Immune-mediated Adverse Events Research Articles

Efficacy and Safety of Pembrolizumab and Chemotherapy in Newly-Diagnosed, Early Unfavorable or Advanced Classic Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study

Introduction: The phase 2 KEYNOTE-C11 study (NCT05008224) evaluates the safety and efficacy of pembrolizumab (pembro) followed by AVD chemotherapy (chemotherapy) and pembro consolidation in patients with untreated, early unfavorable or advanced-stage cHL without radiotherapy. The criteria for study continuation were met at the pre-specified interim futility analysis after pembrolizumab induction and 2 cycles of AVD, with approximately 3 months of follow-up. We present results of an analysis of efficacy and safety in all enrolled patients with an additional 8 months of follow-up. Methods: Patients aged ≥18 years with newly-diagnosed, early unfavorable or advanced stage cHL, received induction with pembrolizumab 200 mg IV on d1 Q3W for 3 cycles, followed by a PET2 to determine response. All patients then received 2 cycles standard dose AVD on d1 and 15 for 2 cycles (chemotherapy phase 1) followed by PET3. Patients who were PET3-negative (Deauville score 1-3) received 2-4 additional cycles AVD based on bulk. Patients aged ≤60 years who were PET3-positive (Deauville score 4-5) received 2-4 cycles of escalated bleomycin plus etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escBEACOPP, chemotherapy phase 2). All patients then received consolidation pembrolizumab 400 mg Q6W for 4 cycles followed by a PET4 assessment. The primary endpoint for this analysis was investigator assessed PET3-negativity response in all treated patients. A posthoc PET analysis was also performed in the actuarial population of all treated patients who reached PET2 or PET3. Results: At data cut-off (Apr 5, 2023), the median (range) follow-up was 11.8 months (9.7-17.6). A total of 146 patients with untreated cHL were enrolled. Median (range) age was 34.5 years (18-78); 32 (22%) patients had bulky disease, 84 (57%) and 62 (43%), respectively, had advanced and early unfavorable disease. Of 146 patients, 137 (94%) had completed pembrolizumab monotherapy, 130 of 136 (96%) who proceeded to chemotherapy phase 1 completed chemotherapy phase 1, and 127 of 130 (98%) completed chemotherapy phase 2 (111 [AVD]; 16 [BEACOPP]). The PET2-negativity rate was 29% and 31% in all treated patients (N=146) and the actuarial population (n=137), respectively. The PET3-negativity rate was 70% and 78% in all treated patients (N=146) and the actuarial population (n=131), respectively. The ORR at end of PET2 and PET3 was 78% and 88%, respectively. Grade ≥3 drug related adverse events (AEs) were reported in 23 of 146 (16%) patients who received pembrolizumab alone or at consolidation, 94 of 136 (69%) patients who received AVD, and in 10 of 17 (59%) patients who received escBEACOPP. Immune mediated AEs were reported in 37 (25%) patients who received pembrolizumab alone and consolidation, most commonly hyperthyroidism (10%) and hypothyroidism (6%). There were no deaths due to study drug related or immune-mediated AEs. Conclusion: Pembrolizumab induction followed by chemotherapy continued to be well tolerated in patients with newly-diagnosed, early unfavorable, or advanced-stage cHL, with 70% achieving a PET3-negative response as assessed by investigator after the initial chemotherapy phase. There were no new safety concerns and study is ongoing.

Safety and Preliminary Efficacy of Sabestomig (AZD7789), an Anti-PD-1 and Anti-TIM-3 Bispecific Antibody, in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma Previously Treated with Anti-PD-(L)1 Therapy

Background Immunotherapies targeting the PD-1/PD-L1 pathway have been shown to induce high response rates in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). However, most responses are partial and not durable. T cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) is implicated as a resistance mechanism following anti-PD-1 therapy, and increased TIM-3 expression has been observed on T cells of patients with cHL post anti-PD-1 therapy. Therefore, we hypothesized that dual targeting of PD-1 and TIM-3 may reinvigorate immune responses and lead to more durable antitumor activity. Sabestomig is a monovalent, bispecific, humanized IgG1 monoclonal antibody that binds PD-1 and a unique epitope in the TIM-3 IgV domain without blocking phosphatidylserine binding, eliciting differential functionality. In preclinical mouse models, sabestomig was more effective at inhibiting growth of solid tumors than treatment targeting only PD-1, and sequential sabestomig after anti-PD-1 therapy increased antitumor responses. Here we report preliminary data from the ongoing dose escalation portion of a Phase I/II, open-label, multicenter study to assess the safety and preliminary efficacy of sabestomig in patients with r/r cHL (NCT05216835). Methods Eligible patients are aged ≥16 years with r/r cHL, an Eastern Cooperative Oncology Group performance status 0-1, at least one positron emission tomography-avid measurable lesion according to modified Lugano Criteria, and exposure to at least 2 prior lines of systemic therapy including a minimum of 3 cycles of an anti-PD-(L)1-based therapy. Sabestomig is intravenously infused over 1 hour following pretreatment with diphenhydramine and acetaminophen every 3 weeks, with planned doses ranging from 2 to 2000 mg across 8 cohorts (A1-A8); cohorts A1 to A4 (2, 7, 22.5 or 75 mg) follow an accelerated titration design with a single patient treated at each dose level, while cohorts A5 to A8 (225-2000 mg) follow a modified toxicity probability interval-2 algorithm. The primary endpoint of the dose escalation part of the study is safety, including dose-limiting toxicities (DLTs). Secondary endpoints include efficacy, pharmacokinetics, and immunogenicity. Data cutoffs were May 17, 2023 for safety and June 20, 2023 for efficacy. Results As of May 17, 2023, 14 patients were treated across the first 6 cohorts (A1-A6; 2-750 mg). They were predominantly male (64.3%) with Stage IV disease (85.7%) and a median age of 41.5 years (range, 25-77). Patients received a median of 6 prior lines of therapy (range, 3-13). Baseline disease characteristics are summarized in Table 1. Four patients received sabestomig 2-75 mg in cohorts A1-A4 (n=1 each), 5 patients received 225 mg in cohort A5, and 5 patients received 750 mg in cohort A6. Median duration of exposure to sabestomig was 8.9 weeks (range, 3.0-34.3) with a median of 3 cycles received (range 1-12). Sabestomig was well tolerated with no Grade ≥3 treatment-related adverse events (AEs) (Table 2). One Grade ≥3 AE occurred, which was fatal (sepsis secondary to gastric ulcer rupture, not related to sabestomig but deemed a DLT by the safety review committee). No immune-mediated AEs were reported, and no AEs led to treatment discontinuation. At the safety data cutoff, treatment was ongoing for 6 patients (42.9%). As of June 20, 2023, 11 patients had their first disease assessment and 4/11 had an objective response based on modified Lugano Criteria: 1 patient in cohort A3 (22.5 mg, a partial response [PR]) and all 3 patients who had their first disease assessment in cohort A6 (750 mg, 2 CRs and 1 PR). Two of these 4 responders (both in cohort A6) had experienced a best overall response of progressive disease during prior anti-PD-1 therapy; the other two initially had a response (1 CR [cohort A6] and 1 PR [cohort A3]) but subsequently progressed on anti-PD-1 therapy. Sustained PD-1 receptor occupancy (≥90%) was observed in peripheral blood at doses ≥225 mg. Conclusions Sabestomig was well tolerated with a manageable safety profile. Early efficacy data at 750 mg is encouraging with objective responses in 3/3 patients who had their first disease assessment, including those who were anti-PD-1 refractory or who relapsed on treatment. Updated data will be presented from ongoing and subsequent patients treated during dose escalation with doses of up to 2000 mg.

