IMPROVED PCR RATES WITH COMBINATION DURVALUMAB, OLAPARIB AND PACLITAXEL IN BREAST CANCERS
CT011 - Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL
The phase 2 I-SPY 2 trial testing the combination of durvalumab, olaparib and paclitaxel in HER2-negative breast cancers was presented by Lajos Pusztai, MD, DPhil (Yale Cancer Center). Given the biological and preclinical evidence of potential synergy between these treatments, this study had the primary goal of increasing pathologic complete response (pCR) rates in HER2- tumors, including those that were HR+/HER2-, as well as triple negative tumors. Patients were unselected for homologous repair deficiency (HRD) and BRCA status.
The experimental treatment, including twelve weeks of durvalumab, olaparib and paclitaxel followed by doxorubicin/cyclophosphamide, was received by 73 patients. The control group included 299 patients receiving chemotherapy alone. Across all HER2- patients in the trial, the durvalumab regimen increased the estimated pCR rate from 20% with control to 37%, pointing to an 81% predicted probability of success in a future phase 3 trial. The largest estimated pCR rate was calculated for triple-negative cancers treated with durvalumab/olaparib, at 47% compared to 27% with control. The durvalumab/olaparib treatment reduced residual cancer burden across almost all RCB categories as well. The safety profile was as expected, with 19% of patients on the experimental arm experiencing an immune-related event. Biomarker analyses indicated that, regardless of treatment or breast cancer subtype, immune-rich tumors showed higher pCR rates. HR+ tumors with an ultra-high MammaPrint signature derived all of the benefit from the experimental treatment in the HR+ subgroup. This study demonstrated preliminary efficacy; however, the immune related adverse event rates and the financial toxicity have to be considered. Confirmatory randomized trials stratified for PD-L1 expression and HRD and BRCA status are required, as stated by discussant Dr. Pamela Munster, University of California, San Francisco.
ADDITION OF ATEZOLIZUMAB BOOSTS EFFICACY OF COBIMETINIB AND VEMURAFENIB IN FRONT-LINE MELANOMA
CT012 - Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial
Grant A. McArthur, PhD (Peter MacCallum Cancer Centre) discussed the phase 3 IMspire150 trial of atezolizumab, cobimetinib and vemurafenib as front-line treatment for BRAFV600-mutant melanoma. As inhibitors of both BRAF and MEK (such as cobimetinib and vemurafenib) may lead to a downregulation of immunosuppressive immune cells and increased tumor infiltration of T cells, the combination of an anti-PD-L1 therapy with BRAF and MEK inhibitors was explored with the primary goal of extending progression-free survival.
A total of 514 patients received cobimetinib and vemurafenib in combination with either atezolizumab or placebo and were followed for nearly 19 months. The primary goal of extended PFS was met: the atezolizumab arm demonstrated a median PFS of 15.1 months versus 10.6 months (p=0.025, investigator-assessed), a benefit which was carried over all prognostic disease subgroups. However, when assessed by an independent review, the PFS statistical significance between arms was not present. The overall response rates between the arms were similar (66 vs. 65%), but, as may be expected with immune checkpoint inhibitors, the duration of response on the atezolizumab treatment was greatly extended by over eight months. Safety profiles were as expected. Given the changes that have occurred in the melanoma treatment landscape since this study was initiated (namely, emergence of frontline treatment with anti-PD-1 and anti-CTLA-4 rather than inhibitors of BRAF and MEK), while this study was positive, the results need to be compared against the combination of PD-1 and CTLA-4 inhibition which is current standard therapy for melanoma.
NO BENEFIT FROM ADDITION OF ATEZOLIZUMAB FOR MCRPC
CT014 - IMbassador250: A phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC)
The phase 3 IMbassador250 trial of enzalutamide with or without atezolizumab for mCRPC was presented by Christopher J. Sweeney, MBBS (Dana-Farber Cancer Institute). Patients had progressed on previous abiraterone and docetaxel or were not candidates for a taxane regimen and were evaluated in this study for the primary endpoint of overall survival.
