Nivolumab Plus Erlotinib in Patients With EGFR-Mutant Advanced NSCLC

Introduction

This phase I study evaluated nivolumab combined with erlotinib in patients with advanced EGFR-mutant NSCLC.

Renal Effects of Crizotinib in Patients With ALK-Positive Advanced NSCLC

IntroductionWe retrospectively analyzed the effects of crizotinib on serum creatinine and creatinine-based estimated glomerular filtration rate (eGFR) in patients with anaplastic lymphoma kinase–positive advanced NSCLC across four trials (NCT00585195, NCT00932451, NCT00932893, and NCT01154140).MethodsChanges from baseline data in serum creatinine and eGFR, calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based equation, were assessed over time. eGFR was graded using standard chronic kidney disease criteria.ResultsMedian serum creatinine increased from 0.79 mg/dL at baseline to 0.93 mg/dL after 2 weeks of treatment (median percentage increase from baseline, 21.2%), was stable from week 12 (0.96 mg/dL) to week 104 (1.00 mg/dL), and decreased to 0.90 mg/dL at 28 days after last dose (median percentage increase from baseline, 13.1%). Median eGFR decreased over time (96.42, 80.23, 78.06 and 75.45 mL/min/1.73 m² at baseline, week 2, week 12, and week 104, respectively) and increased to 83.02 mL/min/1.73 m² at 28 days after the last dose. Median percentage decrease from baseline was 14.9%, 17.0%, and 10.4% at week 2, week 12, and 28 days after last dose of crizotinib, respectively. Overall, 12.6% of patients had a shift from eGFR grade less than or equal to 3a (≥45 mL/min/1.73 m²) at baseline to greater than or equal to 3b (<45 mL/min/1.73 m²) post-baseline.ConclusionsCrizotinib resulted in a decline in creatinine-based estimates of renal function mostly over the first 2 weeks of treatment. However, there was minimal evidence of cumulative effects with prolonged treatment and these changes were largely reversible following treatment discontinuation, consistent with previous reports suggesting this may be predominantly an effect on creatinine secretion as opposed to true nephrotoxicity.     

Safety,Clinical Activity,and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation

IntroductionAlflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M-resistant mutations. We assessed the safety, efficacy, and pharmacokinetics of alflutinib in patients with advanced NSCLC with confirmed EGFR T790M mutation, whose status progressed after the first- or second-generation EGFR tyrosine kinase inhibitor therapy.MethodsIn the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. The primary end points were safety, tolerability, and pharmacokinetics for the dose-escalation study and the objective response rate (assessed by an independent radiological review committee) for the dose-expansion study.ResultsBetween November 30, 2016, and July 24, 2018, a total of 130 patients (14 in dose escalation, 116 in dose expansion) received alflutinib treatment (20 mg, 40 mg, 80 mg, 160 mg, or 240 mg once daily). On October 30, 2018, 79 patients (61%) remained on the treatment. No dose-limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40–240 mg), the overall objective response rate was 76.7% (89 of 116), and it was 70.6% in patients with central nervous system metastases (12 of 17). A total of 79% of all patients had possibly treatment-related adverse events (AEs) (103 of 130); 8% had treatment-related grade 3 or higher AEs (11 of 130). Serious AEs were reported in 15% of patients (20 of 130), and two serious AEs were related to treatment. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state.ConclusionsAlflutinib was clinically effective with an acceptable toxicity profile in patients with advanced NSCLC (including those with central nervous system metastases) with EGFR T790M mutation. Further investigation is ongoing.     

Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases

IntroductionLeptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.MethodsWe conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.ResultsNinety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0–9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [CI]: 4.2–7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7–10.9) compared to 4.2 months (95% CI: 1.6–6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first- and second-generation TKI experienced clinical benefit.ConclusionsTKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure.     

Clinical Experience With Ibrutinib Alone or in Combination With Either Cytarabine or Azacitidine in Patients With Acute Myeloid Leukemia

BackgroundPreclinical studies have suggested a role for Bruton tyrosine kinase (BTK) as a potential therapeutic target in acute myeloid leukemia (AML), and anti-AML activity in vivo has been demonstrated with BTK inhibitors.Patients and MethodsIn this open-label phase 2a study, patients with AML were treated with ibrutinib 560 mg per day alone (cohort 1; n = 7), or ibrutinib in combination with either cytarabine 20 mg administered subcutaneously twice daily for 10 days of a 28-day cycle (cohort 2; n = 21) or azacitidine 75 mg/m² administered intravenously once daily on days 1 to 7 of a 28-day cycle (cohort 3; n = 8). Best overall response (primary end point), overall survival, and safety were summarized.ResultsA total of 36 patients were enrolled and received treatment; median duration of ibrutinib treatment was 5.4 weeks, and median time on study was 16 months. Of 24 patients evaluable for response, 1 partial remission (cohort 3) and 1 complete remission (cohort 2) were observed; the remaining responses were treatment failures. Median overall survival was 4.0 months in cohort 1, 2.2 months in cohort 2, 2.8 months in cohort 3, and 2.4 months for the overall population. No unexpected safety signals were identified. Grade 3 or higher adverse events that occurred in ≥ 10% of patients included AML progression, febrile neutropenia, pneumonia, anemia, thrombocytopenia, fatigue, asthenia, and respiratory failure.ConclusionIbrutinib alone or in combination with cytarabine or azacitidine demonstrated an acceptable safety profile. However, limited efficacy with ibrutinib was observed in patients with AML.     

