene-positive tumors. PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. Previous published data indicated that PM8002 has a tolerable safety profile and potential anti-tumor activity in a variety of solid tumors (SITC2022 abstract #725 and ASCO2023 abstract #2536). Here, we report results of PM8002 in advanced NSCLC patients in an ongoing Phase Ib/IIa trial. Methods: Patients with previously untreated advanced non-squamous NSCLC (EGFR/ALK wild-type and PD-L1+; Cohort 6), advanced non-squamous with EGFR mutations who had failed prior EGFR-TKI treatment (Cohort 7), or EGFR/ALK wild-type who had failed anti-PD-1/L1 therapy and platinum-based chemotherapy regiments (NSCLC IO- and PBC-treated) were enrolled into a Phase I/IIa trial. All patients received PM8002 until observations of unacceptable toxicity, disease progression, or consent withdrawal. Tumor responses were evaluated every 6 weeks. The primary endpoint was objective response rate (ORR), with disease control rate (DCR), progression-free survival (PFS), and safety, as secondary endpoints. Results: As of Dec 20, 2023, 61 patients with advanced NSCLC were enrolled and had at least one tumor assessment. Among 61 evaluable patients 16 partial response (PR) and 32 stable diseases (SD) were observed (all cohorts; see individual cohorts in the table below). Any-grade treatment-related adverse events (TRAEs) occurred in 85.2% patients (52/61) with those ≥ Grade 3 at 18% (11/61). Immune-related AEs (irAEs) occurred in 37.7% patients (23/61). Serious adverse events (SAEs) and treatment-related SAEs were observed in 23% (14/61) and 9.8% (6/61) of patients, respectively. The most common TRAEs (≥15%) were hypertension, hypothyroidism, proteinuria, hypoalbuminemia, hypocalcemia, aspartate aminotransferase increase, and lactate dehydrogenase increase. 8.2% (5/61) of patients discontinued PM8002 due to TRAEs. Conclusions: PM8002 showed preliminary antitumor activity and acceptable safety in patients with advanced NSCLC. Monotherapy and combination trials with chemotherapy for different indications are still ongoing. Clinical trial information: NCT05918445 . [Table: see text]

Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 45-month (mo) follow-up from CheckMate 648.

4034 Background: NIVO + chemo and NIVO + IPI are approved for the treatment of advanced ESCC in the US, EU, Japan, and many other countries based on the results from CheckMate 648 (NCT03143153). Here, we report 45-mo follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. The primary endpoints were overall survival (OS) and progression-free survival (PFS) per blinded independent central review (BICR) in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Results: In total, 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 45-mo minimum follow-up, NIVO + chemo and NIVO + IPI demonstrated continued OS benefit and higher 45-mo OS rates vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Duration of response (DOR) was longer (Table) and the proportion of responders with DOR ≥ 45 mo was greater with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (7% and 23% vs 0%, respectively) and all randomized pts (14% and 18% vs 6%). Any-grade treatment-related adverse events (TRAEs) occurred in 96% of pts with NIVO + chemo, 80% with NIVO + IPI, and 90% with chemo; grade 3/4 TRAEs occurred in 49%, 33%, and 37% of pts, respectively. No additional TRAEs leading to discontinuation and no new treatment-related deaths were reported with longer follow-up. Conclusions: After 45 mo of follow-up, NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo, with no new safety signals. These results further support NIVO + chemo and NIVO + IPI as 1L treatment options for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]

Efficacy and safety of regorafenib and/or immune checkpoint inhibitors as a second-line therapy for advanced hepatocellular carcinoma: A real-world study from a single center.

