Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than ...without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.
Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged ...administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470.
•Concomitant PI3Kδ and SYK inhibition resulted in treatment-emergent pneumonitis, necessitating early study termination.•Initial trials of novel combinations should use conservative designs that are focused on safety.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background In patients (pts) with non-metastatic NSCLC, surgery has curative potential but 30-80% who undergo resection experience recurrence. Neoadjuvant or adjuvant chemo is recommended ...for pts with high recurrence risk; however, benefits are modest and pathological complete response (pCR) with neoadjuvant chemo is low. Although immunotherapy targeting the PD-1 pathway has shown survival benefits in metastatic NSCLC, phase 3 trial results in resectable disease are yet to be reported. Recently, neoadjuvant NIVO, alone or in combination with chemo, has shown encouraging pCR rates in single-arm phase 2 studies. Here, we report the final analysis of one of the primary endpoints, pCR, of CheckMate 816 (NCT02998528)-a randomized, phase 3, open-label study evaluating NIVO + chemo vs chemo as neoadjuvant tx for resectable NSCLC.
Methods Adults with clinical stage IB (≥ 4 cm)-IIIA (per AJCC 7th ed), resectable NSCLC, ECOG PS 0-1, and no known EGFR/ALK alterations were randomized to either NIVO 360 mg + platinum-doublet chemo Q3W or chemo Q3W for 3 cycles, followed by surgery. Stratification was by disease stage (IB/II vs IIIA), PD-L1 (≥ 1% or < 1%), and sex. pCR by blinded independent pathological review (BIPR) and event-free survival by blinded independent central review (BICR) are the primary endpoints. pCR was defined as 0% viable tumor cells in resected lung and lymph nodes; pts who did not undergo surgery were counted as non-responders. Overall survival, major pathological response (MPR; ≤ 10% viable tumor in both lung and lymph nodes) per BIPR, and time to death or distant metastases are secondary endpoints. Key exploratory endpoints are objective response rate (ORR) per BICR and potential predictive biomarkers including PD-L1 and tumor mutational burden (TMB).
Results Baseline characteristics were balanced between arms (n = 179 each). Neoadjuvant NIVO + chemo significantly increased pCR rates vs chemo in the intent-to-treat population (ITT) (24.0% vs 2.2%; odds ratio 13.94 99% CI 3.49-55.75; P < 0.0001). Improvement in pCR with NIVO + chemo vs chemo was consistent across key subgroups including disease stage (IB/II 26.2% vs 4.8%; ≥ IIIA 23.0% vs 0.9%), PD-L1 (< 1% 16.7% vs 2.6%; ≥ 1% 32.6% vs 2.2%), and TMB (low 22.4% vs 1.9%; high 30.8% vs 2.7%). NIVO + chemo also improved MPR rates vs chemo in the ITT (36.9% vs 8.9%), as well as ORR (53.6% vs 37.4%) and radiographic down-staging rates (30.7% vs 23.5%). Definitive surgery occurred for 83.2% of pts treated with NIVO + chemo and 75.4% with chemo; surgery was cancelled rarely due to AEs (2 pts/arm) and due to disease progression in 12 and 17 pts, respectively. Grade 3-4 tx-related AEs and grade 3-4 surgery-related AEs were reported in 33.5% vs 36.9% and 11.4% vs 14.8% of pts in the NIVO + chemo vs chemo arms, respectively.
Conclusions CheckMate 816 met its first primary endpoint with a statistically significant improvement in pCR with neoadjuvant NIVO + chemo vs chemo alone per independent review. The safety profile of NIVO + chemo was consistent with the known profile of this combination regimen, and the addition of NIVO did not decrease the ability to perform surgery. CheckMate 816 is the first positive phase 3 trial demonstrating a significant improvement in pathologic response with neoadjuvant immunotherapy plus chemo in resectable NSCLC.
Citation Format: Patrick M. Forde, Jonathan Spicer, Shun Lu, Mariano Provencio, Tetsuya Mitsudomi, Mark M. Awad, Enriqueta Felip, Stephen Broderick, Julie Brahmer, Scott J. Swanson, Keith Kerr, Changli Wang, Gene B. Saylors, Fumihiro Tanaka, Hiroyuki Ito, Ke-Neng Chen, Cecile Dorange, Junliang Cai, Joseph Fiore, Nicholas Girard. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT003.
