Background

Pembrolizumab is approved in monotherapy for the first-line (1L) of advanced or metastatic NSCLC patients (pts) with PD-L1 ≥50%. Despite long-term survival, about one third of patients experience detrimental survival outcomes, including early death, hyperprogression and fast progression (FP). The impact of clinical factors on the development of FP has not been widely evaluated, so far.

Methods

We designed a retrospective, multicenter study, involving 5 Italian centers, with the primary objective of investigating the clinical features associated with FP in pts with metastatic NSCLC with PD-L1 ≥50%, treated with Pembrolizumab in 1L setting. FP was defined as PD (per investigator) within 12 weeks. Baseline clinical factors of pts with and without FP were collected and analyzed. Logistic regression was performed to identify clinical factors associated to FP. A FP prognostic score was developed based on the logistic model.

Results

Overall, 321 out of 336 NSCLC pts treated with 1L pembrolizumab had completed data for analysis. FP occurred in 137 (42.7%) pts. Female sex, ECOG PS 1 or 2, concomitant steroids, tumor burden, ≥ 2 metastatic sites and the presence of liver/bone/pleural mets were significantly associated with higher risk of FP at univariate analysis. Sex, ECOG PS, steroids, metastatic sites ≥ 2, and the presence of liver/pleural mets were confirmed as independent factors for FP at multivariate analysis. By combining these factors, we developed a FP prognostic score ranged 0–13, with three-risk group stratification: 0–2 (good prognosis), 3–6 (intermediate prognosis), 7–13 (poor prognosis). The AUC of the model was 0.76 (95% CI: 0.70–0.81).

Conclusions

We identified 6 clinical factors independently associated with FP and we developed a prognostic score model for FP-risk to potentially improve clinical practice and selection for 1L pembrolizumab in NSCLC with high PD-L1 (≥50%), in real-world clinical setting.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Passaro: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Roche Genentech; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Janssen. All other authors have declared no conflicts of interest.

Background

Time on treatment, also called time to treatment discontinuation, is a readily available real-world effectiveness endpoint highly correlated at the patient-level with progression-free survival and moderately to highly correlated with overall survival in clinical trials and real-world data. In October 2016, pembrolizumab received FDA approval based on results from KEYNOTE-024, as a first-line monotherapy for patients with metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥50% and no EGFR/ALK genomic aberrations, administered until disease progression, unacceptable toxicity, or up to 24 months. In KEYNOTE-024, 25% (39/154) of patients received 35 cycles (2 years) of pembrolizumab as initially assigned therapy. Our objective was to describe rwToT with first-line pembrolizumab in real-world oncology practice.

Methods

Using the US nationwide Flatiron Health electronic health record-derived, de-identified database, we included adult patients with pathologically confirmed advanced, PD-L1 TPS ≥50% NSCLC who initiated first-line pembrolizumab monotherapy from November 2016-September 2019, with follow-up through September 2020. Eligibility criteria included ECOG performance status 0–2, PD-L1 TPS ≥50%, no EGFR/ALK genomic aberration, and no known ROS1 aberration. Patients enrolled in a clinical trial were excluded. Median rwToT and landmark on-treatment rates were estimated using Kaplan-Meier method.

Results

Conclusions

Patients with key trial-eligible characteristics (ECOG 0–1, PD-L1 TPS ≥50%, EGFR/ALK negative) experienced rwToT with first-line pembrolizumab similar to the phase III pivotal clinical trial. Approximately 23% received at least 2 years of treatment, suggesting long-term benefit of pembrolizumab monotherapy for PD-L1 TPS ≥50% advanced NSCLC in a real-world setting.

Editorial acknowledgement

Editorial assistance was provided by Elizabeth V. Hillyer, DVM (freelance); this assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

V. Velcheti: Advisory/Consultancy: Merck; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Genentech; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Celgene; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy: Fulgent Genetics; Advisory/Consultancy: Reddy Labs; Advisory/Consultancy: Alkermes; Advisory/Consultancy: Nektar Therapeutics; Advisory/Consultancy: Foundation Medicine. X. Hu: Full/Part-time employment: MSD/Merck. Y. Li: Full/Part-time employment: MSD/Merck; Shareholder/Stockholder/Stock options: Merck. T. Burke: Full/Part-time employment: MSD/Merck; Shareholder/Stockholder/Stock options: Merck. B. Piperdi: Full/Part-time employment: MSD/Merck; Shareholder/Stockholder/Stock options: Merck.

