Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study
Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapyin patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC.
Methods
In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs ≥1%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p<0·025 (one sided). Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned study treatment. This trial, which is closed for enrolment but continuing for follow-up, is registered with ClinicalTrials.gov, number NCT02039674.
Findings
Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9–42%]; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia.
Interpretation
Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study.
Funding
Merck & Co.
Introduction
Currently, the standard first-line therapy for patients with advanced non-squamous non-small-cell lung cancer (NSCLC) without targetable genetic aberrations is platinum-doublet chemotherapy. With the exception of bevacizumab,1, 2 and despite extensive study of multiple targeted and cytotoxic agents, the addition of a third agent to platinum-doublet chemotherapy has not been shown to improve progression-free or overall survival over platinum-doublet chemotherapy alone in randomised studies.
Research in context
Evidence before this study
We searched PubMed on Sept 4, 2016, using the following terms: “PD-1 OR PD-L1 OR MK-3475 OR pembrolizumab OR lambrolizumab OR Keytruda OR nivolumab OR BMS-936558 OR Opdivo OR atezolizumab OR MPDL3280A OR Tecentriq OR durvalumab OR MEDI4736 OR avelumab” AND “platinum-doublet chemotherapy OR triple chemotherapy OR triple therapy OR maintenance therapy OR carboplatin and pemetrexed OR cisplatin AND pemetrexed” AND “advanced non–small-cell lung cancer OR NSCLC”. The search was not limited by date, but was limited to articles and abstracts published in English only. We also searched the abstracts for the 2015 and 2016 American Society of Clinical Oncology Annual Meetings, the 2015 European Cancer Congress, and the 2015 World Conference for Lung Cancer using the same search terms. Similar to the phase 1 cohorts of KEYNOTE-021, these two studies suggested that addition of anti-PD-1 or anti-PD-L1 therapy to platinum-doublet chemotherapy had a manageable safety profile and promising antitumour activity. A thorough review of the literature showed that most large, randomised, controlled clinical studies did not show superior efficacy or a favourable benefit-risk profile for the addition of a third agent to platinum-doublet chemotherapy in the first-line advanced non-small-cell lung cancer setting. One notable exception is the addition of bevacizumab to platinum-doublet chemotherapy, which showed superior efficacy to platinum-doublet chemotherapy alone and a manageable safety profile in randomised, controlled clinical studies.
Added value of this study
Results of this cohort of KEYNOTE-021 show that addition of pembrolizumab to carboplatin and pemetrexed improves efficacy and has a favourable benefit-to-risk profile in patients with chemotherapy-naive, advanced non-squamous NSCLC. Not only do these data represent, to the best of our knowledge, the first published report of a randomised, controlled clinical trial in NSCLC to prospectively show a benefit of addition of a PD-1 pathway inhibitor to chemotherapy, they are also among the only randomised data to show a benefit of adding a third agent to platinum-doublet chemotherapy.
Implications of all the available evidence
Our data suggest that the addition of pembrolizumab to platinum-doublet chemotherapy is an effective treatment option with a manageable, predictable safety profile for patients with chemotherapy-naive, advanced, non-squamous NSCLC. The efficacy and safety of addition of pembrolizumab to platinum-doublet chemotherapy as first-line therapy for advanced NSCLC is being further explored in two ongoing international, randomised, double-blind, phase 3 studies: the KEYNOTE-189 study of platinum and pemetrexed with or without pembrolizumab in patients with non-squamous non–small-cell lung cancer (NCT02578680) and the KEYNOTE-407 study of carboplatin and paclitaxel or nab-paclitaxel with or without pembrolizumab in patients with squamous NSCLC (NCT02775435).