Median overall survival was 15.2 months in patients receiving combination therapy (n=379) and 16.6 months with enzalutamide alone (n=380), giving an OS hazard ratio of 1.12 (p=0.28). Therefore, this trial did not meet its primary endpoint, and the study was terminated. Subgroup analyses indicated similar outcomes, with no evidence of benefit for the addition of atezolizumab. Radiographic PFS and time-to-PSA progression were nearly identical in both treatment arms. The frequency of treatment-related adverse events was higher in the combination arm, but the overall profile was as expected. This negative study points to the great difficulty that immunotherapies have faced in prostate cancer, hypothesized to be due to the lack of T cells in previously-treated prostate cancer and impaired immune responses after many prior treatments. In order for immunotherapies to impact mCRPC, additional combination regimens are likely warranted. Dr. Padmanee Sharma (MD Anderson), the discussant for this abstract, advised future preclinical investigation of rational immune mechanism strategies for transforming “cold” tumors into immune responsive disease.
VACCINATION MAY BOOST IMMUNE RESPONSES IN CERVICAL CANCER
CT033 - Efficacy and safety results of pembrolizumab combined with GX-188E, a therapeutic DNA vaccine administration in patients with HPV 16- and/or 18- positive advanced cervical cancer: Phase II interim analysis results
Jung Won Woo, PhD (Genexine, Inc.) presented an interim analysis of a phase 2 trial of pembrolizumab in combination with GX-188E vaccination, a therapeutic DNA vaccine targeting HPV 16/18, in advanced cervical cancer that had failed all standard-of-care therapies. For this presentation, 36 patients were enrolled with 28 included in the safety and 26 in the efficacy populations, and outcomes were compared to a previous study (KEYNOTE-158) of pembrolizumab monotherapy with the primary endpoint of overall response rate.
The overall response rate after at least 45 days of treatment was 42.3% in the overall efficacy population, including four complete responses. All of the CRs were experienced by patients with PD-L1-positive, HPV16-positive squamous cell cervical carcinoma. Responses were durable, ranging from 6 to 16.8 months. Higher rates of response were noted in PD-L1-positive tumors overall. When compared to the ORR of 14.3% in the previous pembrolizumab monotherapy study, a potential synergy from the vaccination was noted. Antigen-specific immune responses were observed in the majority of patients as well, with all responders demonstrating T cell responses by IFN-gamma ELISPOT. The safety profile of the combination treatment was as expected. This study therefore points to the ability to induce tumor-specific immune responses through vaccination strategies in cervical cancer.
PTPN22: A NOVEL SYSTEMIC IMMUNE TARGET
3398 - PTPN22 is a systemic target for augmenting antitumor immunity
The potential of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) in anti-tumor immune responses was discussed by Won Jin Ho, MD (Johns Hopkins University). By exploring GWAS studies of autoimmune disorders, PTPN22 was identified as a potential immunotherapy target, as it plays a key role in T cell activation, negatively regulating T cell signaling.
PTPN22 expression was found to correlate with inflammatory gene signatures and immune inhibitory markers across many cancer types. Using PTPN-knock-out mice, tumor growth was found to be inhibited relative to wild-type mice, with higher levels of immune infiltrates in tumors grown in KO mice. Knock-out mice also demonstrated enhanced TCR signaling and higher PD-1 expression, leading to a higher response to PD-1 blockade therapy than in wild-type mice. A small-molecule inhibitor of PTPN22 was developed, known as L1, and administration in wild-type mice resulted in a similar phenotype to the PTPN22-knock-out mice, decreasing tumor growth and increasing immune infiltration. Given these encouraging results, the investigators are pursuing studies to translate these findings into the clinic.
BENEFITS FOR SMALL CELL LUNG CANCER WITH CAMRELIZUMAB AND APATINIB
CT083 - Camrelizumab plus apatinib in extensive-stage small-cell lung cancer (PASSION): A multicenter, two-stage, phase 2 trial
Jie Wang, MD (Chinese Academy of Medical Sciences) discussed the phase 2 PASSION trial of camrelizumab and apatinib in extensive-stage small cell lung cancer. Patients in this study received previous platinum-based chemotherapy and were evaluated for overall response rate. Three treatment arms were initially tested: apatinib dosed daily, QD with 5 days on and 2 days off, or QD with 7 days on and 7 days off, all in addition to camrelizumab Q2W. The daily dosing regimen was selected to expand to a total of 47 patients.