Background

Despite Pembrolizumab is the new standard of care in metastatic NSCLC with PD-L1 >50%, it was recognized not all patients benefit from it. PET imaging plays an important role in assessing the biologic behavior of NSCLC and defining response to therapy. We explored the predictive values of both the lymphocyte-monocyte ratio (LMr) in peripheral blood and baseline SUVmax of 18F-fluorodeoxyglucose by the primary tumor in positron emission tomography/computed tomography (PET/CT) in patients with metastatic NSCLC treated with Pembrolizumab.

Methods

Between January 2018 and December 2020, 203 newly diagnosed metastatic NSCLC patients treated with Pembrolizumab as first line therapy were recruited. The optimal cut-off values for baseline SUVmax and peripheral LMr were determined by ROC curves. The predictive values of SUVmax and LMr were examined by X-square and Fisher's exact tests; survival functions using the Kaplan–Meier. Log‐rank test and Cox regression were used for statistical comparisons between curves.

Results

The objective response rate (ORR) was significantly different between the high-SUVmax group and the low-SUVmax group (53% vs 87.1%; P = 0.003), as well as between the high-LMR group and the low-LMR group (93.1% vs 45.2%; P = 0.001). We stratified patients by low or high SUVmax and LMr >5.2 or >5.2 into 3 groups with different levels of risk of relapse. The low risk level (low-SUVmax and high-LMR; n = 120, 59%) had a 3‐year PFS of 85% (95% CI: 78–95%), the intermediate level (high-SUVmax or LMr >5.2; n = 27, 13%) had a 3‐year PFS of 67% (95% CI: 55–79%), and the high risk level (high-SUVmax and LMr >5.2; n = 56, 28%) had a 3‐year PFS of 10% (95% CI: 1–29%). The log‐rank test between the intermediate and low levels and between the high and intermediate levels were significant (P = 0.006, P < 0.001, respectively). For OS, the difference between the high and intermediate/low levels was significantly different (P < 0.001).

Conclusions

By combining baseline SUVmax of the primary tumor and the peripheral LMr, we may identify metastatic NSCLC in treatment with Pembrolizumab with poor PFS and OS and who more likely may have a better primary tumor response to Pembrolizumab.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Immune Checkpoint Inhibitors (ICI) have become standard of care in the management of advanced non-small cell lung cancer (aNSCLC). Nevertheless, only a small proportion of patients (pts) benefit from ICI. Diverse biomarkers have been proposed but none of them appears to be the “ultimate biomarker.” Aim of the present study is to assess whether [18F]FDG-PET/CT derived parameters may be used as biomarkers in aNSCLC patients receiving first-line pembrolizumab.

Methods

This is a monocentric retrospective cohort study including pts with aNSCLC (stage IV) and PD-L1 expression ≥50% treated with pembrolizumab within clinical practice. A control group of pts treated with EGFR inhibitors for EGFR mutated NSCLC was also enrolled. Only patients with a positive [18F]18F-FDG PET/CT performed at our center within 60 days from treatment initiation were included. Total Metabolic Tumor Volume (tMTV) was calculated for each lesion by a dedicated software (PET VCAR, GE Healthcare) on transaxial PET images, that semi-automatically delineates the tumour's contours with a SUVmax threshold of 42% within the lesion. TMTV was obtained summing each single lesion's MTV. Potential prognostic parameters for OS were analysed (TMTV, SUVmax, presence of bone/liver mets, neutrophil/lymphocyte ratio ≥ 4, ECOG PS ≥ 2, LDH > ULN).

Results

34 patients treated with first line-pembro and 40 patients treated with EGFR TKI were included. We selected 75 cm³ as cutoff with ROC curve (sensitivity 87%, specificity 71%). In the pembro group, median follow up was 20.3 months, median OS 4.7 months (95% CI 0.3–9.1) for pts with tMTV ≥75 cm³ vs Not Reached (NR) for pts with tMTV <75 cm³ (95% CI NR – NR. HR 5.37; 95% CI 1.72–16.77; p0.004). No difference was found in the control group (HR 1.43; 95% CI 0.61–3.34; p 0.411).