e16165 Background: This study aimed to assess the efficacy and safety of regorafenib and/or immune checkpoint inhibitors (ICIs) as a second-line treatment in patients with pretreated hepatocellular carcinoma (HCC). Methods: Patients diagnosed with advanced HCC who had received regorafenib treatment in our hospital from January 2020 to November 2023 were reviewed. Overall survival (OS) was the primary endpoint. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and toxicity were the secondary end points. Results: Forty-five patients were included with a median age of 61 (31-83) years. Thirty-two patients (71.1%) were in Barcelona Clinic Liver Cancer (BCLC) stage C. Twenty-three patients (51.1%) had extrahepatic metastasis. ICIs were applied to 30 patients (66.7%) at the use of regorafenib. Local treatments were applied to 17 patients (37.8%). The median OS was 14.5 (11.3, 26.4) months in all patients. Regorafenib plus ICIs had a longer survival than regorafenib alone (20.5 [11.6, NA] vs 11.3 [3.0, 13.9] months, P = 0.019). Local treatment had no obvious effect. The median PFS was 6.8 (4.5, 11.7) months in all patients. The median PFS was 9.7 (4.6, 14.5) months in regorafenib plus ICIs that was longer than regorafenib alone with 3.0 (2.0, 8.0) months. Local treatment only showed a trend of prolongation (11.8 [2.5, 22.6] vs 4.7 [3.5, 9.7] months, P = 0.059). The 1-year OS and PFS were 43.2% and 20.0%, respectively. ORR and DCR was 29.0% and 71.0% according to mRECIST criteria, respectively. The most common any-grade treatment-related adverse events (TRAEs) were rash/itching (41.3%), hand-foot syndrome (19.6%), and anorexia (13.0%). Grade≥3 TRAEs occurred in 8.9% (4/45) of the patients and hypertension (4.4%) had the highest proportion. Conclusions: Regorafenib plus ICIs therapy is an effective promising regimen regardless of first-line treatments in advanced HCC. Combined with local treatment only showed a trend of PFS, further prospective research is needed.

Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study

BackgroundProgrammed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3)...

Neoadjuvant chemoradiotherapy combined with sequential perioperative toripalimab in locally advanced esophageal squamous cell cancer

BackgroundProgrammed death 1 (PD-1) inhibitor demonstrated durable antitumor activity in advanced esophageal squamous cell carcinoma (ESCC), but the clinical benefit of perioperative immunotherapy in ESCC remains unclear. This study evaluated...

A phase 1b study of sotorasib combined with panitumumab as second-line treatment of KRAS G12C-mutated colorectal cancer.

128 Background: In the CodeBreaK 101 phase 1b study, sotorasib, a KRASG12C inhibitor, plus panitumumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, showed acceptable safety and promising efficacy for patients with chemorefractory KRAS G12C–mutated metastatic colorectal cancer: an objective response rate (ORR) of 30% and median progression-free survival (PFS) of 5.7 months were observed. Here, we evaluated sotorasib plus panitumumab in the second-line (2L) setting. Methods: CodeBreaK 101 (NCT04185883) subprotocol H includes dose exploration and expansion in multiple cohorts. Patients eligible for the 2L sotorasib plus panitumumab dose-expansion cohort were KRASG12C inhibitor–naïve and had received no more than one prior regimen for metastatic disease. Patients received oral sotorasib at 960 mg daily and IV panitumumab 6 mg/kg every 2 weeks. The primary endpoint was safety. Secondary endpoints included efficacy endpoints. Results: As of May 23, 2023, this cohort was fully enrolled; all 20 patients (50% female, median age 60.0 years) were included in this analysis. All patients received fluoropyrimidine-based treatment and 17 (85%) patients received oxaliplatin-based treatment as first-line therapy. Any-grade treatment-related adverse events (TRAEs) occurred in 19 (95%) patients. The most common any-grade TRAEs were dermatitis acneiform (60%), dry skin (55%), pruritus (45%), and hypomagnesemia (30%). Grade ≥3 TRAEs occurred in 4 (20%) patients and included fatigue, hypomagnesemia, decreased appetite, and rash (5% each). No TRAEs were grade ≥4 or resulted in treatment discontinuation or deaths. Confirmed ORR was 30% (95% CI: 11.9, 54.3). The disease control rate was 90% (95% CI: 68.3, 98.8). At a median follow-up of 11.3 months (95% CI: 5.6, not estimable), median PFS was 8.3 months (95% CI: 4.3, 14.1). Conclusions: This is the first report of safety and efficacy from a 2L cohort evaluating a KRASG12C inhibitor plus an anti-EGFR antibody in KRAS G12C-mutated metastatic colorectal cancer. The toxicities of sotorasib plus panitumumab were consistent with the expected safety profile of the individual agents and with that reported previously for this combination; the ORR was similar to that previously observed for this combination in a more chemorefractory population. The ORR and PFS of sotorasib plus panitumumab compare favorably to current standard approaches in the 2L treatment of metastatic colorectal cancer. Clinical trial information: NCT04185883 .