When used as monotherapy in patients with advanced NSCLC, drugs targeting programmed death 1 (PD-1) and its ligand, PD-L1, have shown a manageable safety profile and robust efficacy, including a significant prolongation of overall survival compared with docetaxel in patients whose disease progressed on platinum-based chemotherapy.3, 4, 5, 6, 7, 8, 9, 10 One of these therapies is pembrolizumab, a humanised, monoclonal antibody against PD-1 that prevents PD-1 from binding to its ligands, PD-L1 and PD-L2. Evidence for the efficacy and safety of pembrolizumab in both treatment-naive and previously treated advanced NSCLC initially came from the large, multicohort KEYNOTE-001 study, which showed a correlation between PD-L1 expression on tumour cells and response to pembrolizumab.3, 4 The efficacy and safety of pembrolizumab monotherapy was confirmed in the international, randomised KEYNOTE-010 study, in which pembrolizumab yielded superior overall survival compared with docetaxel in patients with previously treated, PD-L1-expressing (ie, PD-L1 tumour proportion score ≥1%), advanced NSCLC.5
Increasing evidence suggests that the antitumour activity of chemotherapy is mediated not only though cytotoxic effects, but also through immunological effects, including reducing T-regulatory cell activity and enhancing cross-presentation of tumour antigens.11, 12, 13 Chemotherapy has also been shown to induce PD-L1 expression on tumour cells.14, 15, 16 Combining immunotherapy and chemotherapy could thus synergistically improve the anticancer activity of anti-PD-1 and anti-PD-L1 monotherapy.11, 12, 13 Early clinical data for combinations of chemotherapy with PD-117, 18 and PD-L119 inhibitors have suggested that these regimens have manageable toxicity and promising antitumour activity as first-line therapy for advanced NSCLC with non-overlapping toxicity profiles. In the international, multi-cohort, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov number NCT02039674), the safety and anti-tumour activity of pembrolizumab added to either carboplatin and paclitaxel (cohort A), carboplatin, paclitaxel, and bevacizumab (cohort B), or pemetrexed and carboplatin (cohort C) were assessed.18 All three combinations showed promising antitumour activity irrespective of tumour PD-L1 expression, with manageable safety profiles observed in cohorts A and C. The greatest antitumour activity was observed in cohort C (N=24), where the combination of pembrolizumab, carboplatin, and pemetrexed resulted in 17 (71%) of 24 patients achieving an overall response and a median progression-free survival of 10·2 months (95% CI 6·2–15·2).18
Based on these results and to further explore the potential synergy of combining chemotherapy with immunotherapy, we aimed to compare the efficacy and safety of pembrolizumab at a fixed intravenous dose of 200 mg plus carboplatin and pemetrexed versus those of carboplatin and pemetrexed alone as first-line therapy for patients with advanced NSCLC of non-squamous histology as part of KEYNOTE-021.
Section snippets
Study design and participants
This randomised, controlled, phase 2 study was done at 26 academic medical centres in the USA and Taiwan (appendix p 2). Eligibility criteria stipulated no previous systemic treatment for histologically or cytologically confirmed non-squamous, stage IIIB or IV NSCLC and the absence of targetable EGFR mutations or ALK translocations. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (a 5-point scale where higher numbers indicate greater
Results
Between Nov 25, 2014, and Jan 25, 2016, 219 patients were screened for enrolment at 23 sites in the USA and three sites in Taiwan (figure 1). 123 (56%) of these patients met all eligibility criteria and were randomly assigned; 60 (49%) were allocated to pembrolizumab plus carboplatin and pemetrexed and 63 (51%) to carboplatin and pemetrexed alone (figure 1). One patient in the pembrolizumab plus chemotherapy group had deterioration in their ECOG performance status to a score of 2 after
Discussion
The addition of pembrolizumab to standard-of-care carboplatin and pemetrexed followed by pembrolizumab for 2 years and indefinite pemetrexed maintenance therapy significantly improved the proportion of patients who achieved an objective response compared with carboplatin and pemetrexed alone in patients with chemotherapy-naive, advanced non-squamous NSCLC. In addition, this combination also significantly prolonged progression-free survival in this non-squamous NSCLC population. These data
The combo treatment of chemo/immunotherapy is a promising method in treating cancer patients. The results of Keynote-189 phase III clinical trial showed that chemotherapy drug plus immunotherapy drug reduced mortality compared with chemotherapy drug alone, in which the underlying mechanism has not been well demonstrated. The treatment combination also needs to be tuned for each patient, i.e., personalized medicine. Tumor-on-a-chip aims to mimic the tumor microenvironment (TME) with an in-vitro lung cancer-immune model to provide a potential solution for this application. Gelatin methacryloyl (GelMA)-cancer cells were driven on the ITO electrode track using liquid dielectrophoresis (LDEP) to form the tumor-like hydrogel. Jurkat T cells surrounded the solidified GelMA-A549 cells, resembling the cancer-immune microenvironment. The immune-cell infiltration phenomena of Jurkat T cells into the tumor were activated and enhanced via either IL-1β-treated A549 cells or atezolizumab (immune drugs) on the tumor lab chip. The death of cancer cells significantly increased ∼35% after chemo/immunotherapy combination treatment compared with the single treatment. The distribution of dead cancer cells treated with chemo/immunotherapy revealed their distinct theoretical mechanisms, indicating the promising application of this tumor lab chip for cancer patients in personalized medicine treatments.