Conclusions

TMTV ≥75 cm³ can be used as predictor of poor outcome in aNSCLC PDL1-high pts treated with first line pembro. These pts may require the addition of chemotherapy to pembro.

Legal entity responsible for the study

Filippo G. Dall’ Olio.

Funding

AIRC - Fondazione AIRC per la Ricerca sul Cancro (investigator grant 19026).

Disclosure

A. Ardizzoni: Advisory/Consultancy: BMS; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: MSD; Advisory/Consultancy: Roche. All other authors have declared no conflicts of interest.

Background

Pembrolizumab plus pemetrexed and platinum (pembro combo) is the preferred first-line regimen in US treatment guidelines for advanced nonsquamous NSCLC without actionable genomic aberrations and independent of PD-L1 tumor proportion score (TPS). Time on treatment (ToT) is a surrogate real-world effectiveness endpoint demonstrating high correlation to progression-free survival and moderate-to-high correlation to overall survival. Our aim was to evaluate rwToT with first-line pembro combo in patients with advanced nonsquamous NSCLC.

Methods

Adult patients initiating first-line pembro combo (June 2017-September 2019) were selected from the US nationwide Flatiron Health electronic health record-derived, de-identified database. Patients included in the analysis had nonsquamous NSCLC, stage IIIB or IV disease or recurrent disease, wild-type EGFR/ALK, no known ROS1 fusion, and an ECOG performance status of 0–1, excluding those in therapeutic clinical trials. Median rwToT and on-treatment rates were estimated using the Kaplan-Meier method, with follow-up through September 2020.

Results

The median patient follow-up duration for this cohort was 15.3 months (range: 1 day to 40 months). Baseline cohort characteristics were similar: median age was 66–69 years (overall range, 34–84); 55–57% were men. Median rwToT was 10.0 months for patients with PD-L1 TPS ≥50%, 6.2 months with TPS 1–49%, and 4.9 months with TPS <1%. In the PD-L1 TPS ≥50% cohort, 26% of patients remained on pembrolizumab at 2 years.

Conclusions

The rwToT with pembrolizumab increased with PD-L1 TPS level, although the rwToT with pemetrexed in each cohort was substantially shorter. A considerable proportion of patients remained on pembrolizumab at 2 years, suggesting long-term benefit.

Editorial acknowledgement

Editorial assistance was provided by Elizabeth V. Hillyer, DVM (freelance); this assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

S.V. Liu: Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Beigene; Research grant/Funding (institution): Alkermes; Research grant/Funding (institution): Bayer; Advisory/Consultancy, Research grant/Funding (institution): Blueprint; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Corvus; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Inivata; Advisory/Consultancy: Janssen; Advisory/Consultancy: Jazz Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Lycera; Advisory/Consultancy, Research grant/Funding (institution): Merck/MSD; Research grant/Funding (institution): Merus; Advisory/Consultancy: PharmaMar; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Rain Therapeutics; Research grant/Funding (institution): RAPT; Advisory/Consultancy: Regeneron; Research grant/Funding (institution): Spectrum; Advisory/Consultancy: Takeda; Research grant/Funding (institution): Turning Point Therapeutics. X. Hu: Full/Part-time employment: MSD/Merck. Y. Li: Full/Part-time employment: MSD/Merck; Shareholder/Stockholder/Stock options: Merck. T. Burke: Full/Part-time employment: MSD/Merck; Shareholder/Stockholder/Stock options: Merck. B. Piperdi: Full/Part-time employment: MSD/Merck; Shareholder/Stockholder/Stock options: Merck.

Background

Pembrolizumab was the first anti-PD-1 therapy approved for previously untreated metastatic NSCLC in Europe, based on results from the KEYNOTE-024 trial where the Kaplan-Meier (KM) estimated 12-month overall survival was 70.3%. Our aim was to estimate overall survival (OS) and real-world progression-free survival (rwPFS) in France for pembrolizumab monotherapy as first-line treatment for patients with metastatic NSCLC and PD-L1 tumor proportion score (TPS) ≥50%.

Methods

Using the Epidemiological Strategy Medical Economics Advanced or Metastatic Lung Cancer (ESME-AMLC) Data Platform [NCT03848052], we identified adult patients with histologically confirmed metastatic, PD-L1 TPS ≥50% NSCLC initiating first-line pembrolizumab monotherapy treatment between 12 May 2017 and 31 December 2018. Patients with EGFR/ALK genomic aberration or who enrolled in a clinical trial were excluded. This planned interim analysis was based on a pre-specified statistical analysis plan, with data cut-off on August 31, 2019. OS and rwPFS were estimated using the KM method.

Results

A total of 164 patients were included, with 8 months median follow-up (range: 0, 24). ECOG performance status (PS) at treatment initiation was 0–1 (n = 86, 68.3%), 2 (n = 25, 19.8%), 3–4 (n = 15, 11.9%%), or missing (n = 38). Additional patient characteristics and OS/rwPFS results are shown below.

Conclusions

Clinical outcomes among metastatic NSCLC patients with high PD-L1 expression were consistent with those of KEYNOTE-024, supporting the effectiveness of pembrolizumab in the real-world setting in France.

Clinical trial identification

ESMECSM2019–24.

Legal entity responsible for the study

UNICANCER.

Funding

MSD.

Disclosure

M. Pérol: Advisory/Consultancy, Advisory Boards/Symposium/Institutional grants: Roche; Advisory/Consultancy, Advisory Boards/Symposium: Eli Lilly; Advisory/Consultancy, Advisory Boards/Symposium: Novartis; Advisory/Consultancy, Advisory Boards/Symposium/Institutional grants: AstraZeneca; Advisory/Consultancy, Advisory Boards/Symposium/Institutional grants: Takeda; Advisory/Consultancy, Advisory Boards/Symposium: MSD; Advisory/Consultancy, Advisory Boards/Symposium: Bristol-Myers Squibb; Advisory/Consultancy, Advisory Boards/Symposium/Institutional grants: Boehringer-Ingelheim; Advisory/Consultancy, Advisory Boards/Symposium: Pfizer; Advisory/Consultancy, Symposium: Amgen; Advisory/Consultancy, Symposium/Institutional grants: CHUGAU; Advisory/Consultancy, Symposium: Illumina. T. Filleron: Research grant/Funding (institution): BMS. All other authors have declared no conflicts of interest.

Background

Information on real-world clinical outcomes for pembrolizumab monotherapy among patients with previously treated advanced NSCLC remains limited. Our aim was to estimate overall survival (OS) and real-world progression-free survival (rwPFS) in France for pembrolizumab monotherapy in previously treated, PD-L1-expressing advanced NSCLC patients following approval based on the phase III trial KEYNOTE-010 (KN010), where a 11.8 month median OS (95% CI: 10.4 to 13.1) and a 48.9% 12-month OS rate (95% 45.1, 52.6) were reported.

Methods

Using the Epidemiological Strategy Medical Economics Advanced or Metastatic Lung Cancer (ESME-AMLC) Data Platform [NCT03848052], we identified adult patients with histologically confirmed, PD-L1 TPS ≥1%, advanced (stage IIIB or IV) NSCLC treated with at least one prior chemotherapy regimen and who initiated pembrolizumab monotherapy between 12 May 2017 and 31 December 2018. Patients with EGFR/ALK genomic aberration were required to have been treated with an appropriate targeted therapy prior to pembrolizumab. Patients who received pembrolizumab in a clinical trial were excluded. This planned interim analysis was based on a pre-specified statistical analysis plan, with data cut-off on August 31, 2019. OS and rwPFS were estimated using the KM method.

Results

A total of 304 patients were identified, with a median follow-up of 5.9 months (range: 0, 24). Patient characteristics and OS/rwPFS results are shown below.

Conclusions

Clinical outcomes among previously treated advanced, PD-L1 expressing NSCLC patients were consistent with clinical trial results thus supporting the effectiveness of pembrolizumab in the real-world setting in France.

Clinical trial identification

ESMECSM2019–24.

Legal entity responsible for the study

UNICANCER.

Funding

MSD.