Abstract LB_A12: Initial results from 2 Phase I studies of NMS-03305293, a selective PARP1 inhibitor

Abstract Background PARP-1 has a well-established role in DNA repair. PARP-1 selective inhibitors are a new subclass of PARPi that offer potential for improved tolerability. NMS-03305293 (NMS-293) is an oral, brain-penetrant PARP-1 selective inhibitor with strong antitumor activity in BRCA mutated preclinical models. Furthermore, NMS-293 is synergistic with temozolomide (TMZ) in glioblastoma mouse models. Methods Two phase I/I-II dose-escalation/expansion studies assessed safety, tolerability, and preliminary antitumor activity of NMS-293. Both are actively recruiting. In PARPA-293-001 (NCT04182516), NMS-293 was administered orally, ranging from 20 mg (QD) to 160 mg (BID) for 21 or 28 days on 28-day cycle in adult patients with advanced/metastatic, relapsed/refractory solid tumors who have exhausted standard treatment options. In PARPA-293-002 (NCT04910022), NMS-293 was administered in a range of doses orally, QD or BID on days 1-7 plus TMZ 150mg/m2 QD on days 1-5 in repeated 28-day cycle in adult patients with recurrent diffuse gliomas. Tumor responses were measured by investigator-assessed RANO criteria. Results The unpooled safety database at the data-cut-off (02-AUG-23), includes 45 patients in PARPA-001 and 21 patients in PARPA-002. PARPA-001 showed an MTD of 100 mg BID for 28 days on a 28-day cycle, a dose with meaningful PK relative to preclinical activity. PARPA-002 dose finding is ongoing with no DLTs as of cutoff date. The most frequent (≥10%) any-grade treatment related adverse events (TRAEs) in PARPA-001 were reversible QTcF prolongation, nausea, asthenia, decreased appetite and vomiting, mainly mild/moderate. In PARPA-002, with discontinuous NMS-293 plus TMZ, no G≥3 TRAEs were reported. The most frequent (≥10%) any-grade TRAEs were: nausea, fatigue, vomiting, decreased appetite, and platelet count decreased, mainly G1 adverse events. Overall, no dose-dependent trends of myelosuppression have been observed. 14 recurrent glioma patients across dose levels in PARPA-002 were evaluable for tumor response. A patient with glioblastoma had confirmed partial response (PR) with duration 7.6+ weeks, remaining on treatment at cutoff date. A patient with grade 3 IDH-mutant astrocytoma had unconfirmed PR with ongoing tumor shrinkage at 16.1+ weeks. A patient with glioblastoma had complete radiological disappearance of enhancing non-target lesions, remaining on treatment at cutoff date. NMS-293 PK profiles showed an increase in exposure with the dose with approximately 5 to 13 hours half-life. Conclusion NMS-293, a PARP-1 selective, brain penetrant inhibitor was well tolerated in phase I clinical trials with no dose dependent trends of myelosuppression. Furthermore, NMS-293 showed encouraging clinical activity in combination with TMZ in difficult-to-treat recurrent glioma patients. Citation Format: Marjolein Geurts, Dorothee Gramatzki, Sara Merler, Matteo Duca, Fabio Girardi, Ugur T. Sener, Domenico Roberti, Grazia Saturno, Patrizia Crivori, Alessia Montagnoli, Lisa Mahnke, Siqing Fu, Paola Gaviani, Kurt A. Jaeckle, Jian Zhang, Yehui Shi, Valentina Guarneri, Michael Weller, Sani H. Kizilbash, Martin J. van den Bent, Michele Milella, Silvia Damian. Initial results from 2 Phase I studies of NMS-03305293, a selective PARP1 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A12.

Subgroup Analysis from a Phase 2, Single-Arm Trial of the Oral PI3Kδ Inhibitor Linperlisib in Patients with Relapsed or Refractory Follicular Lymphoma