Recent evidence suggests that PD-1/PD-L1 immunotherapy improves outcomes in patients with brain metastatic non-small cell lung cancer.
Records were searched electronically on MEDLINE, Embase and BIOSIS. Hazard ratios and their 95% confidence intervals for overall survival and progression free survival, and treatment-related adverse events data were extracted. Risk of bias was assessed in included studies using the Cochrane Collaboration's revised tool to assess risk of bias in randomized trials.
PD-1/PD-L1 immunotherapy increased overall survival by 33% and progression free survival by 47% compared with chemotherapy. Two studies had a high risk of bias. Treatment-related adverse events were reported in 95%, 89% and 65% of patients receiving chemoimmunotherapy,chemotherapy and single agent immunotherapy, respectively.
PD-1/PD-L1 inhibitors alone or in addition to chemotherapy increase overall and progression free survival when compared with chemotherapy alone. Chemoimmunotherapy and chemotherapy patients experienced the most treatment-related adverse events.
2024, International Journal of Radiation Oncology Biology Physics
A phase 2 study of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy in metastatic non-small cell lung cancer (mNSCLC) followed by pembrolizumab (STOMP) was designed to explore the dual approach in enhancing single pembrolizumab with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mNSCLC.
STOMP is a single-arm, open-label phase 2 study. Patients with mNSCLC received intratumoral injections of ADV/HSV-tk (5 × 1011 vp) and SBRT (30 Gy in 5 fractions) followed by pembrolizumab 200 mg IV every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR) (complete response [CR] and partial response [PR]). Secondary endpoints included clinical benefit rate (CBR) (CR, PR and stable disease [SD]), progression-free survival (PFS), overall survival (OS), and safety.
28 patients were enrolled, of whom 27 were evaluated for response. The ORR was 33.3%, including 2 CR (7.4%) and 7 PR (25.9%). CBR was 70.4%. Six of eight (75.0%) patients who were immune checkpoint inhibitor (ICI) refractory derived clinical benefits. Responders had durable responses with median PFS, and OS not reached. The entire cohort had a median PFS of 7.4 months (95% CI, 5.1-9.6 months), and median OS of 18.1 months (95% CI, 15.4-20.9 months). The combination was well tolerated, with grade 3 or higher toxicity in 6 (21.4%) patients.
The dual approach of in situ ADV/HSV-tk plus valacyclovir gene therapy and SBRT as a chemotherapy-sparing strategy to enhance the antitumor effect of pembrolizumab is a well-tolerated encouraging treatment in patients with mNSCLC.
Immune checkpoint inhibitors (ICI) plus chemotherapy is the preferred first-line treatment for advanced driver-negative lung adenocarcinoma (LUAD). The DNA damage response (DDR) is the main mechanism underlying chemotherapy resistance, and EGLN3 is a key DDR component.
We conducted an analysis utilizing TCGA and GEO databases employing multiple labels-WGCNA, DEGs, and prognostic assessments. Using bulk RNA-seq and scRNA-seq data, we isolated EGLN3 as the single crucial DDR gene. Spatial transcriptome analysis revealed the spatial differential distribution of EGLN3. TIDE/IPS scores and pRRophetic/oncoPredict R packages were used to predict resistance to ICI and chemotherapy drugs, respectively.
EGLN3 was overexpressed in LUAD tissues (p < 0.001), with the high EGLN3 expression group exhibiting a poor prognosis (p = 0.00086, HR: 1.126 [1.039−1.22]). Spatial transcriptome analysis revealed EGLN3 overexpression in cancerous and hypoxic regions, positively correlating with DDR-related and TGF-β pathways. Drug response predictions indicated EGLN3's resistance to the common chemotherapy drugs, including cisplatin (p = 6.1e−14), docetaxel (p = 1.1e−07), and paclitaxel (p = 4.2e−07). Furthermore, on analyzing the resistance mechanism, we found that EGLN3 regulated DDR-related pathways and induced chemotherapy resistance. Additionally, EGLN3 influenced TGF-β signaling, Treg cells, and cancer-associated fibroblast cells, culminating in immunotherapy resistance. Moreover, validation using real-world data, such as GSE126044, GSE135222, and, IMvigor210, substantiated the response trends to immunotherapy and chemotherapy.
EGLN3 emerges as a potential biomarker predicting lower response to both immunotherapy and chemotherapy, suggesting its promise as a therapeutic target in advanced LUAD.
We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors.
Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B.
In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional.
Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited.