Conference Correspondent – August 2016
In This Article
- Cost-Effectiveness of Immune Checkpoint Inhibitors in NSCLC According to PD-L1 Expression
- PD-L1 Expression and Outcomes with Pembrolizumab versus Docetaxel in Previously Treated NSCLC: KEYNOTE-010
- Pembrolizumab plus Chemotherapy as Front-Line Therapy for Advanced NSCLC: KEYNOTE-021
- Alectinib versus Crizotinib in ALK Inhibitor–Naïve, ALK Mutation–Positive NSCLC: The J-ALEX Study
- Pembrolizumab plus Ipilimumab as Second-Line Therapy for NSCLC: KEYNOTE-021
- TKIs in Advanced NSCLC Associated with Concomitant c-MET Overexpression and EGFR Mutations
- Crizotinib in Advanced, MET Exon 14–Altered NSCLC
- Vandetanib in Advanced, RET-Rearranged NSCLC: The Luret Study
- Nivolumab versus Docetaxel in Advanced NSCLC: A 2-Year Update of CheckMate-017 and CheckMate-057
Cost-Effectiveness of Immune Checkpoint Inhibitors in NSCLC According to PD-L1 Expression
Immune checkpoint inhibitors are active in the treatment of patients with non–small-cell lung cancer (NSCLC). PD-L1 expression is being studied as a predictive biomarker for this therapy.
Pedro Nazareth Aguiar, MD, MSc, Federal University of Sao Paulo, Brazil, and colleagues evaluated the cost-effectiveness of nivolumab and pembrolizumab with and without the use of PD-L1 as a biomarker in patients with NSCLC. A systematic literature review of online databases and oncology conference presentations included studies that assessed PD-L1 expression as a biomarker.
A decision-analytic model was developed to determine the cost-effectiveness of PD-L1 testing and second-line treatment with nivolumab and pembrolizumab versus docetaxel, in patients with advanced NSCLC. Health effects were expressed as quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated.
Overall, 13 studies (4 of which were randomized) with 2700 patients were included in the model. PD-L1 expression was associated with a greater likelihood of response (relative risk [RR], 2.08), which was more intense in nonsquamous (RR, 3.13) than squamous tumors (RR, 2.12).
PD-L1 expression was also correlated with longer progression-free survival (PFS) and better overall survival (OS). Regarding cost-effectiveness, PD-L1 expression ≥1% improved incremental QALY of nivolumab versus docetaxel for patients with nonsquamous tumors by 67%, leading to a 40% reduction in the ICER (from $176K to $105K). This effect was not observed in patients with squamous tumors.
For pembrolizumab, using a 50% cutoff instead of a 1% cutoff increased the incremental QALY by 18%, leading to a 15% reduction in ICER (from $163K to $138K).The use of PD-L1 expression as a biomarker may increase the cost-effectiveness of treatment with immune checkpoint inhibitors, but this effect is less robust in patients with squamous than nonsquamous NSCLC.
Source: Aguiar PN, Tadokoro H, Noia Barreto CM, et al. Cost effectiveness of immune checkpoint inhibitors in NSCLC according to PD-L1 expression. J Clin Oncol. 2016;34(15 suppl). Abstract 9033.
PD-L1 Expression and Outcomes with Pembrolizumab versus Docetaxel in Previously Treated NSCLC: KEYNOTE-010
Pembrolizumab is a humanized, anti–PD-1 monoclonal antibody approved for PD-L1–expressing advanced NSCLC that progressed after platinum-based chemotherapy and an approved EGFR or ALK inhibitor. In the phase 3 KEYNOTE-010 study, pembrolizumab 2 mg/kg and 10 mg/kg provided superior OS over docetaxel in patients with previously treated PD-L1–positive advanced NSCLC with tumor proportion score (TPS) ≥1% (Herbst RS, et al. Lancet. 2016;387:1540-1550).
Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, and colleagues assessed OS, PFS, and objective response rate (ORR) in the KEYNOTE-010 study when PD-L1 was further categorized as TPS 1% to 24%, 25% to 49%, 50% to 74%, and ≥75%. Patients with disease progression after ≥2 cycles of platinum-doublet chemotherapy and PD-L1 TPS ≥1% were randomized to pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or docetaxel 75 mg/m2 every 3 weeks for 24 months or until disease progression, intolerable toxicity, or other reasons.