Background In our previous phase 2 trial (NCT04370405), linperlisib, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, demonstrated encouraging activity and manageable safety in adult patients with relapsed/refractory (R/R) follicular lymphoma (FL) who had received at least 2 prior systemic therapies. It's crucial to note that FL patients with bone marrow involvement (BMI) generally present more unfavorable prognosis. Here, we present a subgroup analysis from this phase 2 study, which is specifically focused on BMI at baseline. Methods Details of the trial design and study population have been previously reported. In brief, eligible patients (age &amp;gt; 18 years; histologically confirmed relapsed or refractory FL; disease progression post at least 2 prior systemic therapies) received 80 mg linperlisib tablets daily in a 28-day cycle, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC); secondary endpoints included the duration of response (DOR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety profile. For this subgroup analysis, patients were grouped based on the presence or absence of BMI at baseline. For those with baseline BMI, biopsies were evaluated to confirm complete responses. Evaluations of antitumor response were conducted every 2 treatment cycles, following the guidelines of the International Research Working Group. Results As previously reported, 84 patients included in the full analysis set (FAS). By subgroup, 25 had baseline BMI and 59 did not. Baseline characteristics by subgroup are shown in Table 1. In this subgroup analysis, a trend toward higher response rate was seen in R/R FL patients with BMI compared to those without such involvement: ORR based on IRC assessment was 88.0% vs 76.3%; best overall response (BOR) of CR was 24.0% vs 11.9%; BOR of PR was 64.0% vs 64.4%. Patients with BMI had DCR that was consistent with those without BMI (92.0% vs 93.2%). The median DOR and PFS were similar across this subgroup (DOR: 11.7 months vs 13.0 months; PFS: 13.3 months vs 13.7 months) (Table 2). Although the median OS was not reached, 12-month OS rates for patients with and without BMI was 91.7% and 91.5%, respectively (Table 2). Safety was evaluated in all R/R FL patients who had received ≥1 dose of linperlisib. Rates of any-grade treatment-related adverse events (TRAEs) were similar across this subgroup and comparable with the overall population (Table 2). When compared to the overall population, patients without BMI experienced fewer grade ≥3 TRAEs, while a marginally higher incidence of grade ≥3 TRAEs was observed in patients with BMI (Table 2). Conclusions This subgroup analysis indicated that linperlisib is an effective and well-tolerated treatment option for patients with R/R FL, irrespective of BMI. Although minor differences were observed in this subgroup, their significance is limited due to the small sample sizes and probably do not alter the overall clinical benefit of linperlisib. Nevertheless, these findings warrant further investigation.

Alrizomadlin (APG-115) Alone or Combined with Azacitidine (AZA) in Patients (pts) with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) or Relapsed or Progressive Higher-Risk Myelodysplastic Syndrome (HR-MDS): Phase 1b Trial Results

*Drs. Yifan Zhai and Jianxiang Wang are co-corresponding authors. Background Pts with R/R AML and HR-MDS failing hypomethylating agents have limited therapeutic options and relatively dismal outcomes with available therapies. Investigational alrizomadlin is a novel, orally active, potent, small-molecule selective inhibitor that destabilizes the p53-MDM2 complex and activates p53-mediated apoptosis in tumor cells and has shown apoptotic activity in AML and MDS xenograft models, alone and combined with AZA. Here, we present safety and efficacy results of this therapy in these pts. Methods This open-label dose escalation and expansion trial included adults with R/R AML or relapsed/progressed HR-MDS (IPSS-R ≥ 4.5). MTD and RP2D of alrizomadlin ± AZA were determined by dose escalation. Alrizomadlin (100/150/200/250 mg) was administered orally on Days (D) 1-7 in 28-day cycles. In the combination dose escalation group, alrizomadlin (100/150/200 mg) + AZA (75 mg/m 2) was administered orally once daily on D 1-7 in 28-day cycles and at the combination RP2D during dose expansion. Responses were assessed per revised International Working Group (IWG) Response Criteria 2003, ELN 2017 classifications for AML, and IWG 2006 for MDS. Extensive pharmacokinetic (PK) analyses were performed. Results As of June 1, 2023, 29 pts were enrolled in China. In the monotherapy group, 21 pts (median [range] age, 65 [32-76] years; 76.2%, R/R AML) had a median (range) of 2 (1-10) prior lines of therapy. In the combination group, 8 pts (median [range] age of 69.5 [20-76] years; 50%, R/R AML) had a median (range) of 2 (1-4) prior lines of therapy. In both groups, common any-grade treatment-related adverse events (TRAEs; ≥ 20%) were hematologic- and gastrointestinal-related toxicities, hypokalemia, and dizziness, and most grade ≥ 3 TRAEs were hematologic toxicities. No grade ≥ 3 gastrointestinal toxicities were reported (Figure 1). One DLT, a pulmonary embolism (PE), was reported among 6 evaluable patients at the alrizomadlin 100 mg + AZA dose level: a 59-year-old pt with MDS had a prior COVID-19 infection and abnormal coagulation function before (and during) study treatment. The study investigator attributed the PE to the pt's COVID-19 infection, age, primary disease, and long-term bed rest. One pt in each arm discontinued treatment because of AEs. In pts with AML, the overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic recovery (CRi) + partial response (PR) + morphologic leukemia-free state (MLFS). In pts with MDS, ORR was defined as CR + PR + marrow CR (mCR). In the monotherapy group, the ORR and CR/CRi rates among pts with R/R AML were 25% (4/16) and 18.75% (3/16), respectively. Three of 6 pts with MDS that progressed to R/R AML experienced responses, including 2 CRis and 1 MLFS. One of 10 pts with R/R AML treated with venetoclax + HMA experienced a CRi. In the monotherapy cohort, 4 pts with MDS refractory to HMAs were evaluated, of whom 2 experienced an mCR. The monotherapy RP2D was determined as 200 mg. In the combination group, 6 pts had an efficacy evaluation at least once. Among these pts, 3 of 3 with MDS experienced an mCR and 1 of 3 with R/R AML, MLFS. Among 4 pts with prior venetoclax + HMA treatment, 2 with MDS experienced an mCR and 2 with R/R AML showed a half marrow blast reduction at the end of C1 (Table 1). No PK drug-drug interaction between alrizomadlin and AZA was observed. Conclusions Alrizomadlin alone or combined with AZA demonstrated a manageable safety profile and preliminary efficacy in pts with R/R AML and HMA-refractory MDS. An antileukemic effect was observed in both monotherapy and combination settings, including a few pts whose disease failed on prior venetoclax treatment. Evaluation of the alrizomadlin + AZA cohort is ongoing. Internal study (CT.gov) identifiers: APG-115-AC101 (NCT04275518).