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Early-Stage Classical Hodgkin Lymphoma (SGN35-027 Part C)

Introduction Brentuximab vedotin (BV) with AVD is approved in classical Hodgkin lymphoma (cHL) and has demonstrated statistically significant improvement in 6-year overall survival (OS) as compared with ABVD; associated neuropathy and neutropenia may be related to overlapping mechanisms of BV and vinblastine (Ansell 2022). A study in nonbulky early-stage cHL showed preserved efficacy with improved safety when omitting vinblastine in the BV-AD regimen (Abramson 2023). Here, we present results of a phase 2 trial adding nivolumab to the BV-AD regimen without radiation in patients (pts) with nonbulky early-stage cHL (SGN35-027 Part C). Methods SGN35-027 (NCT03646123) Part C enrolled pts with Ann Arbor stage I or II cHL without bulky disease, defined as those with a single node or nodal mass with a <10-cm diameter on computed tomography imaging. Pts received 4 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m 2 [A], and dacarbazine 375 mg/m 2 [D] intravenously on days 1 and 15 of each 28-day cycle). Per protocol, G-CSF prophylaxis was not required for subjects receiving the treatment regimen. The primary endpoint is complete response (CR) rate at end of treatment (EOT). Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and duration of complete response (DOCR), as well as safety and tolerability. The Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) incorporating Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2016) per investigator was used to assess disease response and progression. Exploratory endpoints include baseline and longitudinal circulating tumor DNA analysis on a subset of pts. Results Part C has completed enrollment with 154 pts having received at least 1 dose of study treatment. The majority of treated pts were white (84%), aged <65 years (92%), and female (55%), and presented with nonbulky stage I (11%) or II (89%) cHL. Median age was 31.0 years (range, 18-77). All findings were based on a data cutoff of 22 May 2023. Among 150 efficacy evaluable pts, the ORR was 98% (95% CI, 94.3-99.6) and the CR rate was 93% (95% CI, 87.3-96.3) at EOT (Table 1). Among all pts treated (N = 154), the ORR was 95% (95% CI, 90.9-98.2) and the CR rate was 90% (95% CI, 84.4-94.4) at EOT. With a median follow-up of 15.2 months, 3 of 154 pts (2%) had progressive disease (at 12.5, 16.4, and 24.0 months) and no deaths occurred. The PFS rate at 12 months was 100% (95% CI, 100-100) (Figure 1). A total of 99.2% of pts (95% CI, 94.3-99.9) had a DOR of least 12 months, and 97.2% (95% CI, 91.5-99.1) had a DOCR of at least 12 months. The planned treatment course of 4 cycles was completed by 94% of pts. Forty-four percent received G-CSF, primarily for primary prophylaxis, for 1 or more cycles. Three percent of pts discontinued treatment (all drugs) due to treatment-emergent adverse events (TEAEs). No events of febrile neutropenia were reported. Thirty four percent of pts experienced grade ≥3 treatment-related TEAEs, and 3% experienced grade ≥3 treatment-related peripheral sensory neuropathy. The most common grade ≥3 treatment-related TEAEs were neutropenia (9%), increased alanine aminotransferase (ALT) (7%), and increased aspartate aminotransferase (5%). Treatment-emergent immune-mediated adverse events (IMAEs) occurred in 22% of pts, and grade ≥3 treatment-emergent IMAEs occurred in 7% of pts. The most common treatment-emergent IMAE of any grade was hypothyroidism (6%). Twelve percent of pts experienced treatment-related serious TEAEs. The most common treatment-related serious TEAEs were pyrexia (3%), increased ALT (1%), and peripheral sensory neuropathy (1%). Conclusions Results from SGN35-027 Part C show promising efficacy and an acceptable safety profile for BV and nivolumab in combination with chemotherapy (AN+AD) for pts with nonbulky early-stage cHL. Pts had high ORR (98%) and CR rates (93%) at EOT, and a 12-month PFS of 100% with a median follow-up of 15.2 months. There was a low incidence of grade 3 or higher neuropathy and there were no cases of febrile neutropenia. AN+AD demonstrates encouraging efficacy in nonbulky early-stage cHL and may avoid toxicities associated with radiation, bleomycin, and vinblastine. Follow-up of Part C is ongoing with 92% of pts in long-term follow-up.

Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer

Addition of pembrolizumab to anthracycline-based chemotherapy improves pathologic complete response (pCR) and event-free survival (EFS) in triple-negative breast cancer (TNBC). The efficacy of anthracycline-free chemoimmunotherapy in TNBC has not been assessed. To assess the efficacy of the anthracycline-free neoadjuvant regimen of carboplatin and docetaxel plus pembrolizumab in TNBC. This was an open-label phase 2 clinical trial including a single group of patients with stage I to III TNBC enrolled at 2 sites who received neoadjuvant carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles. Participants were enrolled from 2018 to 2022. Carboplatin (with an area under the free carboplatin plasma concentration vs time curve of 6) and docetaxel (75 mg/m2) plus pembrolizumab (200 mg) every 21 days for 6 cycles. Myeloid growth factor support was administered with all cycles. Primary end point was pathologic complete response (pCR) defined as no evidence of invasive tumor in breast and axilla. The secondary end points were residual cancer burden, EFS, toxicity, and immune biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. Specimens were classified as positive or negative for the 44-gene DNA damage immune response (DDIR) signature and for the 27-gene tumor immune microenvironment (TIM; DetermaIO) signature using predefined cutoffs. Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated using standard criteria. Programmed cell death-ligand 1 (PD-L1) testing was performed using a standard immunohistochemical assay. Among the eligible study population of 115 female patients (median [range] age, 50 [27-70] years) who enrolled from September 2018 to January 2022, 39% had node-positive disease. pCR and residual cancer burden 0 + 1 rates were 58% (95% CI, 48%-67%) and 69% (95% CI, 60%-78%), respectively. Grade 3 or higher immune-mediated adverse events were observed in 3.5% of patients. sTILs, PD-L1, DDIR, and TIM were each predictive of pCR in multivariable analyses. The areas under curve for pCR were 0.719, 0.740, 0.699, and 0.715 for sTILs, PD-L1, DDIR, and TIM, respectively. Estimated 3-year EFS was 86% in all patients; 98% in pCR group and 68% in no-pCR group. The findings of the phase 2 clinical trial indicate that neoadjuvant carboplatin and docetaxel plus pembrolizumab shows encouraging pCR and 3-year EFS. The regimen was well tolerated, and immune enrichment as identified by various biomarkers was independently predictive of pCR. These results provide data on an alternative anthracycline-free chemoimmunotherapy regimen for patients who are not eligible for anthracycline-based regimens and support further evaluation of this regimen as a chemotherapy de-escalation strategy in randomized studies for TNBC. ClinicalTrials.gov Identifier: NCT03639948.

Pediatric model-based dose optimization using a pooled exposure-response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma.

An exposure-response (E-R) safety analysis was conducted across adult and pediatric (<18 years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to <18 years) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab-ipilimumab daily average exposure and time to grade 2+ immune-mediated adverse events (gr2+ IMAEs). Results from the E-R safety model showed ipilimumab, but not nivolumab, exposure to be a statistically significant predictor of gr2+ IMAEs. Significant covariates included sex (41% higher risk for women than men), line of therapy (19% higher for first-line than later-line), and treatment setting (26% lower for adjuvant than advanced melanoma). Younger age and lower body weight (BW) were each associated with a lower risk of gr2+ IMAEs (hazard ratio [HR]: 0.830 for 15-year-olds versus 60-year-olds and 0.84 for BW 52 kg versus 75 kg). For adolescents with melanoma treated with nivolumab in the advanced or adjuvant settings, these results are supportive of nivolumab flat dosing regimens for adolescents greater than or equal to 40 kg and BW-based dosing for adolescents less than 40 kg. These results also support adult weight-based dosing regimens for nivolumab plus ipilimumab in adolescents with advanced melanoma. This analysis suggests that although higher exposures are predicted in adolescents with lower weight compared with adults, there is no predicted immune-mediated safety risk when treated with the approved adult dosing of nivolumab with/without ipilimumab.

Keynote-B68: Updated Efficacy and Safety of Pembrolizumab Every Six Weeks in Relapsed/Refractory Classical Hodgkin Lymphoma or Primary Mediastinal B-Cell Lymphoma

Background: Pembrolizumab 200 mg Q3W demonstrated robust antitumor activity and manageable safety in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and R/R primary mediastinal B-cell lymphoma (PMBCL), resulting in FDA approval. Recently, the FDA granted accelerated approval of pembrolizumab 400 mg Q6W in all approved indications based on data in solid tumors. The global Phase 2 KEYNOTE-B68 trial (NCT04875195) evaluates the efficacy and safety of pembrolizumab 400 mg Q6W in patients (pts) with R/R cHL or R/R PMBCL. We previously reported ORR of 65% for pts with R/R cHL, and 50% for pts with R/R PMBCL with approximately 9 months (mo) of follow up. Here we present data from 66 patients (pts) with an additional 6 mo of follow up. Methods: In this nonrandomized, open-label trial, pts aged ≥18 years with PD-1 inhibitor naïve R/R cHL or PMBCL received 400 mg pembrolizumab Q6W for ≤ 18 cycles, until progression, unacceptable toxicity, or withdrawal. Eligible pts with cHL must have relapsed or failed to respond after ≥1 prior lines of therapy or relapsed or failed to respond after ≥1 prior multiagent lines of therapy, or autologous stem cell transplant (ASCT). Eligible pts with PMBCL must have relapsed or failed to respond after ≥2 prior lines of therapy including rituximab and relapsed or failed to respond to or were ineligible for ASCT. The primary endpoint was ORR per Lugano criteria by investigator. Secondary endpoints were DOR per Lugano criteria by investigator and safety. Exploratory endpoints were PFS per Lugano criteria by investigator and OS. Data cut-off date was May 15, 2023. Results: At data cut-off, 66 pts (60 R/R cHL, 6 R/R PMBCL) were enrolled. Pts had a median age of 32.5 years (range, 19 to 85), and 35 (53%) were female. Overall, 47 (71%) pts discontinued treatment, 34 (52%) due to progressive disease, 8 (12%) due to ASCT, 2 (3%) due to adverse events (AE), 2 (3%) withdrawals and 1 (2%) due to physician decision. A total of 57 pts with cHL and 5 with PMBCL had ≥2 prior lines of therapy. The median follow-up was 15.7 mo (range, 7.8 -22.7) for pts with R/R cHL and 17.5 mo (range, 12.0 - 22.2) with R/R PMBCL. The ORR was 66.7% (95% CI, 53.3 -78.3 [35.0% CR; 31.7% PR]) for pts with R/R cHL, and 50% (95% CI, 11.8 -88.2 [33.3% CR; 16.7% PR]) for R/R PMBCL. The median DOR was 16.6 mo (range, 1.6 -17.0) for pts with R/R cHL and 9.7 mo (range, 2.6 -9.7) for R/R PMBCL. Treatment-related AEs occurred in 26 pts with R/R cHL and 2 with R/R PMBCL. The most common treatment-related AEs were hypothyroidism in 8 pts with R/R cHL and 1 with R/R PMBCL, and neutropenia in 3 pts with R/R cHL and 1 with R/R PMBCL. Grade ≥3 treatment-related AEs occurred in 3 (5%) pts with R/R cHL and 1 (17%) with R/R PMBCL. No grade 5 treatment-related AE occurred. Immune-mediated AEs occurred in 14 (23%) pts with R/R cHL and 1 (17%) with R/R PMBCL. Grade 3 infusion-related reactions and immune-mediated AE of toxic epidermal necrolysis occurred in 2 (3%) pts and 1 (2%) pt, respectively, with R/R cHL. No grade 4-5 immune-mediated AEs occurred in pts with R/R cHL and no grade ≥3 immune-mediated AEs occurred in pts with R/R PMBCL. Antitumor activity is summarized in the Table. Conclusions: Following 15 months of follow-up the ORR and PFS rates in the cHL patient population have increased, further highlighting the consistency to pembrolizumab 200 mg Q3W as observed in KN-087 and KN-204 patient populations. Additionally, no new safety concerns occurred in either cHL or PMBCL patient populations. This KEYNOTE-B68 trial further demonstrates the continued antitumor activity in patients and confirms the acceptability of Q6W dosing in heme indications.