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC

IntroductionFirst-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC.MethodsThis open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety.ResultsA total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6–19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6–18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67–1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5–8.5) and 3.2 months (95% CI: 2.7–5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52–0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04–2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS.ConclusionsThe addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.     

Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II Study

PurposeDespite high tumor mutationburden, immune checkpoint blockade has limited efficacy in SCLC. We hypothesized that poly (ADP-ribose) polymerase inhibition could render SCLC more susceptible to immune checkpoint blockade.MethodsA single-arm, phase II trial (NCT02484404) enrolled patients with relapsed SCLC who received durvalumab, 1500 mg every 4 weeks, and olaparib, 300 mg twice a day. The primary outcome was objective response rate. Correlative studies included mandatory collection of pretreatment and during-treatment biopsy specimens, which were assessed to define SCLC immunephenotypes: desert (CD8-positive T-cell prevalence low), excluded (CD8-positive T cells in stroma immediately adjacent/within tumor), and inflamed (CD8-positive T cells in direct contact with tumor).ResultsA total of 20 patients were enrolled. Their median age was 64 years, and most patients (60%) had platinum-resistant/refractory disease. Of 19 evaluable patients, two were observed to have partial or complete responses (10.5%), including a patient with EGFR-transformed SCLC. Clinical benefit was observed in four patients (21.1% [95% confidence interval: 6.1%–45.6%]) with confirmed responses or prolonged stable disease (≥8 months). The most common treatment-related adverse events were anemia (80%), lymphopenia (60%), and leukopenia (50%). Nine of 14 tumors (64%) exhibited an excluded phenotype; 21% and 14% of tumors exhibited the inflamed and desert phenotypes, respectively. Tumor responses were observed in all instances in which pretreatment tumors showed an inflamed phenotype. Of the five tumors without an inflamed phenotype at baseline, no during-treatment increase in T-cell infiltration or programmed death ligand 1 expression on tumor-infiltrating immune cells was observed.ConclusionsThe study combination did not meet the preset bar for efficacy. Pretreatment and during-treatment biopsy specimens suggested that tumor immune phenotypes may be relevant for SCLC responses to immune checkpoint blockade combinations. The predictive value of preexisting CD8-positive T-cell infiltrates observed in this study needs to be confirmed in larger cohorts.     

Association of Early Palliative Care With Chemotherapy Intensity in Patients With Advanced Stage Lung Cancer: A National Cohort Study

Introduction

Patients with advanced lung cancer have a poor prognosis, but both chemotherapy and early palliative care (EPC) have been shown to improve survival and quality of life (QOL). The relationship between palliative care and receipt of chemotherapy receipt is understudied. We sought to determine if EPC is associated with chemotherapy receipt and intensity among patients with advanced stage lung cancer.

Body Mass Index (BMI), BMI Change,and Overall Survival in Patients With SCLC and NSCLC: A Pooled Analysis of the International Lung Cancer Consortium

IntroductionThe relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied.MethodsIndividual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots.ResultsOverall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m²; aHR = 1.56; 95% confidence interval [CI]:1.43–1.70) or morbidly overweight (BMI > 40 kg/m²; aHR = 1.09; 95% CI: 0.95–1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m² ≤ BMI < 30 kg/m²; aHR = 0.89; 95% CI: 0.85–0.95) or obese (30 kg/m² ≤ BMI ≤ 40 kg/m²; aHR = 0.86; 95% CI: 0.82–0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2–1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0–1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets.ConclusionsBoth being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.     