A phase 1/2a trial of yttrium-90 radioembolization in combination with durvalumab for locally advanced unresectable hepatocellular carcinoma.

Synergistic effect of radiotherapy and immunotherapy for the treatment of hepatocellular carcinoma (HCC) has been reported. This phase 1/2a pilot trial evaluated preliminary efficacy and safety of combination of radioembolization with yttrium-90 microspheres (Y90-radioembolization) and durvalumab in patients with locally advanced unresectable HCC. Patients with Child-Pugh score ≤7 and locally advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B HCC or BCLC-C disease without extrahepatic metastases, received Y90-radioembolization followed by intravenous durvalumab 1500 mg 7-14 days after Y90-radioembolization and every 4 weeks thereafter. Primary endpoint was time to progression (TTP) assessed by modified RECIST (mRECIST). Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) determined by mRECIST, and safety. All 24 patients enrolled received Y90-radioembolization and 23 received at least one dose of durvalumab. Median follow-up duration was 19.0 months (range, 2.2-24.2). Median TTP was 15.2 months (95% confidence interval [CI], 6.1-not estimated). Median OS was not reached and 18-month OS rate was 58.3% (95% CI, 36.4-75.0). Median PFS was 6.9 months (95% CI, 5.4-15.2). Seven (29.2%) patients had a complete response and 13 (54.2%) had a partial response; ORR was 83.3% (95% CI, 62.6-95.3). Eleven (47.8%) patients experienced any-grade treatment-related adverse events. Two (8.7%) patients had grade 3 treatment-related adverse events (neutropenia and fever). None experienced any treatment-related serious adverse events. In patients with locally advanced unresectable HCC, the combination of Y90-radioembolization and durvalumab demonstrated promising efficacy and safety, warranting further evaluation in large-scale controlled trials.

Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma

AbstractPrevious analyses of the phase 2 KEYNOTE-087 (NCT02453594) trial of pembrolizumab monotherapy demonstrated effective antitumor activity with acceptable safety in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). However, long-term response durability and outcome of patients who receive a second course after treatment discontinuation after complete response (CR) remain of clinical interest. We present KEYNOTE-087 data after >5 years of median follow-up. Patients with R/R cHL and progressive disease (PD) after autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV; cohort 1), salvage chemotherapy and BV without ASCT (cohort 2), or ASCT without subsequent BV (cohort 3), received pembrolizumab for ≤2 years. Patients in CR who discontinued treatment and subsequently experienced PD were eligible for second-course pembrolizumab. Primary end points were the objective response rate (ORR) using blinded central review and safety. The median follow-up was 63.7 months. ORR was 71.4% (95% confidence interval [CI], 64.8-77.4; CR, 27.6%; partial response, 43.8%). Median duration of response (DOR) was 16.6 months; median progression-free survival was 13.7 months. A quarter of responders, including half of complete responders, maintained a response for ≥4 years. Median overall survival was not achieved. Among 20 patients receiving second-course pembrolizumab, ORR for 19 evaluable patients was 73.7% (95% CI, 48.8-90.8); median DOR was 15.2 months. Any-grade treatment-related adverse events occurred in 72.9% of patients and grade 3 or 4 adverse events occurred in 12.9% of patients; no treatment-related deaths occurred. Single-agent pembrolizumab can induce durable responses, particularly in patients achieving CR. Second-course pembrolizumab frequently reinduced sustained responses after relapse from initial CR.

Camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC): A single-arm, phase II trial.

4048 Background: This study (NCT05476380) aimed to evaluate the safety and efficacy of neoadjuvant camrelizumab plus chemotherapy in patients with locally advanced ESCC, and to explore the potential risk factors of tumor immune microenvironment (TIM) which affect the efficiency of immunotherapy. Methods: Patients with resectable locally advanced thoracic ESCC, staged as T1b-4a, N2-3 (≥3 stations), and M0 or M1 lymph node metastasis (confined to supraclavicular lymph nodes) were enrolled. Eligible patients received intravenous camrelizumab (200 mg, day 2) plus paclitaxel (175 mg/m2, day 1) and cisplatin (75 mg/m2, day 1) for three 21-day cycles before surgery. The primary endpoint was major pathological response (MPR), defined as ≤10% residual viable tumor cells in resected tissue. In order to screen out the potential biomarkers, the dissected lymph nodes were collected in the pathological complete response (pCR) and non-pCR groups. The infiltrated immune cells and the status of PD-L1 was evaluated by flowcytometry. Results: From February 20, 2021 to July 7, 2022, 38 patients were enrolled. 34 (89.5%) patients completed the full three-cycle treatment successfully. 34 patients underwent surgery and all received R0 resection. The MPR and pCR rates were 67.6% (23/34) and 17.6% (6/34), respectively. There were 2 (5.9%) patients having complete response of the primary tumor but residual disease in lymph nodes alone (ypT0N+). 32 (94.1%) patients had any-grade treatment-related adverse events, with the most common being leukocytopenia (73.5%). 18 (52.9%) patients had adverse events of grade 3 or worse. No treatment-related deaths occurred. Based on our findings, positive lymph nodes were one of the important reasons that the patients could not achieved pCR. TIM of the lymph nodes were then tested. Compared with MPR group, the infiltrated lymphocyte cells in the non-MPR group decreased from 93% to 52.4% (p = 0.02), the infiltrated CD8+ T cells also decreased from 11.8% to 5.9% (p = 0.02). However, the CD4+ T cells showed no significant difference between the MPR and non-MPR groups (46.2% vs 55%, p = 0.27). The expression of PD-L1 in the immune cells is one of the biomarkers for checkpoint inhibitors. In this trial, the expression of PD-L1 in the CD8+ T cells showed significant difference between the MPR and non-MPR groups (14.5% vs 6.7%, p = 0.02). Myeloid-derived suppressor cells (MDSCs) are a group of vastly heterogeneous immunosuppressive cells derived from immature myeloid progenitors that have been linked to poor patient prognosis and immunosuppression. We found more infiltrations of MDSCs in the non-MPR group compared with the MPR group (9.7% vs 4.7%, p = 0.04). Conclusions: Neoadjuvant camrelizumab combined with chemotherapy shows promising efficacy and good safety in ESCC patients. Poor response to immunotherapy was related to lymph node metastasis in the TIM. Clinical trial information: NCT05476380 .

Randomized phase 3 study of first-line AZD3759 (zorifertinib) versus gefitinib or erlotinib in EGFR-mutant (EGFRm+) non–small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis.