The overall response rate in the expanded cohort was 34%, comprising entirely of partial responses. The ORR was slightly higher in chemotherapy-sensitive patients (those who relapsed more than 90 days after chemotherapy treatment) at 37.5% compared to 32.3% in the chemotherapy-resistant population. Responses were maintained for a median of 6.2 months in the expanded cohort, and the median overall survival was 8.4 months in the same population. The most common treatment-related adverse events included hypertension (25% grade 3+), increased AST, and decreased white blood and platelet counts. The authors are pursuing additional studies based on these promising findings.
STK11 AND KEAP1 MUTATIONS DO NOT APPEAR TO IMPACT PEMBROLIZUMAB EFFICACY IN NSCLC
CT084 - Relationship between STK11 and KEAP1 mutational status and efficacy in KEYNOTE-042: pembrolizumab monotherapy versus platinum-based chemotherapy as first-line therapy for PD-L1-positive advanced NSCLC
The impact of STK11 and KEAP1 mutations on outcomes in the KEYNOTE-042 study were presented by Byoung Chul Cho, MD, PhD (Yonsei University). Whole-exome sequencing (WES) was utilized to analyze both tumor tissue and matched normal DNA from blood. Of all patients in the 042 trial, 34% (429/1274) had both samples available for testing and were included in this analysis.
Mutations in STK11 were found in 7.7% of patients, while 14.9% had KEAP1 mutations and 2.8% of patients had both. Mutations in both markers were more common in patients with non-squamous NSCLC than in those with squamous histology. PD-L1 TPS was found to be lower in STK11-mutated tumors, while no correlation between PD-L1 and KEAP1 was observed. Mutations in either marker were associated with higher tumor mutational burden. The ORR, PFS and OS of patients treated with pembrolizumab were similar regardless of STK11 or KEAP1 status; however, tumors with STK11 mutations demonstrated lower chemotherapy efficacy than those tumors without the mutation. As in the entire KEYNOTE-042 study, pembrolizumab was associated with improved outcomes in all patient subgroups. Therefore, STK11 and KEAP1 status do not appear to impact immune checkpoint inhibition outcomes in NSCLC patients.
POSITIVE STUDY OF ATEZOLIZUMAB PLUS COBIMETINIB IN BILIARY TRACT CANCERS
CT043 - A multicenter randomized phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): A NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study
Biliary tract cancers were treated using atezolizumab with or without cobimetinib in a trial presented by Mark Yarchoan, MD (Johns Hopkins University), representing the first randomized trial in this difficult-to-treat disease. Patients with previously-treated metastatic disease were evaluated for the primary endpoint of progression-free survival.
Seventy-seven patients were treated on the study between the two arms. The PFS endpoint was met, with median values of 57 days with atezolizumab monotherapy and 111 days with the combination regimen (p=0.0268). The disease control rate was also higher with the combination treatment, at 45.2% compared to 32.4%. There was also some indication that patients with intrahepatic cholangiocarcinoma drove the benefit of the combination treatment. Following combination treatment, an increased CD8/FoxP3 ratio was found in tumor samples. A higher incidence of grade 3 treatment-related adverse events was noted in the combination arm, with 44.7% compared to 38.5% of patients experiencing such an event, and there was a trend toward higher treatment discontinuation due to adverse events with the combination. This combination treatment therefore represents a potential treatment option in a typically immunotherapy-unresponsive disease.
BIOMARKERS FOR BENEFIT OF ATEZOLIZUMAB + BEVACIZUMAB IN HCC IDENTIFIED
CT044 - Genomic correlates of clinical benefits from atezolizumab combined with bevacizumab vs. atezolizumab alone in patients with advanced hepatocellular carcinoma (HCC)
Andrew X. Zhu, MD, PhD (Massachusetts General Hospital and Jiahui International Cancer Center) presented an exploratory analysis of genetic correlates in the Phase 1b GO30140 trial. Patients received atezolizumab as monotherapy or in combination with bevacizumab for management of unresectable hepatocellular carcinoma, and archival tumor tissues or fresh biopsies prior to treatment were analyzed using whole-exome sequencing and RNAseq.