Preclinical Modeling of Osimertinib for NSCLC With EGFR Exon 20 Insertion Mutations

IntroductionNSCLC with EGFR exon 20 insertion mutations is the third most common type of EGFR-mutant NSCLC and is resistant to EGFR tyrosine kinase inhibitors (TKIs). This study was conducted to evaluate the efficacies of first- to third-generation EGFR TKIs against NSCLC cells harboring EGFR exon 20 insertion mutations.MethodsWe developed seven EGFR exon 20 insertion-mutant Ba/F3 models and one patient-derived NSCLC (SNU-3173) of subtypes A763insFQEA, V769insASV, D770insSVD, D770insNPG, P772insPR, H773insH, H773insNPH, and H773insAH. Cell viability assays, immunoblotting, and N-ethyl-N-nitrosourea mutagenesis screenings were performed. EGFR exon 20 insertion–mutant structures and couplings with osimertinib, a third-generation EGFR TKI, were modeled and compared.ResultsEGFR exon 20 insertion–mutant NSCLC cells, excluding EGFR A763insFQEA, were resistant to first-generation EGFR TKIs (concentration that inhibits 50% [IC₅₀], 1.1 ± 0.067 to 5.4 ± 0.115 μM). Mutants were sensitive to second-generation EGFR TKIs (IC₅₀, 0.02 ± 0.0002 to 161.8 ± 18.7nM), except EGFR H773insH (IC₅₀, 46.3 ± 8.0 to 352.5 ± 22.7nM). The IC₅₀ ratios for mutant to wild-type cells were higher than those for third-generation EGFR TKIs. Third-generation EGFR TKI osimertinib was highly potent against EGFR exon 20 insertion–mutant cells (IC₅₀, 14.7-62.7 nM), including EGFR H773insH, and spared wild-type EGFR cells. N-ethyl-N-nitrosourea mutagenesis screening of EGFR exon 20 insertion–mutant Ba/F3 cells showed various second sites for EGFR mutations, mostly at exons 20 and 21, including E762K, P794S, and G796D. In addition, osimertinib-resistant cells were established by stepwise exposure to osimertinib and harbored EGFR E762K mutation.ConclusionsOsimertinib is active against EGFR exon 20 insertion–mutant NSCLC and flexibly binds within drug-binding pockets in preclinical models.     

Improved Prognosis and Increased Tumor-Infiltrating Lymphocytes in Patients Who Have SCLC With Neurologic Paraneoplastic Syndromes

BackgroundApproximately 10% of patients with SCLC develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor-infiltrating lymphocytes and immune recognition.MethodsWe queried 2,512,042 medical records from a single institution to identify patients who have SCLC with and without PNS and performed manual, retrospective chart review. We then performed multiplexed fluorescence immunohistochemistry and automated quantitative analysis (AQUA Technology) on tumors to assess CD3, CD4, and CD8 T cell infiltrates and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interactions. T cell infiltrates and PD-1/PD-L1 interaction scores were compared among patients with neurologic PNS, endocrinologic PNS, and a control group without PNS. Clinical outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards models.ResultsWe evaluated 145 SCLC patients: 55 with PNS (25 neurologic and 30 endocrinologic) and 90 controls. Patients with neurologic PNS experienced improved overall survival compared to patients with endocrinologic PNS and controls (median overall survival of 24 months versus 12 months versus 13 months, respectively). Of the 145 patients, we identified tumor tissue from 34 patients that was adequate for AQUA analysis. Among 37 specimens from these 34 patients, patients with neurologic PNS had increased T cell infiltrates (p = 0.033) and PD-1/PD-L1 interaction (p = 0.014) compared to tumors from patients with endocrinologic PNS or controls.ConclusionsTumor tissue from patients with SCLC with neurologic PNS showed increased tumor-infiltrating lymphocytes and PD-1/PD-L1 interaction consistent with an inflamed tumor microenvironment.     

Safety,Efficacy, and Pharmacokinetics of Rezivertinib (BPI-7711) in Patients With Advanced NSCLC With EGFR T790M Mutation: A Phase 1 Dose-Escalation and Dose-Expansion Study

IntroductionRezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M mutations. This study was designed to evaluate the safety, efficacy, and pharmacokinetics of rezivertinib for patients having advanced NSCLC with EGFR T790M mutation.MethodsThis phase 1 study (NCT03386955) was conducted across 20 sites in the People's Republic of China. Patients received rezivertinib at six oral dose levels (30 mg, 60 mg, 120 mg, 180 mg, 240 mg, 300 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were safety for the dose-escalation phase and objective response rate by the blinded independent central review for the total study population.ResultsA total of 19 patients in dose-escalation phase using the standard 3 + 3 design principle and 153 patients in dose-expansion phase were enrolled from September 11, 2017, to August 23, 2019. The data cutoff date was on June 15, 2020. No dose-limiting toxicity occurred in the dose-escalation phase. The treatment-related adverse events were observed in 82.0% (141 of 172) of patients, and 17.4% (30 of 172) had grade greater than or equal to 3, among which decreased neutrophil count (2.9%), leukopenia (2.9%), and pneumonia (2.9%) were the most common. The overall blinded independent central review–evaluated objective response rate was 59.3% (102 of 172, 95% confidence interval: 51.6–66.7), and the median progression-free survival was 9.7 (95% confidence interval: 8.3–11.1) months.ConclusionsRezivertinib was found to have promising efficacy with a manageable safety profile in patients with EGFR T790M-mutated advanced NSCLC. Further study is warranted.     