9001 Background: Patients (pts) with EGFRm+ NSCLC have high rates of CNS metastasis, few treatment options, and a poor prognosis. So far there are no solid evidence from head to head phase 3 trials in this setting. The potent EGFR TKI AZD3759 has high blood–brain barrier penetration, preliminary data has shown promising intracranial (IC) and systemic antitumor activity, and a tolerable safety profile. Methods: This was the first phase 3, open-label, multicenter, randomized controlled trial to compare the efficacy and safety of first-line AZD3759 with first generation EGFR TKIs specifically in pts with EGFRm+ (L858R and/or exon 19Del) NSCLC and CNS metastasis. Adult pts were randomized 1:1 to receive AZD3759 (200 mg twice daily) or first generation EGFR TKIs (the control group, gefitinib 250 mg or erlotinib 150 mg once daily). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1. Results: Between Feb 1, 2019, and Jan 12, 2021, 439 pts were randomized: 220 to AZD3759 and 219 to the control group. As of July 12, 2022, median follow-up was 20.4 months (mo) for both. Median PFS (95% CI) was significantly superior with AZD3759 vs the control group (9.6 [8.2–9.7] vs 6.9 [6.3–8.0] mo; HR 0.719, 95% CI 0.580–0.893; p=0.0024). The objective response rate (ORR; BICR/RECIST 1.1) was 68.6% for AZD3759 vs 58.4% for the control group ( p=0.027), with a trend toward longer median duration of response (DoR) with AZD3759 (8.2 vs 6.8 mo; p=0.0997). IC PFS, ORR, and DoR with AZD3759 were all superior vs the control group regardless of the assessor or evaluation criteria. The overall survival was immature. The incidence of any-grade treatment-related adverse events (TRAEs) was similar between the two groups (97.7% vs 94.0%). Grade ≥3 TRAEs occurred in 65.9% (AZD3759) and 18.3% (the control group) of pts. The main TRAEs were skin and subcutaneous tissue events, gastrointestinal system events and abnormal liver function. No new safety signals arose. Conclusions: First-line AZD3759 demonstrated superior systemic and IC antitumor efficacy compared with first generation EGFR TKIs in pts with EGFRm+ NSCLC and CNS metastasis. Adverse events were as expected and manageable. IC antitumor activity. Clinical trial information: NCT03653546 . [Table: see text]

Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: final analysis of KEYNOTE-170

AbstractPrevious analyses of the phase 2 KEYNOTE-170 (NCT02576990) study demonstrated effective antitumor activity and acceptable safety of pembrolizumab 200 mg given every 3 weeks for up to 35 cycles (∼2 years) in patients with relapsed/refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) whose disease progressed after or who were ineligible for autologous stem cell transplantation. The end points included objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR) according to the investigator per 2007 Response Criteria; overall survival (OS); and safety. In this final analysis, median duration of follow-up was 48.7 months (range, 41.2-56.2). The ORR was 41.5% (complete response, 20.8%; partial response, 20.8%). The median DOR was not reached; no patients who achieved a complete response progressed at the data cutoff. The median PFS was 4.3 months; the 4-year PFS rate was 33.0%. The median OS was 22.3 months; the 4-year OS rate was 45.3%. At the data cutoff, 30 patients (56.6%) had any-grade treatment-related adverse events (AEs); the most common were neutropenia, asthenia, and hypothyroidism. Grade 3/4 treatment-related AEs occurred in 22.6% of the patients; no grade 5 AEs occurred. After 4 years of follow-up, pembrolizumab continued to provide durable responses, with promising trends for long-term survival and acceptable safety in R/R PMBCL.

The safety profile of nivolumab plus ipilimumab combination therapy in Japanese patients with renal cell carcinoma: results from post-marketing surveillance.

Nivolumab and ipilimumab combination therapy is approved in Japan for unresectable or metastatic renal cell carcinoma. Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. The observation period was 13weeks. Safety data included treatment-related adverse events with a particular emphasis on the gastrointestinal-related (colitis, enteritis, diarrhoea and gastrointestinal perforation) and liver-related (hepatic failure, hepatic function abnormal, hepatitis and cholangitis sclerosing) treatment-related adverse events that are listed in the risk management plan for nivolumab and ipilimumab combination therapy. Of the 203 patients registered, safety data were available for 159 (119 males/40 females) with a median age of 67years (range 22-88). Seventy-one patients received nivolumab and ipilimumab combination therapy four times per usual clinical therapy, and 33 continued nivolumab monotherapy thereafter. Any-grade treatment-related adverse events were reported in 102 (64.2%) patients and grade≥3 in 63 (39.6%). Hepatic function abnormalities (13.2%), rash (8.8%) and interstitial lung disease (7.5%) were the most common treatment-related adverse events. Five patients died following treatment-related adverse events. Gastrointestinal-related and liver-related treatment-related adverse events occurred in 10 (6.3%; four with grade≥3 treatment-related adverse events) and 27 (17.0%; 19 with grade≥3 treatment-related adverse events) patients, respectively. This post-marketing surveillance in patients with unresectable or metastatic renal cell carcinoma revealed a safety profile for nivolumab and ipilimumab combination therapy consistent with CheckMate 214. Furthermore, no new safety concerns were identified including gastrointestinal-related and liver-related treatment-related adverse events.

Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial.

603 Background: First-line nivolumab plus cabozantinib (N+C) demonstrated superiority over sunitinib (S) with 25.4 mo minimum follow-up (median, 32.9 mo) in patients (pts) with aRCC in the CheckMate 9ER trial. Here, we report survival, response per blinded independent central review (BICR), and safety after 3 y minimum follow-up in all randomized pts and by IMDC risk score. Methods: Pts were randomized 1:1 (stratified by IMDC risk score, tumor PD-L1 expression, region) to N 240 mg flat dose IV Q2W + C 40 mg PO QD vs SUN 50 mg PO for 4 wk (6-wk cycles) until disease progression or unacceptable toxicity (max N treatment, 2 y). Primary endpoint: progression-free survival (PFS) by BICR. Secondary endpoints: overall survival (OS), objective response rate (ORR) by BICR, and safety. Results: In total, 323 pts were randomized to N+C and 328 to S. With 36.5 mo minimum follow-up (median, 44.0 mo), PFS and OS benefits were maintained with N+C vs S in intent-to-treat pts. Median PFS was 16.6 vs 8.4 mo (HR 0.59 [95% CI 0.49–0.71], P &lt; 0.0001) and median OS was 49.5 vs 35.5 mo (HR 0.70 [95% CI 0.56–0.87], P = 0.0014). ORR (95% CI) was higher with N+C vs S (56% [50–62] vs 28% [23–33]), and 13% vs 5% of pts achieved complete response (CR), respectively. Median duration of response was 22.1 vs 16.1 mo for N+C vs S. PFS, OS, and response are reported across prespecified IMDC risk groups in the table. Any-grade treatment-related adverse events (TRAEs) occurred in 97% vs 93% of pts treated with N+C vs S (grade ≥ 3 TRAE, 67% vs 55%). TRAEs led to discontinuation of C only in 10% of pts, N only in 10% of pts, N+C in 7% of pts, N or C in 28% of pts, and S in 11% of pts. Conclusions: After 3 y minimum follow-up, survival and response benefits were maintained with N+C and remained consistent with previous follow-ups. Median OS with N+C improved by 11.8 mo since the previous data cut. Responses with N+C were durable, with higher CR rates with N+C vs S regardless of IMDC risk group. No new safety signals emerged with additional follow-up in either arm. These results continue to support N+C as a first-line treatment for pts with aRCC. Clinical trial information: NCT03141177 . [Table: see text]

Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): 29-month (mo) follow-up from CheckMate 648.

290 Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in CheckMate 648 (NCT03143153), leading to approvals in the US, EU, Japan, and other countries. We report longer follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR). Hierarchical testing was done first in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%, then in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 29-mo minimum follow-up, NIVO + chemo and NIVO + IPI continued to show improvement in OS vs chemo, including higher 24-mo OS rates, in pts with tumor cell PD-L1 ≥ 1% and all randomized pts. Responses were more durable and a larger proportion of responders had a duration of response (DOR) ≥ 24 mo with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (22%, 36%, 13%, respectively) and all randomized pts (21%, 29%, 13%). Additional efficacy data by PD-L1 status will be presented. Any-grade treatment-related adverse events (TRAEs) occurred in 96% (grade 3/4, 49%) of pts with NIVO + chemo, 80% (33%) with NIVO + IPI, and 90% (36%) with chemo. Any-grade TRAEs leading to discontinuation occurred in 35% of pts with NIVO + chemo, 19% with NIVO + IPI, and 21% with chemo. Treatment-related deaths occurred in 2% of pts in each arm. Conclusions: NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit vs chemo, durable objective responses, and acceptable safety profiles with longer follow-up. This further supports each regimen as a new 1L treatment option for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]