PD-L1 TPS 1% to 49% versus TPS ≥50% was a randomization stratification factor. Response was assessed centrally according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Of the 1478 patients who met the eligibility criteria and enrolled in the study, PD-L1 TPS was 1% to 24% in 45.6% of patients, 25% to 49% in 11.6% of patients, 50% to 74% in 15.3% of patients, and ≥75% in 27.5% of patients.
Docetaxel outcomes were similar regardless of TPS. However, for patients who received pembrolizumab, OS, PFS, and ORR generally increased along with TPS, with the longest OS and PFS and the highest ORR in patients with TPS ≥75%. Furthermore, pembrolizumab provided a longer OS than docetaxel in all 4 TPS categories, and a significantly higher ORR than docetaxel in patients with TPS of 50% to 74% and 75% to 100%.
Source: Baas P, Garon EB, Herbst RS, et al. Relationship between level of PD-L1 expression and outcomes in the KEYNOTE-010 study of pembrolizumab vs docetaxel for previously treated, PD-L1–positive NSCLC. J Clin Oncol. 2016;34(15 suppl). Abstract 9015.
Pembrolizumab plus Chemotherapy as Front-Line Therapy for Advanced NSCLC: KEYNOTE-021
The anti–PD-1 antibody pembrolizumab exhibited robust antitumor activity in patients with advanced NSCLC in the KEYNOTE-001 and KEYNOTE-010 studies (Garon EB, et al. N Engl J Med. 2015;372:2018-2028; Herbst RS, et al. Lancet. 2016;387:1540-1550). Shirish M. Gadgeel, MD, Kamanos Cancer Institute, Detroit, MI, and colleagues evaluated pembrolizumab plus various chemotherapy combinations in advanced NSCLC in cohorts A-C of the KEYNOTE-021 study.
Patients with chemotherapy-naïve, advanced, EGFR/ALK mutation–negative NSCLC were randomized to pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks plus carboplatin 6 mg/mL/min plus paclitaxel 200 mg/m2 (cohort A, any histology); carboplatin 6 mg/mL/min plus paclitaxel 200 mg/m2 plus bevacizumab 15 mg/kg (cohort B, nonsquamous); or carboplatin 5 mg/mL/min plus pemetrexed 500 mg/m2 (cohort C, nonsquamous) for 4 cycles, followed by maintenance pembrolizumab (cohort A), pembrolizumab plus bevacizumab (cohort B), or pembrolizumab plus pemetrexed (cohort C).
Response was assessed every 6 weeks by a central imaging vendor. As of December 16, 2015, 74 patients (25 in cohort A, 25 in cohort B, and 24 in cohort C) received treatment, with a median follow-up of 12 months (cohort A, 13 months; cohort B, 9 months; cohort C, 16 months). Overall, 25 patients had PD-L1 expression.
The ORR was 52% in cohort A, 48% in cohort B, and 71% in cohort C. The ORR was 60% in patients with PD-L1 expression. The ORR was 62% in patients who received pembrolizumab 2 mg/kg (N = 37), and 51% in patients who received pembrolizumab 10 mg/kg (N = 37).
Grade 3/4 adverse events (AEs) occurred in 36%, 46%, and 42% of patients in cohorts A, B, and C, respectively, and most often included elevations in liver enzyme levels, anemia, neutropenia, and febrile neutropenia. Overall, 1 treatment-related death occurred in cohort B because of a pericardial effusion.
A randomized phase 3 study evaluating pemetrexed plus platinum chemotherapy with or without pembrolizumab is currently recruiting participants.
Source: Gadgeel SM, Stevenson J, Langer CJ, et al. Pembrolizumab (pembro) plus chemotherapy as front-line therapy for advanced NSCLC: KEYNOTE-021 cohorts A-C. J Clin Oncol. 2016;34(15 suppl). Abstract 9016.
Alectinib versus Crizotinib in ALK Inhibitor–Naïve, ALK Mutation–Positive NSCLC: The J-ALEX Study
Alectinib showed promising efficacy and tolerability in the phase 1/2 study AF-001JP (Seto T, et al. Lancet Oncol. 2013;14:590-598; Takeuchi K, et al. Ann Oncol. 2016;27:185-192). Hiroshi Nokihara, MD, PhD, National Cancer Center Hospital, Tokyo, Japan, and colleagues conducted the randomized, open-label, phase 3 clinical trial J-ALEX to prove superior PFS of alectinib to crizotinib in patients with ALK mutation–positive NSCLC without previous treatment with an ALK inhibitor.