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine for Advanced Stage Classical Hodgkin Lymphoma: Efficacy and Safety Results from the Single Arm Phase 2 Study

Introduction: Brentuximab vedotin (BV) is an antibody-drug conjugate approved for multiple cancer types, including previously untreated stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine (AVD) in adults. The combination of BV and nivolumab are both individually active and well tolerated in patients with cHL and have distinct and complementary mechanisms of action. BV and nivolumab have been previously studied in combination and with multiagent chemotherapy as BV+AD (omitting vinblastine) and N+AVD. It was hypothesized that the combination of BV and nivolumab with doxorubicin and dacarbazine (AN+AD) would result in high response rates and a well-tolerated safety profile with potentially less toxicity than vinblastine-containing regimens. SGN35-027 (NCT03646123; EudraCT Number 2020-004027-17; Part B) is an open-label, multiple-part, multicenter, phase 2 clinical trial. Preliminary results of this study showed promising efficacy (objective response rate [ORR] 93%; complete response [CR] rate 88% at end of therapy [EOT]) with no cases of febrile neutropenia or grade 5 adverse events (AEs) (Lee ASCO 2022). Of the patients with stage III or IV cHL who relapse, most will relapse within 18 to 24 months of treatment initiation. Methods: Part B enrolled patients with stage II bulky mediastinal disease (≥10 cm), stage III, or stage IV cHL. Patients received up to 6 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m 2 [A], and dacarbazine 375 mg/m 2 [D]). The primary efficacy endpoint was CR rate at EOT. Key secondary endpoints included safety and tolerability, ORR, duration of response (DOR), duration of complete response (DOCR), and progression-free survival (PFS). Disease response and progression were assessed by investigator using Lugano Classification Revised Staging System for malignant lymphoma, incorporating Lymphoma Response to Immunomodulatory Therapy Criteria for nodal non-Hodgkin and Hodgkin lymphomas. Results: Fifty-eight patients were enrolled; all but 1 patient received ≥1 dose of study drug (data cutoff 22 May 2023). Median age was 35 years (range, 19-78 years). Among efficacy evaluable patients (n = 56), ORR (CR+ PR) at EOT was 95% (95% CI: 85.1, 98.9); CR rate was 89% (95% CI: 78.1, 96.0) (Table 1). A total of 88.3% (95% CI: 75.7, 94.6) of responders had a DOR of at least 24 months, and 88.4% (95% CI: 76.0, 95.0) of responders had a DOCR of at least 24 months. Seven patients (12%) had a PFS event: 6 with disease progression and 1 who died (sepsis, outside safety reporting period). The estimated PFS rate at 24 months was 88.3% (95% CI: 75.7, 94.6) (Figure 1). Median follow-up was 24.2 months (95% CI: 23.4, 26.9). The most common treatment-related AEs of any grade were nausea (37 patients [65%]), fatigue (28 patients [49%]), and peripheral sensory neuropathy (25 patients [44%]). Of the patients with treatment-related peripheral sensory neuropathy, most (23 of 25 patients [92%]) were grade 1 or 2; the remaining 2 patients had grade 3 peripheral sensory neuropathy. Dose modifications due to peripheral sensory neuropathy occurred in 9 patients (16%). Grade ≥3 treatment-related AEs occurred in 19 patients (33%) (most common: alanine aminotransferase increased in 6 [11%] and neutropenia in 5 [9%]). No febrile neutropenia or Grade 5 AEs occurred. Treatment-related serious AEs (SAEs) occurred in 8 patients (14%). Seven patients (12%) had a treatment-emergent AE that led to discontinuation of BV. Treatment-emergent immune-mediated AEs (IMAEs) occurred in 19 patients (33%); treatment-emergent IMAEs that occurred in ≥5% of patients were hypothyroidism (5 patients [9%]) and pneumonitis and rash maculopapular (3 patients [5%] each). All cases of pneumonitis resolved. Conclusions: The use of 2 active, targeted agents with distinct and complementary mechanisms of action for the frontline treatment of advanced stage cHL resulted in promising efficacy, safety, and tolerability. These results demonstrate continued tolerability of AN+AD with no new safety signals observed. AN+AD may provide a future first-line treatment option for patients with advanced stage cHL; long-term follow-up is ongoing.

Evaluating Oncologists' Practice Patterns and Decision-Making in Locally Advanced or Metastatic Urothelial Carcinoma: The US Physician PARADIGM Study.

The treatment landscape for locally advanced/metastatic urothelial carcinoma (la/mUC) has evolved. This study examined US prescribing patterns and clinical decision-making for first-line (1L) and first-line maintenance (1LM) treatment. US-based oncologists (N = 150) completed an online survey on patient demographics, practice patterns, and important factors considered in 1L/1LM selection. Multivariable logistic regression was used to assess factors associated with more vs less frequent 1L/1LM prescribing. Physician reports estimated that 23% of patients with la/mUC had not received any systemic therapy in the previous 6 months; however, 46% received 1L, 32% received second-line, and 22% received subsequent-line systemic treatments. Of patients who were receiving 1L treatment, 72% were estimated to be receiving 1L platinum-based chemotherapy. Around 69% of patients eligible for 1LM received the treatment. Physicians categorized as frequent prescribers reported overall survival (OS), disease control rate (DCR), and rate of grade 3/4 adverse events (AEs) as factors associated with 1L treatment selection (all P < .05). OS, rate of grade 3/4 immune-mediated AEs, and inclusion in institutional guidelines were reported as attributes used in 1LM treatment selection (all P < .05). Multivariable analysis revealed OS, DCR, and rate of grade 3/4 AEs as important factors in oncologists' 1L treatment selection; academic practice setting and use of Response Evaluation Criteria in Solid Tumors version 1.1 were associated with 1LM use (all P < .05). OS and AEs were found to be relevant factors associated with offering 1L and 1LM treatment. Variability exists in physicians' decision-making in the real-world setting for la/mUC.

PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond

The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3Kδ activity being crucial for immune cell development and function. Genetic hyperactivation of PI3Kδ causes the inborn error of immunity activated phosphoinositide 3-kinase δ syndrome (APDS). Several PI3Kδ inhibitors have been investigated as treatment options for APDS, but only leniolisib has shown both efficacy and tolerability. In contrast, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3Kδ inhibitors due to its structure, specific inhibitory properties selectively targeting the δ isoform without overinhibition of the δ or γ isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action.

Anti-TIGIT Antibody Tiragolumab Alone or With Atezolizumab in Patients With Advanced Solid Tumors

Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in programmed death ligand 1-selected tumors. To evaluate the safety and antitumor activity of the anti-TIGIT antibody tiragolumab and its combination with atezolizumab in patients with advanced solid tumors. The GO30103 open-label, first-in-human phase 1a/1b dose-escalation and dose-expansion nonrandomized controlled trial was conducted at 13 sites in 6 countries (Australia, Canada, France, Korea, Spain, and the US). The start dates were May 23, 2016, for phase 1a and October 11, 2016, for phase 1b. Patients were aged 18 years or older with measurable disease at baseline. The clinical cutoff date was October 1, 2021. Data analysis was performed on January 24, 2022. Patients received fixed-dose intravenous tiragolumab on day 1 of each 21-day cycle (2 mg escalating to 1200 mg) in phase 1a, plus fixed-dose intravenous atezolizumab (1200 mg every 3 weeks) in phase 1b. Patients were treated until disease progression, loss of clinical benefit, or development of unacceptable toxicity. The primary end points included the safety, tolerability, and recommended phase 2 dose (RP2D) of tiragolumab or combination tiragolumab plus atezolizumab. The secondary end point included the investigator-assessed objective response rate (ORR). Counts and percentages are used for categorical variables, and medians and ranges are used for continuous variables. Among the phase 1a (n = 24) and 1b (n = 49) dose-escalation cohorts, the median age was 60 (range, 40-77) and 54 (range, 25-81) years, respectively. More than half of patients were women (14 of 24 [58%] and 25 of 49 [51%]), and more than a third (10 [42%] and 18 [37%]) had received 4 or more prior cancer therapies. No dose-limiting toxicities occurred, and the maximum tolerated dose of tiragolumab was not reached (NR). The most frequent treatment-related adverse events (AEs) were fatigue (5 of 24 [21%]) in phase 1a and pruritus (5 of 49 [10%]) in phase 1b; the majority of AEs were grade 1 or 2. Immune-mediated AEs occurred in 4 of 24 (17%) and 29 of 49 (59%) patients during phases 1a and 1b, respectively (primarily grade 1 or 2). The RP2D of tiragolumab was 600 mg intravenously every 3 weeks, which was tested in phase 1b dose expansion. The confirmed ORR was 0% during phase 1a, with evidence of antitumor activity in 6% of patients (n = 3) during phase 1b. The safety profile of combination tiragolumab plus atezolizumab in phase 1b was similar in the dose-escalation and dose-expansion cohorts. The confirmed ORR was 46% (6 of 13) in the non-small cell lung cancer (NSCLC) cohort (median duration of response [DOR], NR) and 28% (5 of 18) in the esophageal cancer (EC) cohort (median DOR, 15.2 [95% CI, 7.0 to NR] months). In this nonrandomized controlled trial, tiragolumab was well tolerated with or without atezolizumab; no new safety signals were observed. Preliminary antitumor activity was demonstrated for the combination regimen in patients with cancer immunotherapy-naive metastatic NSCLC or EC. ClinicalTrials.gov Identifier: NCT02794571.

Impact of proton pump inhibitors on the onset of gastrointestinal immune-related adverse events during immunotherapy.

The gut microbiota (GM) can influence the pathogenesis of immune-mediated adverse events (irAEs). Proton pump inhibitors (PPIs) can affect the integrity of GM, but their role in promoting irAEs is still poorly understood. In this retrospective single-center cohort study, the primary endpoint was the evaluation of the incidence of gastrointestinal (GI) irAEs in cancer patients on PPIs (exposed) versus cancer patients who were not on PPIs (unexposed). Three hundred and sixty three patients' records (248 M/115F, median age 69) were reviewed. Twenty-three exposed patients (92%) developed GI irAEs while only two unexposed patients (8%) developed GI irAEs (hazard ratio [HR] 13.22, 95% confidence interval [CI] 3.11-56.10, p < 0.000). This HR was confirmed after weighting for the propensity score (HR15.13 95% CI 3.22-71.03, p < 0.000). Chronic PPI use is associated with an increased risk of GI irAES.

Nivolumab and daratumumab combination regimens for the treatment of relapsed and refractory multiple myeloma: results of a randomized phase I/II clinical trial