Peptide Receptor Radionuclide Therapy for Patients With Advanced Lung Carcinoids

Neuroendocrine neoplasms (NEN) are a family of malignancies of diverse origin, including the lung, gastrointestinal tract, and pancreas. Lung NEN include well differentiated neuroendocrine tumors (NET) classified as typical carcinoids or atypical carcinoids, and poorly differentiated neuroendocrine carcinomas classified as small-cell lung carcinoma or large-cell neuroendocrine carcinoma. According to a recent analysis of a large, population-based registry, approximately one-third of all patients with lung typical/atypical carcinoids have distant metastases at diagnosis, and median survival for these patients is 24 months. At present, only 1 therapy is approved by the US Food and Drug Administration (FDA) for patients with advanced lung typical/atypical carcinoids, everolimus, indicating a clear need for more treatment options in this patient population. Although not yet supported by results from randomized prospective trials, somatostatin analogues are considered an acceptable treatment option for patients with lung typical/atypical carcinoids expressing somatostatin receptors. Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE was recently approved by the FDA for the treatment of gastroenteropancreatic NET; however, the role of PRRT in patients with lung typical/atypical carcinoids remains unclear, because they were not included in the pivotal NETTER-1 (Neuroendocrine Tumors Therapy) trial. Herein we provide a comprehensive review of the available clinical evidence for efficacy and safety of PRRT in patients with lung typical/atypical carcinoids. On the basis of the preliminary evidence of efficacy and the consistent safety profile in this patient group, we propose that experienced multidisciplinary NET teams may consider PRRT alongside everolimus as an option for patients with advanced somatostatin receptor-positive lung typical/atypical carcinoids whose disease is progressing during first-line treatment with somatostatin analogues.     

Long-Term Follow-Up of Ground-Glass Nodules After 5 Years of Stability

IntroductionSmall ground-glass nodules (GGNs) or those with an indeterminate risk on low-dose computed tomography (LDCT) of the chest are recommended at 5-year follow-up, but the rationale for follow-up beyond 5 years is unclear.MethodsAn observational study was conducted to investigate the natural course of GGNs that had been stable for 5 years by LDCT over 10 years. All eligible GGNs were detected during regular health checkups. Baseline characteristics were compared between GGNs with and without growth. Risk factors for GGN growth were evaluated.ResultsA total of 208 GGNs were detected in 160 participants. GGN growth was identified in 27 (13.0%) GGNs during a follow-up of 136 months on LDCT scans. In approximately 95% of these GGNs, the initial size was less than 6 mm, with 3.2 mm of growth over 8.5 years. Biopsies were performed in 3 of 27 GGNs, revealing adenocarcinoma. In 8 of 27 cases, GGN growth preceded the development of a new solid component. In a multivariate analysis, bubble lucency (p = 0.001), a history of cancer other than lung cancer (p = 0.036), and development of a new solid component (p < 0.001) were significant risk factors for GGN growth.ConclusionsGGNs should not be ignored, even when smaller than 6 mm and stable for 5 years, especially when a new solid component appears during follow-up.     

Chronological Trends in Progression-Free,Overall, and Post-Progression Survival in First-Line Therapy for Advanced NSCLC

BackgroundThere is a debate about the merits of progression-free survival (PFS) versus overall survival (OS) as primary endpoints in NSCLC. It has been postulated that post-progression therapy may influence OS in both arms. To investigate this issue, we analyzed chronological trends in PFS and OS in advanced NSCLC using restricted mean survival times (RMSTs).MethodsWe digitized survival curves from first-line phase III trials published between 1998 and 2015 in 13 leading journals to compute RMSTs for PFS and OS at three truncation landmarks (5, 12, and 18 months).ResultsAmong the 161 trials identified, RMSTs could be computed for both endpoints in 102, 97, and 82 trials for the 5-, 12-, and 18-month truncation landmarks, respectively. Post-progression survival in the control arm, quantified as mean OS minus mean PFS truncated at 18 months, was on average 3.3 months between 1998 and 2003, 4.4 months between 2004 and 2009, and 5.4 months between 2010 and 2015. This increase was due to increasing RMST for OS over time, with no increase in RMST for PFS. The average within-trial difference in RMSTs between experimental and control arm was close to 0 for OS and less than 1 month for PFS.ConclusionsThere is a progressive increase in post-progression survival in NSCLC trials, likely from salvage therapy. These results question both PFS and OS as sensitive endpoints in first-line trials, but suggest that the outlook for patients is improving regardless of within-trial gains.