Tumor mutation burden was not associated with responses or progression-free survival in patients treated with atezolizumab and bevacizumab combination therapy. However, a number of gene signatures indicated higher likelihoods of response and PFS. The high presence of immune genes correlated with response, including genes involved in interferon responses, complement activation, and markers of exhaustion. On the other hand, gene signatures for Notch signaling and angiogenesis were higher in non-responding tumors. Higher expression of PD-L1 and T-effector signatures were found in patients with a CR or PR and extended PFS. An added benefit from the addition of bevacizumab to atezolizumab was found for tumors with high expression of VEGFR2 and high levels of Tregs, with similar outcomes for tumors with low levels of these two markers regardless of combination or monotherapy treatment. This investigation may help guide patient selection for future trials of the combination in HCC.
INHIBITION OF PI3K-GAMMA AND -DELTA IMPROVES ANTI-TUMOR EFFICACY
CT045 - Synergistic anti-tumor efficacy of the dual PI3K-δ/PI3K-γ inhibitor duvelisib with PD-1 blockade in solid tumor and lymphoma models
A preclinical investigation of the PI3k-delta/gamma inhibitor duvelisib was presented by Jonathan A. Pachter, PhD (Verastem Oncology). Several in vitro, ex vivo and in vivo studies were discussed, to investigate the impact of duvelisib as monotherapy and in combination with PD-1 checkpoint blockade.
Using T cells from healthy donors or CLL patients, the investigators demonstrated T cell expansion after duvelisib treatment, including an expansion of particularly early memory T cells and reduction of exhaustion markers. As PI3K-gamma inhibition particularly reduces M2 macrophages, and inhibition of PI3K-delta reduces regulatory T cells, it was hypothesized that duvelisib, which inhibits both, may be particularly efficacious in treating tumors in combination with immune checkpoint blockade. This was tested using both lymphoma (A20) and colorectal cancer mouse models (CT26). In both models, an improved tumor growth inhibition was observed with combination duvelisib and anti-PD-1 over either monotherapy (81% inhibition with combination, 59% with duvelisib, and 49% with anti-PD-1 in colorectal models, for example). The reduced tumor growth also led to increased survival with the combination. Additionally, mice treated with the combination were later immune to tumor rechallenge. The investigators are pursuing duvelisib in clinical trials for several indications in combination with both immune checkpoint inhibitors and adoptive cellular therapies.
COMPARISON OF PANEL AND WES TMB MEASUREMENTS CONDUCTED
5671 - Alignment of TMB measured on clinical samples: Phase IIB of the Friends of Cancer Research TMB Harmonization Project
The correspondence between TMB values obtained from whole-exome sequencing and panel-based approaches was discussed by Diana Merino Vega, PhD (Friends of Cancer Research), through the Friends of Cancer Research TMB Harmonization Project. Given the importance of TMB with outcomes on immune checkpoint inhibitors, accurate estimation of this value is crucial in the clinic, but panels may not accurately represent a TMB measurement from WES.
This phase of the TMB Harmonization Project involved analysis of tumor and normal DNA at various laboratories using their own techniques, the results of which were then compared to gold-standard WES TMB measurement of the same samples. Calibration approaches were also analyzed, in order to better match panel approaches to WES TMB.
The variability between laboratory TMB values and WES TMB measurements varied similarly across sample types, including previous TCGA analyses, cell lines and clinical samples. Calibration curves were developed for each individual lab by plotting the panel TMB versus WES TMB for each measured sample. Optimal calibration was achieved using the analysis of TCGA samples, given the large sample size, and these calibrations were applied to the analysis of the clinical tissue samples. This resulted in panel estimates that better mimicked the WES TMB values. Ongoing studies will further test these calibrations and aim to develop more consistent TMB measurements.
LACK OF BENEFIT AND SAFETY PROFILE LIMIT DEVELOPMENT OF ABEMACICLIB AND PEMBROLIZUMAB COMBINATION
CT108 - A phase 1b study of abemaciclib in combination with pembrolizumab for patients (pts) with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) (NCT02779751): Preliminary results
Hope S. Rugo, MD (University of California, San Francisco) presented the preliminary results of a phase 1b trial investigating combination abemaciclib and pembrolizumab in HR+/HER2- metastatic breast cancer. With the primary goal of safety analysis, 26 patients were enrolled in this study, the majority of whom had visceral disease.