PurposeThe phase I/II trial CheckMate 039 (NCT01592370) evaluated the safety, tolerability, and efficacy of nivolumab-daratumumab (ND) in patients with relapsed/refractory multiple myeloma (RRMM).MethodsPatients with RRMM were randomized to receive ND with or without pomalidomide-dexamethasone (Pd) in cohort A and ND or D monotherapy in cohort B. The primary endpoint was safety. Secondary endpoints included minimal residual disease (MRD) negativity status, overall response rate (ORR), duration of response, and progression-free survival (PFS).ResultsCohort A (n = 11) was terminated early due to safety concerns observed with immunomodulatory agents and checkpoint inhibitor combinations in other clinical trials. In the small number of patients treated in cohort A, no new safety concerns were observed but patients who received NDPd had numerically more grade 3/4 adverse events (AEs) and serious AEs compared with ND. Grade 3/4 AEs occurring in ≥ 1 patient in the ND group was anemia (3/6 patients); in the NDPd group, these were neutropenia (3/5 patients), upper respiratory tract infection (2/6 patients), and pneumonia (2/6 patients). In cohort B (n = 63), AE rates were similar between ND and D (any-grade: 87.8% vs 95.5%; grade 3/4: 53.7% vs 45.5%). Grade 3/4 AEs occurring in ≥ 1 patient in the ND group were neutropenia (19.5%), anemia (9.8%), thrombocytopenia (9.8%), and bronchitis (7.3%); in the D group these were anemia and pneumonia (both 9.1%). Immune-mediated AEs for ND were consistent with the known safety profile of nivolumab. In cohort A, all patients (5/5) receiving NDPd and 4/6 receiving ND achieved a response. In cohort B, the ORR with ND was numerically higher than D (22/41 [53.7%] vs 9/22 [40.9%]) and both groups had a median PFS of 6.6 months. ND also showed promising MRD negativity results (next-generation sequencing 10-5, 24.0%; next-generation flow 10-5, 22.2%).ConclusionNDPd demonstrated no new safety signals and encouraging efficacy despite its early termination. ND was well tolerated with a manageable toxicity and few AEs leading to discontinuation, and demonstrated a numerically higher ORR but equivalent PFS compared with D. Any clinical benefits to OS require a longer follow-up.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT01592370.

Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot randomised controlled trial

BackgroundSelf-reported penicillin allergies are highly prevalent in hospitalised patients and are associated with poor health and health service outcomes. Critically ill patients have historically been underrepresented in prospective delabelling studies in part due to concerns around clinical stability and reliability of penicillin skin testing. Allergy assessment tools exist to identify low-risk penicillin allergy phenotypes and facilitate direct oral challenge delabelling. PEN-FAST is a clinical decision rule that has been validated to predict true penicillin allergy in a cohort of non-critically ill patients. There is however limited evidence regarding the feasibility, safety and efficacy of direct oral challenges and the use of delabelling clinical decisions rules in the intensive care setting.MethodsCritically ill patients in the intensive care unit (ICU) with low-risk penicillin allergy phenotypes (PEN-FAST score < 3) will be randomised 1:1 to direct oral penicillin challenge (single dose 250 mg oral amoxicillin or implicated penicillin) or routine care, followed by a 2-h observation period. Patients will receive a second oral challenge/observation prior to hospital discharge (with subsequent observation for 2 h). An assessment for antibiotic-associated adverse events will also be undertaken at 24 h and 5 days post each challenge/observation and again at 90 days post-randomisation. The primary outcome measures are feasibility (proportion of eligible patients recruited and protocol compliance) and safety (proportion of patients who experience an antibiotic-associated immune-mediated adverse event or serious adverse event).DiscussionWe will report the feasibility and safety of point-of-care penicillin direct oral challenge in this first randomised controlled trial of low-risk penicillin allergy in critically ill hospitalised patients. Upon completion of the project, important findings will inform the design of planned large prospective multi-centre clinical trials in Australian and international ICUs, further examining safety and efficacy and exploring antimicrobial prescribing-related outcomes following penicillin oral challenge.Trial registrationAustralian New Zealand Clinical Trials RegistryRegistration Number: ACTRN12621000051842Date registered: 20/01/2021https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379735&isReview=true

Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy

Fewer than 5% of patients labeled with a penicillin allergy are truly allergic. The standard of care to remove the penicillin allergy label in adults is specialized testing involving prick and intradermal skin testing followed by an oral challenge with penicillin. Skin testing is resource intensive, limits practice to specialist-trained physicians, and restricts the global population who could undergo penicillin allergy delabeling. To determine whether a direct oral penicillin challenge is noninferior to the standard of care of penicillin skin testing followed by an oral challenge in patients with a low-risk penicillin allergy. This parallel, 2-arm, noninferiority, open-label, multicenter, international randomized clinical trial occurred in 6 specialized centers, 3 in North America (US and Canada) and 3 in Australia, from June 18, 2021, to December 2, 2022. Eligible adults had a PEN-FAST score lower than 3. PEN-FAST is a prospectively derived and internationally validated clinical decision rule that enables point-of-care risk assessment for adults reporting penicillin allergies. Patients were randomly assigned to either direct oral challenge with penicillin (intervention arm) or a standard-of-care arm of penicillin skin testing followed by oral challenge with penicillin (control arm). The primary outcome was a physician-verified positive immune-mediated oral penicillin challenge within 1 hour postintervention in the intention-to-treat population. Noninferiority was achieved if a 1-sided 95% CI of the risk difference (RD) did not exceed 5 percentage points (pp). A total of 382 adults were randomized, with 377 patients (median [IQR] age, 51 [35-65] years; 247 [65.5%] female) included in the analysis: 187 in the intervention group and 190 in the control group. Most patients had a PEN-FAST score of 0 or 1. The primary outcome occurred in 1 patient (0.5%) in the intervention group and 1 patient (0.5%) in the control group, with an RD of 0.0084 pp (90% CI, -1.22 to 1.24 pp). The 1-sided 95% CI was below the noninferiority margin of 5 pp. In the 5 days following the oral penicillin challenge, 9 immune-mediated adverse events were recorded in the intervention group and 10 in the control group (RD, -0.45 pp; 95% CI, -4.87 to 3.96 pp). No serious adverse events occurred. In this randomized clinical trial, direct oral penicillin challenge in patients with a low-risk penicillin allergy was noninferior compared with standard-of-care skin testing followed by oral challenge. In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label. ClinicalTrials.gov Identifier: NCT04454229.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data.

The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed death cell ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. The present study investigated the efficacy and safety of this new standard treatment in a real-world setting. The analysed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 17 Italian centres. The primary endpoint of the study was progression-free survival (PFS), whereas secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model. From February 2022 to November 2022, 145 patients were enrolled. After a median follow-up of 8.5 months (95% CI: 7.9-13.6), the median PFS was 8.9 months (95% CI: 7.4-11.7). Median OS was 12.9 months (95% CI: 10.9-12.9). The investigator-assessed confirmed ORR was 34.5%, and the disease control rate was 87.6%. Any grade adverse events (AEs) occurred in 137 patients (94.5%). Grades 3-4 AEs occurred in 51 patients (35.2%). The rate of immune-mediated AEs (imAEs) was 22.7%. Grades 3-4 imAEs occurred in 2.1% of the patients. In univariate analysis, non-viral aetiology, ECOG PS >0 and NLR ≥3 correlated with shorter PFS. The results reported in this first real-world analysis mostly confirmed the results achieved in the TOPAZ-1 trial in terms of PFS, ORR and safety.