Patients with ALK mutation–positive NSCLC were randomized in a 1:1 ratio to alectinib (300 mg twice daily) or crizotinib (250 mg twice daily) and stratified by the Eastern Cooperative Oncology Group performance status (0/1 vs 2), treatment line (first vs second), and clinical stage (IIIB/IV vs recurrence). Treatment was continued until disease progression or unacceptable toxicity.
The primary end point was PFS as assessed by a blinded independent review board. The secondary end points included OS, ORR, and safety. Overall, 207 patients were enrolled at 41 centers in Japan; 98% of patients had performance status 0-1, 73% had stage IV NSCLC, and 64% were receiving first-line therapy.
On an interim analysis, the Independent Data Monitoring Committee recommended the release of study data because of the superiority in PFS of alectinib over crizotinib (hazard ratio, 0.34; P <.0001). The median PFS was not reached in the alectinib arm compared with 10.2 months in the crizotinib arm.
Constipation was the only AE reported in >30% of patients receiving alectinib, whereas nausea (74%), diarrhea (73%), vomiting (59%), visual disturbance (55%), dysgeusia (52%), constipation (46%), elevation in alanine aminotransferase levels (32%), and elevation in aspartate aminotransferase levels (31%) were observed in the crizotinib arm. Grade 3/4 AEs occurred more frequently with crizotinib versus alectinib (51% vs 27%, respectively). There were no treatment-related deaths in either treatment arm.
Source: Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): primary results from the J-ALEX study. J Clin Oncol. 2016;34(15 suppl). Abstract 9008.
Pembrolizumab plus Ipilimumab as Second-Line Therapy for NSCLC: KEYNOTE-021
The checkpoint inhibitor combination pembrolizumab (anti–PD-1) plus ipilimumab (anti–CTLA-4) yielded promising antitumor activity and manageable toxicity in patients with previously treated NSCLC in a dose-finding cohort of the KEYNOTE-021 study (Patnaik A, et al. J Clin Oncol. 2015;33(15 suppl). Abstract 8011). Matthew A. Gubens, MD, MS, University of California San Francisco, and colleagues presented data on additional patients with advanced NSCLC who received at least 1 previous therapy regimen and who were enrolled in the pembrolizumab plus ipilimumab dose-finding (cohort D) and expansion (cohort H) cohorts of the KEYNOTE-021 clinical trial.
The first 6 patients in cohort D received pembrolizumab plus ipilimumab at 1 of 3 doses every 3 weeks (for 4 cycles), followed by maintenance therapy with pembrolizumab. Based on emerging ipilimumab toxicity data from other studies, ipilimumab and pembrolizumab doses were reduced from 3 mg/kg to 1 mg/kg and from 10 mg/kg to 2 mg/kg, respectively. These lower doses were also used in cohort H. Response was assessed every 6 weeks according to RECIST v1.1 and central imaging review.
Overall, 45 patients received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg; 6 additional patients in cohort D received the higher doses (pembrolizumab 10 mg/kg plus ipilimumab 3 mg/kg or 1 mg/kg). The median follow-up was 7 months. Treatment-related AEs were reported in 30 (67%) patients—11 (24%) patients had grade 3/5 AEs, which most frequently included diarrhea, and 4 (9%) patients discontinued treatment because of AEs. One treatment-related death (pancreatitis) was reported.
The ORR was 25% (2 complete remissions, 9 partial remissions [PRs], and 17 stable disease); 8 (18%) patients had progressive disease. The median duration of response (DOR) was 14 months. The median PFS and OS were 6 months and 17 months, respectively. There was no link between PD-L1 status and clinical outcomes.
Longer follow-up may help define whether there are true differences in outcomes between different PD-L1 subsets that merit further exploration.
Source: Gubens MA, Sequist LV, Stevenson J, et al. Phase I/II study of pembrolizumab (pembro) plus ipilimumab (ipi) as second-line therapy for NSCLC: KEYNOTE-021 cohorts D and H. J Clin Oncol. 2016;34(15 suppl). Abstract 9027.
TKIs in Advanced NSCLC Associated with Concomitant c-MET Overexpression and EGFR Mutations
The common driver genes in NSCLC include EGFR, ALK, and KRAS. C-MET amplification coexisting with EGFR mutations is recognized as a mechanism of primary resistance to EGFR tyrosine kinase inhibitors (TKIs) (Sequist LV, et al. J Clin Oncol. 2008;26:2442-2449; Benedettini E, et al. Am J Pathol. 2010;177:415-423). Na Na Lou, Guangdong General Hospital, Guangzhou, China, and colleagues investigated the frequency of c-MET overexpression coexisting with EGFR mutations, response to EGFR TKIs, and survival in patients with advanced NSCLC with such coalterations.