Disclosure

M. Pérol: Advisory/Consultancy, Advisory Boards/Symposium/Institutional grants: Roche; Advisory/Consultancy, Advisory Boards/Symposium: Eli Lilly; Advisory/Consultancy, Advisory Boards/Symposium: Novartis; Advisory/Consultancy, Advisory Boards/Symposium/Institutional grants: AstraZeneca; Advisory/Consultancy, Advisory Boards/Symposium/Institutional grants: Takeda; Advisory/Consultancy, Advisory Boards/Symposium: MSD; Advisory/Consultancy, Advisory Boards/Symposium: Bristol-Myers Squibb; Advisory/Consultancy, Advisory Boards/Symposium/Institutional grants: Boehringer-Ingelheim; Advisory/Consultancy, Advisory Boards/Symposium: Pfizer; Advisory/Consultancy, Symposium: Amgen; Advisory/Consultancy, Symposium/Institutional grants: CHUGAU; Advisory/Consultancy, Symposium: Illumina. T. Filleron: Research grant/Funding (institution): BMS. All other authors have declared no conflicts of interest.

Background

Pembrolizumab plus platinum-based chemotherapy (PC) and pembrolizumab monotherapy (PM) both become standard of care in patients with advanced non-small cell lung cancer (NSCLC) and a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) greater than 50%. This study aimed to figure out the better treatment choice.

Methods

In this retrospective analysis, we compared the clinical efficacy of PM and PC as first-line treatment in NSCLC patients with a PD-L1 ≥50% and negative for genomic alterations in the EGFR and ALK genes.

Results

Among the population, 115 patients received PC and 91 patients received PM. Up to Dec 30, 2020, median follow-up was 15.52 months. The median progression-free survival (PFS) of PC and PM were 12.37 and 9.60 months (HR:0.44, p <0.001), respectively. The median overall survival (OS) of PC had not reached while the OS of PM was 28.91 months (HR:0.40, p = 0.008). Subgroup analysis found that the PFS benefit of PC was evident in most subgroups excepting patients with brain metastasis. The 1-year overall survival rate of PC and PM were 89.0% and 78.3%, respectively. The ORR were 61.7% and 46.9% (p = 0.040), respectively.

Conclusions

In patients with previously untreated, PD-L1≥50%, advanced NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard platinum-based chemotherapy should be recommended as the preferred treatment.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Non-small cell lung cancer (NSCLC) is a type of lung cancer with a poor prognosis rate. Atezolizumab is a monoclonal antibody against PD-L1 that can restore anticancer immunity & improve overall survival in patients with advanced NSCLC. This study aims to evaluate the efficacy of atezolizumab versus chemotherapy as first-line therapy for NSCLC.

Methods

Data was collected from PMC, PubMed, Google Scholar, Science Direct, and Scopus from January 4th- 5th 2020, using a combination of keywords associated with NSCLC and treatment using atezolizumab in relation to their overall survival & were then evaluated by 7 people to minimize bias. Inclusion criteria for studies are original clinical trials published ≥ 2015 with a study population of adults (>18 years old) in manuscripts limited to English. The quality of each included study was assessed using the Newcastle-Ottawa Scale (NOS) & GRADE. 

Results

 11 clinical trial studies consisting of 8224 advanced NSCLC patients were included. The included studies were assessed using NOS & were all in good quality. 6 studies showed that atezolizumab shows significant improvement in OS compared to chemotherapy as the first-line treatment of advanced NSCLC. 5 studies found that patients treated with atezolizumab + chemotherapy (bevacizumab, carboplatin, and paclitaxel) have a more significant improvement in OS compared to those who are only treated with chemotherapy. Pooled analysis showed that atezolizumab alone significantly improve OS (HR = 0.66; 95% CI, 0.54–0.81; p < 0.0001). Combination of atezolizumab & chemotherapy also significantly improve OS (HR = 0.75; 95% CI, 0.65–0.86; p < 0.0001) in comparison with chemotherapy alone. Based on GRADE, the result of this systematic review & meta-analysis proved to be moderate in quality as there are no inconsistencies and variability in results & there are no publication biases.