ENDOCRINE TOXICITY OF IMMUNE CHECKPOINT INHIBITORS IN CLINICAL PRACTICE

Relevance: Immunological control points significantly changed cancer therapy worldwide after a new class of inhibitor drugs was registered. Based on clinical studies, this type of treatment was associated with better survival in sensitive patients than cytostatic therapy. Checkpoint inhibitors exert their effect by regulating the immune response to malignant cells, blocking the usual inhibitory pathways of T-cell regulation. The receptors of cytotoxic T-lymphocytic antigen-4 (CTLA-4) and programmed cell death protein (PD-1) or its associated ligand (PD-L-1) are the target of inhibitors. CTLA-4 acts at an early stage of triggering an antigenic response, and PD-1 and PD-L-1 act by modulating interaction with peripheral tissue&#x0D; However, treatment with checkpoint inhibitors (ICTs) is accompanied by a wide range of immune mediated adverse events associated with the activation of the immune system. Despite the positive effect on survival, side effects with endocrine effects were noted in about 10% of patients.&#x0D; The study aimed to assess the incidence of immune mediated adverse events from the thyroid gland in clinical practice in patients with different localization of malignant tumors in the first and subsequent lines of therapy with checkpoint inhibitors.&#x0D; Methods: The study utilized anamnestic, laboratory, and instrumental tests. Laboratory analysis included determining the blood levels of TSH, T3, T4, ACTH, and cortisol. Data analysis was carried out using the Microsoft Excel program.&#x0D; Results: The frequency of development of immune mediated thyroiditis against the background of therapy with blockers of control points of the immune pathway in our observation was 29%. The debut of thyroid disorders was diagnosed in the first 12-16 weeks of therapy, beginning with hyperthyroidism against the background of thyroid destruction, followed by a transition to persistent hypothyroidism after 1-3 months.&#x0D; Conclusion: When analyzing the safety profile of ICTs in patients in our study, immune mediated adverse reactions did not differ in frequency and spectrum from world practice. The spectrum of toxicity did not depend on the localization of the tumor. Early diagnosis of thyroid lesions necessary for optimal and effective treatment can be carried out using laboratory tests. Knowing the timing of the development of adverse events during ICT therapy allows timely diagnosing and correcting complications from the thyroid to continue effective therapy.

ENDOCRINE TOXICITY OF IMMUNE CHECKPOINT INHIBITORS IN CLINICAL PRACTICE

Relevance: Immunological control points significantly changed cancer therapy worldwide after a new class of inhibitor drugs was registered. Based on clinical studies, this type of treatment was associated with better survival in sensitive patients than cytostatic therapy. Checkpoint inhibitors exert their effect by regulating the immune response to malignant cells, blocking the usual inhibitory pathways of T-cell regulation. The receptors of cytotoxic T-lymphocytic antigen-4 (CTLA-4) and programmed cell death protein (PD-1) or its associated ligand (PD-L-1) are the target of inhibitors. CTLA-4 acts at an early stage of triggering an antigenic response, and PD-1 and PD-L-1 act by modulating interaction with peripheral tissue&#x0D; However, treatment with checkpoint inhibitors (ICTs) is accompanied by a wide range of immune mediated adverse events associated with the activation of the immune system. Despite the positive effect on survival, side effects with endocrine effects were noted in about 10% of patients.&#x0D; The study aimed to assess the incidence of immune mediated adverse events from the thyroid gland in clinical practice in patients with different localization of malignant tumors in the first and subsequent lines of therapy with checkpoint inhibitors.&#x0D; Methods: The study utilized anamnestic, laboratory, and instrumental tests. Laboratory analysis included determining the blood levels of TSH, T3, T4, ACTH, and cortisol. Data analysis was carried out using the Microsoft Excel program.&#x0D; Results: The frequency of development of immune mediated thyroiditis against the background of therapy with blockers of control points of the immune pathway in our observation was 29%. The debut of thyroid disorders was diagnosed in the first 12-16 weeks of therapy, beginning with hyperthyroidism against the background of thyroid destruction, followed by a transition to persistent hypothyroidism after 1-3 months.&#x0D; Conclusion: When analyzing the safety profile of ICTs in patients in our study, immune mediated adverse reactions did not differ in frequency and spectrum from world practice. The spectrum of toxicity did not depend on the localization of the tumor. Early diagnosis of thyroid lesions necessary for optimal and effective treatment can be carried out using laboratory tests. Knowing the timing of the development of adverse events during ICT therapy allows timely diagnosing and correcting complications from the thyroid to continue effective therapy.

Pembrolizumab Every 6 Weeks Versus Every 3 Weeks in Advanced Non-Small Cell Lung Cancer.

The survival benefits and adverse effects of pembrolizumab 2 mg/kg intravenously (IV) every 3 weeks (Q3W) in advanced non-small lung cancer (NSCLC) are well documented in the literature. Based on pharmacokinetic models, a pembrolizumab 4 mg/kg IV every 6 weeks (Q6W) dosing regimen is also approved in some countries. To date, there is no direct comparison in the literature between these 2 regimens in advanced NSCLC. This retrospective study included 80 patients with advanced NSCLC who received pembrolizumab monotherapy 4 mg/kg Q6W between March 1, 2020 and December 31, 2021 and 80 patients with advanced NSCLC who received pembrolizumab monotherapy 2 mg/kg Q3W between January 1, 2017 and January 15, 2019 at Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). The primary outcomes of this study were to compare overall survival (OS), progression-free survival (PFS) as well as the occurrence and severity of immune-mediated adverse events (AEs) in patients with advanced NSCLC who received pembrolizumab Q6W vs Q3W. Data cutoff date was December 15, 2022. Median follow-up was 14.5 ± 8.6 months in the Q6W group and 18.3 ± 19.6 months in the Q3W group. Median PFS was 6.9 months (CI 95% 5.0-10.7) in the Q6W group vs 8.9 months (CI 95% 5.6-14.1) in the Q3W group (adjusted HR 1.27 (CI 95% 0.85-1.89), P = .25). Median OS was not reached in the Q6W group vs 20.5 months (CI 95% 13.7-29.8) in the Q3W group (adjusted HR 0.80 (CI 95% 0.50-1.29), P = .36). Immune-mediated AEs of grade ≥ 3 occurred in 18% of patients in the Q6W group and in 19% of those in the Q3W group. In this unicentric retrospective study, the pembrolizumab Q6W dosing regimen was comparable to the Q3W in terms of OS, PFS, and toxicity.

Heparin-induced thrombocytopenia: An illustrated review

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect from unfractionated or low-molecular-weight heparin that results in thrombocytopenia and potentially catastrophic thrombosis. HIT occurs due to the development of platelet-activating antibodies against multimolecular complexes of platelet factor 4 and heparin. Given the frequency of thrombocytopenia and heparin use among hospitalized patients, calculation of the 4Ts Score is recommended to identify patients at increased likelihood of HIT and direct further evaluation. In patients with an intermediate or high probability 4Ts Score, an immunoassay and functional assay are recommended to confirm or refute the diagnosis of HIT. Heparin avoidance and initiation of nonheparin anticoagulation are the mainstays of acute HIT management. In this illustrated review, we provide visual summaries of the diagnosis and management of HIT, highlighting connections between pathophysiology and clinical care as well as summarizing efforts in quality improvement in the field. We further emphasize common pitfalls and pearls in diagnosis and management to encourage evidence-based care. We include graphical representation of the unique challenges of HIT with cardiopulmonary bypass and also delineate autoimmune HIT and its subtypes.

Updated Findings of the Phase II LCMC3 Trial of Lung Cancer Patients

Lung Cancer: Lung CancerResults from an exploratory analysis of the Phase II LCMC3 trial showed that patients with resectable Stage IB-IIIB non-small cell lung cancer (NSCLC) who received adjuvant atezolizumab following neoadjuvant atezolizumab and resection had improved disease-free survival compared with those who were not administered adjuvant atezolizumab. These findings, presented during the 2023 European Lung Cancer Congress, also demonstrated a trend toward improved overall survival among patients who underwent adjuvant atezolizumab (Abstract 145MO). “Neoadjuvant chemoimmunotherapy (IO) treatment without adjuvant treatment in CheckMate 816 has shown to improve pathologic responses and event-free survival outcomes,” noted study author David P. Carbone, MD, PhD, the Barbara J. Bonner Chair in Lung Cancer Research and Director of the James Thoracic Center at The James Ohio State University Comprehensive Cancer Center. “However, it is completely unclear what the role of adjuvant immunotherapy is after neoadjuvant immunotherapy and there is no current study testing the role of adjuvant IO.” LCMC3 (NCT02927301) is an open-label, single-arm, Phase II study of neoadjuvant followed by optional adjuvant atezolizumab (anti-PD-L1) in resectable NSCLC. The primary endpoint—major pathological response (MPR)—was met with an observed MPR rate of 20 percent after neoadjuvant atezolizumab in patients without EGFR or ALK alterations who underwent surgery (Nature Med 2022; doi: 10.1038/s41591-022-01962-5). Carbone and colleagues report updated disease-free survival, overall survival, and safety data from patients who received adjuvant atezolizumab versus those who did not. Methods & Findings Patients eligible for this study included those 18 years or older who had Stage IB-IIIA or select IIIB NSCLC, as well as an ECOG performance status of 0-1. The primary endpoint was major pathologic response (≤10% viable tumor cells). Secondary endpoints included pathologic response by PD-L1 and radiographic response by PD-L1, TMB, neoantigen, and GEP. Disease-free survival, overall survival, and biomarkers were exploratory endpoints. Safety was also examined during the adjuvant phase. Study participants received neoadjuvant atezolizumab (1,200 mg IV for ≤2 cycles) followed by surgery. Individuals without disease progression had the option to undergo adjuvant atezolizumab every 3 weeks for ≤12 months. With a data cutoff of October 21, 2022, the primary efficacy population included 137 patients without EGFR/ALK alterations who had surgery and MPR assessment. Of those, 53 (39%) received adjuvant atezolizumab and 84 (61%) did not. The baseline characteristics between these two groups were generally well-balanced, according to Carbone. However, he did note that patients who received adjuvant atezolizumab had a higher rate of squamous NSCLC (47% vs. 31%). They were also more likely to have a PD-L1 tumor proportion score (TPS) of 50 percent or higher (40% vs. 27%) and MPR status (42% vs. 8%) when compared to their counterparts who did not receive adjuvant atezolizumab. Study authors reported an updated 3-year disease-free survival and overall survival rate for the entire cohort of 72 percent and 82 percent, respectively. Disease-free and overall survival rates for Stage I/II were 75 percent and 82 percent, and 68 percent and 81 percent for Stage III. In the MPR-evaluable population, the 3-year disease-free survival rate was 83 percent for those who were given adjuvant atezolizumab versus 64 percent for those who did not receive this treatment. Among patients without MPR (n=108), Carbone reported a 3-year disease-free survival of 80 percent for individuals who underwent adjuvant atezolizumab compared with 62 percent for those who did not. Three-year overall survival was 87 percent and 75 percent, respectively. Carbone reported no unexpected safety findings. Among patients in the adjuvant atezolizumab safety population (n=57), any-grade adverse events (AEs) were observed in 96 percent of patients, including Grade 3/4 (40%) and Grade 5 (5%) adverse events. Treatment-related adverse events of any grade were reported in 63 percent of patients. Twenty-one percent had a Grade 3 treatment-related adverse event. Study authors reported that 23 percent of patients experienced any-grade AEs that led to treatment discontinuation, including 19 percent with Grade 3/4 (19%) and Grade 5 (2%) adverse events. Immune-mediated adverse events were seen in 46 percent of patients treated with adjuvant atezolizumab. This included 16 percent with a Grade 3/4 event. Study authors reported that 33 percent of patients experienced any-grade immune-mediated treatment-related adverse events with 16 percent being Grade 3/4. Significance & Implications This exploratory analysis suggests that LCMC3 patients with resectable NSCLC who received adjuvant atezolizumab may have improved disease-free survival and showed a trend toward improved overall survival when compared with those who did not receive adjuvant atezolizumab, according to Carbone. “The non-MPR subgroup also showed a trend toward improved disease-free survival and overall survival in patients who received adjuvant atezolizumab,” he said, while also emphasizing that adjuvant atezolizumab was well-tolerated with no new safety concerns. “This single-arm study showed that outcomes were better than anticipated in patients who received adjuvant atezolizumab, which may prompt further studies of IO monotherapy,” Carbone concluded. Catlin Nalley is a contributing writer.