Overall, 149 patients with NSCLC were screened for c-MET overexpression concomitant with EGFR mutations. C-MET overexpression was detected via immunohistochemistry in which ≥50% of tumor cells with moderate- to high-intensity staining were defined as c-MET–positive. C-MET amplification was detected by fluorescence in situ hybridization (FISH), and FISH-positive was defined as gene focal amplification or high polysomy (at least 15% cells with ≥5 copy numbers). EGFR mutations were detected by DNA sequencing or Scorpion Amplification Refractory Mutation System.
The frequency of concomitant c-MET overexpression and EGFR mutation was 39% in patients with advanced NSCLC. However, the frequency of c-MET amplification was 14%. The frequency of primary resistance to EGFR TKIs was 24% in patients with concomitant c-MET overexpression and EGFR mutations, and 14% in those with only EGFR mutations (P = .13); the response rates to EGFR TKIs were 48% and 71%, respectively (P = .004). In addition, the median PFS was 10.7 months versus 11.2 months, respectively (P = 0.82).
Primary resistance to EGFR TKIs was found in 2 patients with concomitant c-MET amplification and EGFR mutations, but these patients responded to the combination of EGFR and MET inhibitors. Therefore, resistance to EGFR TKIs may be overcome by treating patients with a combination of EGFR and MET inhibitors.
Source: Lou NN, Wu Y-L, Yang J-J, et al. Response to tyrosine kinase inhibitors in advanced non-small-cell lung cancer with concomitant c-MET overexpression and EGFR mutation. J Clin Oncol. 2016;34(15 suppl). Abstract 9054.
Crizotinib in Advanced, MET Exon 14–Altered NSCLC
MET alterations leading to exon 14 skipping occur in approximately 4% of lung carcinomas, resulting in MET activation and sensitivity to MET inhibitors in vitro (Tong JH, et al. Clin Cancer Res. 2016;22:3048-3056). Crizotinib has demonstrated activity in tumors harboring MET exon 14 alterations.
Alexander E. Drilon, MD, Memorial Sloan Kettering Cancer Center, New York, NY, and colleagues evaluated crizotinib in patients with advanced MET exon 14–altered NSCLC who were enrolled in an expansion cohort of the ongoing phase 1 PROFILE 1001 study.
Patients received crizotinib 250 mg twice daily. The responses were assessed using RECIST v1.0. Overall, 21 patients with MET exon 14–altered NSCLC had enrolled in the study, and 18 patients were evaluable for response.
Two patients discontinued treatment. Overall, 71% of patients had adenocarcinoma, 18% had sarcomatoid adenocarcinoma, 6% had adenosquamous carcinoma, and 6% had squamous-cell carcinoma. Of these patients, 65% were former smokers, and 35% never smoked. The duration of treatment ranged from 0.5 months to approximately 9.1 months, with 88% of patients still receiving treatment as of October 30, 2015. The ORR was 44%, all with confirmed PRs (all seen at the first scheduled tumor assessment at 8 weeks); there were 5 unconfirmed complete responses or PRs.
The median PFS could not be calculated, with no deaths or progressive disease by the data cutoff date. AEs were reported in 82% of patients; the most common AEs included edema (35%), nausea (35%), vision disorder (29%), bradycardia (24%), and vomiting (24%). The majority of AEs were grade 1/2 in severity. MET exon 14 alterations are actionable drivers, and patients with NSCLC should be screened for these mutations.
Source: Drilon AE, Camidge DR, Ignatius Ou S-H, et al. Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). J Clin Oncol. 2016;34(15 suppl). Abstract 108.
Vandetanib in Advanced, RET-Rearranged NSCLC: The Luret Study
RET fusions are new driver oncogenes in NSCLC, and have been reported in 1% to 2% of all patients with NSCLC (Tsuta K, et al. Br J Cancer. 2014;110:1571-1578). Vandetanib is a multitargeted TKI with RET kinase activity. In a multicenter, single-arm, phase 2 study with vandetanib in patients with advanced, RET-rearranged NSCLC that did not respond to at least 1 treatment with systemic chemotherapy, Takashi Seto, MD, PhD, National Kyushu Cancer Center, Fukuoka, Japan, and colleagues administered vandetanib 300 mg orally once daily in 28-day cycles.