Conclusions

Atezolizumab exhibits a significant improvement in OS compared to chemotherapy, and therefore may pose as a better first-line treatment option for patients with advanced NSCLC. Studies also found that atezolizumab combined with chemotherapy is the best treatment option, with remarkable efficacy and manageable safety profile.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

PD-(L)1 inhibitors, alone and in association with chemotherapy (CT), improved the outcomes of advanced, PD-L1 high non-small cell lung cancer (NSCLC) patients as compared to CT alone. Nonetheless, no direct comparison exists between these agents.

Methods

A meta-analysis of available randomized clinical trials (RCT) was performed to assess and compare efficacy and safety of PD-(L)1 inhibitor monotherapy and in addition to CT as compared to CT alone for advanced, PD-L1 high NSCLC.

Results

13 RCT (6 testing immunotherapy vs CT and 7 testing the addition of a PD-(L)1 inhibitor to CT vs CT) were included in the analysis. PD-(L)1 inhibitor monotherapy significantly improved Progression-Free Survival (PFS) [HR: 0.67; 95% CI, 0.60–0.75], Overall Survival (OS) [HR: 0.68; 95% CI, 0.60–0.76], and Objective Response Rate (ORR) [RR: 1.30; 95% CI, 1.16–1.46] as compared to CT. PD-(L)1 inhibitor monotherapy resulted to be better tolerated compared to CT, with lower incidence of grade 3–5 treatment-related adverse events (TRAEs) [RR: 0.45; 95% CI, 0.41–0.50]. A subgroup analysis performed according to the type of targeted receptor (PD-1 vs PD-L1) did not demonstrate any statistically significant difference in terms of PFS (p = 0.67), OS (p = 0.86) and ORR (p = 0.06) between PD-1 and PD-L1 inhibitors monotherapies, although a significant difference (p = 0.05) in terms of grade 3–5 TRAEs in favor of PD-1 inhibitors was reported. We then used a meta-regression analysis to compare the outcomes obtained with PD-(L)1 inhibitor monotherapy or in addition to CT vs CT in the PD-L1 high population. The combination strategy led to better PFS [HR: 0.60; 95% CI, 0.44–0.84; p = 0.002] and ORR [RR: 1.66; 95% CI, 1.14–2.42; p = 0.008] compared to PD-(L)1 inhibitor monotherapy, while no OS differences were documented [HR: 0.99; 95% CI, 0.77–1.27; p = 0.95].

Conclusions

Based on this meta-analysis, PD-1 inhibitor monotherapy might lead to better ORR and less incidence of grade 3–5 TRAEs compared to PD-L1 inhibitor monotherapy. The combination of PD-(L)1 inhibitor and CT led to improved PFS and ORR, but similar OS, as compared to PD-(L)1 inhibitor monotherapy in PD-L1 high NSCLC patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Ardizzoni: Research grant/Funding (institution): BMS; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Celgene. All other authors have declared no conflicts of interest.

Background

Nivolumab is a type of immunotherapy consisting of human IgG4 monoclonal antibody that blocks Programmed cell Death Protein-1 (PD-1). Meanwhile, ipilimumab is also a monoclonal antibody medication used to target Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4). Nivolumab and ipilimumab both show significant improvement in overall survival in the treatment of advanced non-small cell lung cancer (NSCLC). This study aims to assess the efficacy of nivolumab plus ipilimumab as first line treatment for patients with advanced NSCLC.

Methods

On January 6th 2020, data was collected from PMC, PubMed, Google Scholar, Science Direct, and Scopus, using combination of keywords associated with advanced NSCLC & treatment using nivolumab plus ipilimumab as first line treatment. Publication are published ≥2014 with English manuscripts, were all evaluated by the authors. All the studies had an inclusion criteria of any patient ≥18 years old & exclusion criteria of any patient with autoimmune disease. The quality of each included studies was assessed using the Newcastle-Ottawa Scale (NOS).

Results

A total of 8 studies consisting of 7 clinical trials & 1 cohort with a total of 7443 advanced NSCLC patients were included. All included studies were assessed using NOS, revealing 6 studies of good quality & 2 studies of moderate quality. 7 studies yield that compared to chemotherapy, nivolumab plus ipilimumab is proven to be superior & more beneficial. 1 study proved greater objective response rate (ORR), 2 studies presented improvement in overall survival, 1 study revealed greater progression-free survival rate, & 3 studies unveiled good safety profile & encouraging clinical activity & improvement in nivolumab plus ipilimumab. 1 study also proved nivolumab plus ipilimumab showed greater improvement compared to nivolumab plus chemotherapy.