In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in
in 2022. The goal of CheckMate 816 was to find out if
, an immunotherapy that ...activates a person's immune system (the body's natural defense system) to fight cancer,
works better than
when given before surgery in people with non-small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC).
Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive
, and 179 people were randomly assigned to receive
. The researchers assessed whether people who received
lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe.
Researchers found that people who
lived longer without the cancer getting worse or coming back compared with those who took
. More people in the
group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took
instead of
had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries.
did not lead to an increase in the rate of side effects compared with
, and side effects were generally mild and manageable.
Results from CheckMate 816 support the benefit of using
before surgery for people with resectable NSCLC.
: NCT02998528 (ClinicalTrials.gov).
LBA8010 Background: The phase 3 CheckMate 816 study established neoadjuvant NIVO + chemo as a standard of care for eligible pts with resectable NSCLC. Here, we report the 4-year survival update from ...this study, representing the longest follow-up among all global phase 3 studies evaluating neoadjuvant or perioperative immunotherapy-based treatments. Methods: Adults with stage IB (≥ 4 cm)–IIIA (per AJCC v7) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK alterations were randomized 1:1 to receive NIVO 360 mg + chemo Q3W or chemo alone Q3W for 3 cycles, followed by surgery. Event-free survival (EFS) and pathologic complete response (pCR; both per blinded independent review) were primary endpoints and were both statistically significant. Overall survival (OS) was a key secondary endpoint. Exploratory analyses included efficacy by pCR status and extent of resection. Results: At the 23 Feb 2024 database lock (median follow-up, 57.6 mo), NIVO + chemo continued to improve EFS vs chemo (median, 43.8 mo vs 18.4 mo; HR 95% CI, 0.66 0.49–0.90); 4-year EFS rates were 49% vs 38%. EFS favored NIVO + chemo vs chemo regardless of whether pts had lobectomy or pneumonectomy (Table), with 56%–57% vs 40%–43% of pts without disease recurrence at 4 years. NIVO + chemo also continued to show OS improvement vs chemo (HR 98.36% CI, 0.71 0.47–1.07; P = 0.0451; median OS was not reached NR in both arms, and the significance boundary was not met at this interim analysis). An OS improvement of 13% was sustained over time for NIVO + chemo vs chemo; 4-year OS rates were 71% vs 58%. Pts in the NIVO + chemo arm who had pCR continued to have improved OS vs those who did not (HR 95% CI, 0.08 0.02–0.34); 4-year OS rates, 95% vs 63%); a similar trend was seen in the chemo arm, although few pts had pCR with chemo (n = 4). No new safety signals were observed at this update. Additional survival analyses in pt subgroups and by ctDNA levels will be presented. Conclusions: In this 4-year analysis from CheckMate 816, neoadjuvant NIVO + chemo sustained EFS and OS separation vs chemo over time and demonstrated the long-term survival benefit of having pCR in pts with resectable NSCLC. These data provide the first understanding of the long-term benefits of neoadjuvant immunotherapy when added to chemo, reinforcing neoadjuvant NIVO + chemo as a standard of care, and providing a benchmark to assess the benefits of all perioperative immunotherapy-based treatments. Clinical trial information: NCT02998528 . Table: see text
Background
Real‐world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm ...the real‐world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC).
Subjects, Materials, and Methods
Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression‐free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health‐related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical‐trial‐eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non‐clinical‐trial‐eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups.
Results
Six hundred fifty‐seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval CI, 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment‐related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups.
Conclusion
PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real‐world clinical setting.
Implications for Practice
PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real‐world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first‐line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months.
The PRINCIPAL study evaluated the efficacy and safety of pazopanib in patients with advanced/metastatic renal cell carcinoma in a multinational, real‐world clinical setting. Results are reported here.