The primary end point was ORR as assessed by an independent review committee. The secondary end points included PFS, disease control rate (DCR), DOR, OS, and safety.
Overall, 19 patients (10 KIF5B-RET subtype, 6 CCDC6-RET subtype, and 3 unknown-RET subtype) enrolled in the study, and 17 patients were eligible for efficacy analysis. All patients had adenocarcinoma, and 68% never smoked. Overall, 63% had received 2 or more cycles of chemotherapy.
Among 17 eligible patients, the median ORR was 53%, of which 9 PRs met the primary end point, and the DCR was 90%. The median PFS was 4.7 months. According to the RET fusion subtypes, the ORR and the median PFS were 83% and 8.3 months, respectively, in patients with the CCDC6-RET subtype versus 20% and 2.9 months, respectively, in those with the KIF5B-RET subtype. The median OS was 11.1 months, with a 1-year OS of 47%.
The safety profile of vandetanib was similar to that reported in previous studies. The most common grade 3/4 toxicities were hypertension (58%), rash (16%), diarrhea (11%), and QTc prolongation (11%).
Source: Seto T, Yoh K, Satouchi M, et al. A phase II open-label single-arm study of vandetanib in patients with advanced RET-rearranged non-small cell lung cancer (NSCLC): Luret study. J Clin Oncol. 2016;34(15 suppl). Abstract 9012.
Nivolumab versus Docetaxel in Advanced NSCLC: A 2-Year Update of CheckMate-017 and CheckMate-057
In an analysis by Hossein Borghaei, DO, MS, Fox Chase Cancer Center, Philadelphia, PA, and colleagues, patients with squamous (CheckMate-017 study) or nonsquamous (CheckMate-057 study) NSCLC were randomized in a 1:1 ratio to nivolumab 3 mg/kg every 2 weeks or to docetaxel 75 mg/m2 every 3 weeks until disease progression or treatment discontinuation because of toxicity or other reasons.
The primary clinical end point in each study was OS. Multivariate exploratory analyses of baseline serum cytokines were performed separately in patients with squamous and nonsquamous NSCLC. A squamous cytoscore derived from evaluable patients in the CheckMate-017 and CheckMate-063 (single-arm, phase 2 study of nivolumab in squamous NSCLC) studies, and a nonsquamous cytoscore derived from evaluable patients in the CheckMate-057 study were generated to quantify the effect of each identified cytokine set on OS (using 18-month data cutoffs).
In the CheckMate-017 study, the median OS with nivolumab and docetaxel was 9.2 months versus 6 months, respectively (18-month OS, 28% vs 13%, respectively; P = .0004).
In the CheckMate-057 study, the median OS with nivolumab and docetaxel was 12.2 months versus 9.4 months, respectively (18-month OS, 39% vs 23%, respectively; P = .0009). A greater magnitude of benefit was noted in patients with PD-L1–expressing nonsquamous NSCLC; PD-L1 expression was neither prognostic nor predictive of benefit in patients with squamous NSCLC.
Treatment-related AEs were less frequent with nivolumab versus docetaxel in both clinical trials. Preliminary results showed an association of squamous and nonsquamous cytoscores with OS. Nivolumab resulted in improved OS and a favorable safety profile versus docetaxel across NSCLC histologies. Select sets of baseline serum cytokines were associated with OS benefit in patients with advanced squamous and nonsquamous NSCLC.
The 2-year update of these data demonstrated durable, long-term improved OS and PFS with nivolumab compared with docetaxel. The 2-year OS rates were 29% with nivolumab compared with 16% with docetaxel in patients with nonsquamous disease, and 23% with nivolumab versus 15% with docetaxel in patients with squamous disease; this difference was most pronounced (45% with nivolumab vs 13% with docetaxel) in patients with PD-L1 expression ≥10%.
The 2-year PFS was 16% with nivolumab compared with 7% with docetaxel in patients with nonsquamous disease, and 12% with nivolumab versus 1% with docetaxel in patients with squamous disease. The occurrence of treatment-related AEs was not significantly different at 2 years compared with 1 year of therapy.
At the 2-year follow-up, cytoscores were not associated with the treatment effect, and, therefore, were not predictive of benefit from nivolumab.
Source: Borghaei H, Brahmer JR, Horn L, et al. Nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses. J Clin Oncol. 2016;34(15 suppl). Abstract 9025.