Conclusions

Nivolumab plus ipilimumab had shown significant improved benefits when treating patients with advanced NSCLC compared to chemotherapy. It demonstrates good safety profile, efficacy, and clinical improvement despite a longer duration of exposure. Therefore, nivolumab and ipilimumab should be greatly considered as first-line therapy in treatment of advanced NSCLC patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

EMPOWER-Lung 4 is a phase II study evaluating cemiplimab monotherapy, and combination therapy with cemiplimab + ipilimumab, as 2L treatment in patients (pts) with advanced NSCLC and programmed cell death-ligand 1 (PD-L1) <50%. We previously reported on this study, showing that numerically better objective response rates (ORR) were observed with cemiplimab + ipilimumab vs cemiplimab monotherapy. Here, we present follow-up data including survival outcomes not previously reported.

Methods

Pts received cemiplimab 350 mg every 3 weeks (Q3W) (Arm A); or cemiplimab 350 mg Q3W plus ipilimumab 50 mg every 6 weeks (Arm B); or cemiplimab 1050 mg Q3W (Arm C), for up to 108 weeks or until progression. Primary endpoint was ORR per independent review committee (IRC). Data cut-off was 30 Jun 2020.

Results

Of 28 pts enrolled, 27 received treatment (Arm A, n = 8; Arm B, n = 11; and Arm C, n = 8). Median duration of treatment exposure was 10.8 (Arm A), 17.9 (Arm B) and 10.8 (Arm C) weeks. Median follow-up was 2.6 (Arm A), 17.4 (Arm B) and 3.9 (Arm C) months. ORR (95% confidence interval [CI]) remained unchanged since the previous report: 0% (0.0–36.9%) in Arm A, 45.5% (16.7–76.6%) in Arm B, and 11.1% (0.3–48.2%) in Arm C, with a median duration of response not reached (NR) in Arm B and 11.2 months in Arm C. Median overall survival (OS) (95% CI) per IRC was 5.1 months (1.7–not evaluable [NE]) in Arm A, NR (2.2–NE) in Arm B and 8.4 months (0.3–NE) in Arm C. Median progression-free survival (PFS) (95% CI) per IRC was 2.0 months (0.7–8.3) in Arm A, NR (1.2–NE) in Arm B and 1.8 months (0.3–12.7) in Arm C. Grade ≥3 treatment-emergent adverse events (AEs) occurred in 25.0% (Arm A), 72.7% (Arm B) and 75.0% (Arm C) of pts. Across all arms, increased alanine aminotransferase was the only Grade ≥3 immune-related AE reported in >1 pt (n = 2 [18.2%]; both in Arm B).

Conclusions

This follow-up analysis which includes OS/PFS data shows that combination of ipilimumab 50 mg with cemiplimab 350 mg provides additional survival improvement in pts with advanced NSCLC and PD-L1 <50%. Moreover, consistency in ORR with the previous analysis demonstrates durability of responses to cemiplimab 350 mg + ipilimumab 50 mg.

Clinical trial identification

NCT03430063.

Editorial acknowledgement

Medical writing support was provided by Atif Riaz, PhD of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc. and Sanofi.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc. and Sanofi.

Funding

Regeneron Pharmaceuticals, Inc. and Sanofi.

Disclosure

S. Lee: Shareholder/Stockholder/Stock options, Full/Part-time employment: Regeneron Pharmaceuticals, Inc. J. de Castro Carpeño: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses: Hoffmann-la Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp and Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Takeda. M. Majem Tarruella: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Kyowa Kirin; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche. Y. Summers: Advisory/Consultancy: Bristol-Myers Squibb. Y. Xu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Regeneron Pharmaceuticals, Inc. I. Lowy: Shareholder/Stockholder/Stock options, Full/Part-time employment: Regeneron Pharmaceuticals, Inc. P. Rietschel: Shareholder/Stockholder/Stock options, Full/Part-time employment: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.