Abstract
Background: CheckMate 816 (NCT02998528), a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo for resectable NSCLC, met its first primary endpoint with a statistically significant ...improvement in pathological complete response (pCR) rate (24% vs 2%; odds ratio 13.94 99% CI, 3.49-55.75; P < 0.0001). pCR benefit was consistent across key subgroups, including disease stages, histologies, and PD-L1 expression levels. Notably, neoadjuvant NIVO + chemo did not impede feasibility of surgery nor increase incidence of surgical complications or adverse events (AEs) vs chemo alone. We report results from the first prespecified interim analysis of EFS, the other primary endpoint.
Methods: Adults with stage IB (≥ 4 cm)-IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ALK alterations were randomized to NIVO 360 mg + chemo Q3W or chemo Q3W for 3 cycles (n = 179 each). Primary endpoints were EFS and pCR (both assessed by blinded independent review) in the randomized population. EFS was defined as the length of time from randomization to any disease progression precluding surgery, disease progression or recurrence after surgery, or death due to any cause. An exploratory analysis of EFS by pCR status was conducted.
Results: At a median follow-up of 29.5 mo (database lock, October 20, 2021), neoadjuvant NIVO + chemo significantly improved EFS vs chemo in the randomized population (median 95% CI, 31.6 mo 30.2-not reached (NR) vs 20.8 mo 14.0-26.7; HR 97.38% CI, 0.63 0.43-0.91; P = 0.0052; 2-year EFS rates, 64% vs 45%). EFS results in the subgroups by disease stages, histologies, and PD-L1 expression levels are shown in the
Table: In the pooled patient population (NIVO + chemo and chemo arms combined), EFS was improved in patients with pCR compared with those without (median, NR vs 21.1 mo; HR 95% CI, 0.11 0.04-0.29). Incidence of grade 3-4 treatment-related (33.5% vs 36.9%) and surgery-related AEs (11.4% vs 14.8%) was similar between the NIVO + chemo and chemo arms, as reported previously.
Conclusions: In CheckMate 816, neoadjuvant NIVO + chemo showed a statistically significant and clinically meaningful improvement in EFS vs chemo alone. These results, along with the significant improvement in pCR, support NIVO + chemo as a potential new treatment option for patients with stage IB-IIIA resectable NSCLC.
Subgroups Median EFS, mo (95% CI) HR (95% CI) NIVO + chemo Chemo Overall (n = 358) 31.6 (30.2-NR) 20.8 (14.0-26.7) 0.63 (0.43-0.91)a Baseline disease stage IB-II (n = 127) NR (27.8-NR) NR (16.8-NR) 0.87 (0.48-1.56) IIIA (n = 228) 31.6 (26.6-NR) 15.7 (10.8-22.7) 0.54 (0.37-0.80) Tumor histology Squamous (n = 182) 30.6 (20.0-NR) 22.7 (11.5-NR) 0.77 (0.49-1.22) Non-squamous (n = 176) NR (27.8-NR) 19.6 (13.8-26.2) 0.50 (0.32-0.79) PD-L1 expression level < 1% (n = 155) 25.1 (14.6-NR) 18.4 (13.9-26.2) 0.85 (0.54-1.32) ≥ 1% (n = 178) NR (NR-NR) 21.1 (11.5-NR) 0.41 (0.24-0.70) 1-49% (n = 98) NR (27.8-NR) 26.7 (11.5-NR) 0.58 (0.30-1.12) ≥ 50% (n = 80) NR (NR-NR) 19.6 (8.2-NR) 0.24 (0.10-0.61) a97.38% CI reported. Chemo, chemotherapy; CI, confidence interval; EFS, event-free survival; HR, hazard ratio; mo, months; NIVO, nivolumab; NR, not reached; PD-L1, programmed death ligand 1.
Citation Format: Nicolas Girard, Jonathan Spicer, Mariano Provencio, Shun Lu, Stephen Broderick, Mark M. Awad, Tetsuya Mitsudomi, Keith Kerr, Julie Brahmer, Scott J. Swanson, Enriqueta Felip, Changli Wang, Gene B. Saylors, Ke-Neng Chen, Fumihiro Tanaka, Moishe Liberman, Cecile Dorange, Javed Mahmood, Junliang Cai, Patrick M. Forde. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment for resectable (IB-IIIA) non-small cell lung cancer (NSCLC): Event-free survival (EFS) results from the phase 3 CheckMate 816 trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT012.
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