All patients on the study experienced at least one adverse event, with 69% experiencing a grade 3 or higher event. The overall adverse event profile, including types of AEs, was consistent with the expected profiles of both drugs; however, several concerning safety signals were noted. Interstitial lung disease occurred in four patients on-study, including two grade 5 pneumonitis events. Liver enzymes (AST, ALT) were elevated in 46% of patients, leading to 7 patients discontinuing the therapy. Early efficacy results from this study point to a numerically lower ORR than that of other studies in this patient population, such as those involving abemicilib and NSAIs. The ORR in this study was 23%, with a disease control rate of 84.6%. Given the side effect profile and apparent limited clinical benefit, this combination therapy is not undergoing future clinical development.
EXPLORATION OF FAK AND PD-1 INHIBITION IN PANCREATIC CANCER SHOWS PROMISE
CT118 - Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: Experiences of pancreatic ductal adenocarcinoma (PDAC) patients
A phase 1 study of the focal adhesion kinase inhibitor, defactinib, in combination with pembrolizumab and gemcitabine in patients with pancreatic cancer was presented by Andrea Wang-Gillam, MD, PhD (Washington University). This study initially enrolled patients with any advanced solid tumor in the dose escalation phase; however, the dose expansion cohort consisted entirely of patients with pancreatic cancer, with either refractory disease (progression on >=1 previous therapy) or stable disease on previous gemcitabine/nab-paclitaxel (maintenance cohort).
No new safety signals were seen, without any dose-limiting toxicities. The study determined the recommended phase 2 dose to be defactinib 400 mg twice daily, gemcitabine 1000 mg/m2 on days 1 and 8, and pembrolizumab 200 mg on day 1 of each 21-day cycle. Paired biopsies indicated an increase in CD8+ T cells and a decrease in regulatory T cells and tumor-associated macrophages after the combination treatment. These favorable immune changes led to similar efficacy results across the cohorts in this study. A partial response was noted in one patient each in the escalation and maintenance cohorts, while stable disease was achieved in 38%, 60%, and 50% of patients in the escalation, maintenance, and refractory populations. Notably, both of the partial responses were in microsatellite-stable tumors. In the refractory population, the median PFS was 3.7 months, and median overall survival was 7.8 months, pointing to a potential future treatment option for advanced pancreatic cancer.
ENCOURAGING RESULTS FROM COMBINATION OF ONCOLYTIC VIRUS AND PD-1 INHIBITION IN RCC
CT121 - A phase Ib study of recombinant vaccinia virus in combination with immune checkpoint inhibition (ICI) in advanced renal cell carcinoma (RCC)
The combination of an oncolytic virus and anti-PD-1 therapy was discussed by Sun Young Rha, MD, PhD (Yonsei University). This study involved intravenous administration of Pexastimogene Devacirepvec (Pexa-Vec), a vaccinia virus engineered to express GM-CSF, in combination with cemiplimab in patients with metastatic or unresectable clear cell renal cell carcinoma in dose escalation and expansion cohorts.
Sixteen patients were enrolled between the escalation and expansion arms. No dose-limiting toxicities were encountered in this trial, but 41% of patients experienced an adverse event of grade 3 or higher. Nine patients experienced a tumor burden reduction of at least 30%, with 75% of all patients demonstrating some tumor reduction. Best responses in the study included one complete response, five partial responses, and six patients with stable disease. Given the encouraging responses of this study, further investigation of this combination, including in immune checkpoint inhibitor-refractory patients, is in development.
DURVALUMAB BENEFIT MAINTAINED REGARDLESS OF SMOKING STATUS IN NSCLC
CT213 - Impact of smoking on outcomes with durvalumab following chemoradiotherapy in unresectable Stage III NSCLC (PACIFIC)
The impact of smoking history on outcomes for patients treated with durvalumab for non-small cell lung cancer was discussed by David Planchard, MD, PhD (Gustave Roussy). This exploratory post-hoc analysis compared treatment outcomes and adverse events for never-smoker patients (9% of total randomized patients) compared to ever/current smokers.
The baseline characteristics of the two arms were largely balanced; however, the non-smoker arm contained a higher proportion of patients who were women, Asian, and had non-squamous histology. Across all populations, durvalumab provided a benefit over placebo in this trial. Median progression-free survival was 16.8 vs. 6.4 months for ever/current smokers treated with durvalumab vs. placebo; at the same time, the median PFS was not reached (>18 months) vs. 3.0 months for never-smokers treated with durvalumab or placebo, respectively. A similar trend was noted for overall survival: never-smokers and ever/current smokers had median overall survivals of 34.9 months and not-reached with durvalumab, respectively, and 18.7 and 29.1 months on placebo. The adverse event profiles were broadly similar, but the overall incidence of pneumonitis and grade 3-4 events in general were elevated in ever/current smokers. While the sample size of never-smokers was small in this analysis, this study points to similar outcomes and slightly different adverse event profiles for patients treated with immune checkpoint inhibitors depending on their smoking history. Notably, correlation of smoking status and PDL-1 expression may be warranted in the future.
CANAKINUMAB + PEMBROLIZUMAB + CHEMOTHERAPY COMBINATION INVESTIGATED IN 1ST LINE NSCLC
CT214 - CANOPY-1: Safety run-in results from phase (ph) 3 study of canakinumab (CAN) or placebo (PBO) in combination (comb) with pembrolizumab (PEM) plus platinum-based doublet chemotherapy (Ctx) as 1st line therapy in patients (pts) with advanced or metastatic NSCLC
Bruce E. Johnson, MD (Dana-Farber Cancer Institute) discussed findings from the safety run-in study of canakinumab and pembrolizumab in patients with advanced/metastatic NSCLC in the front-line setting. The combination of the IL-1beta inhibitor with PD-1 inhibition was tested in three cohorts to determine the recommended phase 3 dose: non-squamous NSCLC with carboplatin + pemetrexed induction chemotherapy (cohort A), non-squamous NSCLC with cisplatin + pemetrexed induction (cohort B), and squamous or non-squamous NSCLC with carboplatin + paclitaxel chemotherapy induction (cohort C).
A total of 30 patients were enrolled in the safety study: 10 to arm A, 11 to B, and 9 to C. Treatment was ongoing for 80% of patients, with discontinuation primarily due to progressive disease in 5 patients. One dose-limiting toxicity was reported – grade 3 hepatitis – but was deemed unrelated to canakinumab and attributed to pembrolizumab. While none were attributed to canakinumab, serious adverse events were reported by 2 patients in cohort A and 3 patients each in arms B and C. One grade 4 cardiac tamponade was reported, unrelated to the study drug. The overall safety profile of the combination therapy was deemed acceptable, and the recommended phase 3 dose of canakinumab was 200 mg Q3W in combination with standard pembrolizumab and chemotherapy dosing.
BENEFIT MAINTAINED FOR ABCP REGIMEN IN METASTATIC NSCLC
CT216 - IMpower150 final analysis: Efficacy of atezolizumab (atezo) + bevacizumab (bev) and chemotherapy in first-line (1L) metastatic nonsquamous (nsq) non-small cell lung cancer (NSCLC) across key subgroups
The final analysis of the Impower150 trial of atezolizumab, bevacizumab and chemotherapy for front-line treatment of metastatic NSCLC was presented by Mark A. Socinski, MD (AdventHealth Cancer Institute). This study involved three treatment arms: A – atezolizumab + carboplatin + paclitaxel (ACP); B – atezolizumab + bevacizumab + carboplatin + paclitaxel (ABCP); and C – bevacizumab + carboplatin + paclitaxel (BCP). Patients were assessed based on EGFR/ALK mutation status, and the primary endpoint of the study were PFS and OS in the intent-to-treat population without mutations in these markers (ITT-WT).
After a minimum follow-up of 32.4 months, a numerical but not statistically significant increase in OS was noted for ITT-WT patients in arm A compared to arm C, at 19.0 vs. 14.7 months. Overall survival was further extended with the addition of bevacizumab to the ACP regimen: patients in arm B had a median OS of 19.5 months. This benefit for the ABCP regimen over the BCP regimen was maintained across subgroup analyses, including for patients with PD-L1-positive tumors, EGFR/ALK mutations, and liver metastases. The ACP regimen provided benefit for PD-L1-positive tumors (OS HR = 0.71), while OS was similar for other key subgroups. This final analysis points to the continued importance of this combination regimen in the management of metastatic NSCLC.