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ASCO 2018 NSCLC TRACK
SPOTLIGHT ON LUNG CANCER
By: Anne John Michael | Last updated: 25 June 2018 | In: ASCO 2018 Annual Meeting, Lung Cancer, Oncology, Chemotherapy, Immunotherapy, Targeted Therapies
Non-small cell lung cancer (NSCLC) is a key feature of the American Society of Clinical Oncology (ASCO) 2018 annual meeting. This year, encouraging results with single-agent immunotherapy (I-O) and combinations of I-O with chemotherapy (CTx), including the CheckMate 227 with nivolumab (NIVO), IMpower131 and IMpower150 studies with atezolizumab (ATEZO), and KEYNOTE-042 and KEYNOTE-407 studies with pembrolizumab (PEMBRO) were presented. Furthermore, important Asian data on treatments for epidermal growth-factor receptor (EGFR) mutation-positive (mu+) NSCLC (ARCHER 1050, NEJ009, NEJ026, and JO25567) were featured. Welcome to the summary of the ASCO 2018 NSCLC track.
ASCO 2018 NSCLC Keywords
pembrolizumab, squamous cell lung cancer, AstraZeneca, Genentech, Merck, erlotinib, Tecentriq, Roche, dacomitinib, BMS, AZ, nivolumab, Iressa, gefitinib, Bavencio, atezolizumab, lorlatinib, Merck Serono, Imfinzi, avelumab, Merck KGaA, mesothelioma, Alecensa, Pfizer, Merckgroup, Keytruda, alectinib, ipilimumab, SCLC, MSD, Avastin, durvalumab, Tarceva, Bristol-Myers Squibb, Xalkori, crizotinib, Opdivo, non-squamous cell lung cancer, bevacizumab, Yervoy
ASCO 2018 NSCLC Immunotherapy
All histology: single-agent immunotherapy and combinations in NSCLC.
Several studies reported single-agent and CTx combination with PD-1/PD-L1 antibodies in the first-line treatment of NSCLC.
The phase III KEYNOTE-042 (NCT02220894) study compared PEMBRO 1:1 with platinum-based CTx in 1247 patients with untreated squamous and non-squamous NSCLC and a PD-L1 TPS of ≥1%.1Lopes G et al. J Clin Oncol 2018;36(suppl):Abstr LBA4 Patients in the CTx-arm received either carboplatin (C) and paclitaxel (P) or C plus pemetrexed (PEM). The median OS in all patients (PD-L1 TPS ≥1%) was 16.7 months (PEMBRO) vs 12.1 months (CTx). In patients with a PD-L1 TPS of ≥20% (N=818, 62.2%) the median OS was 17.7 months (PEMBRO) vs 13.0 months (CTx). Finally, in patients with a PD-L1 TPS of ≥50% (N=599, 47.0%) the median OS was 20.0 months (PEMBRO) vs 12.2 months (CTx). Grade 3-5 treatment-related adverse events (TRAEs) were less frequent with PEMBRO (17.8%) vs CTx (41.0%).
The CheckMate 227 study ( NCT02477826) is a Phase III study comparing first-line anti-PD-1 plus anti-CTLA4 antibodies nivolumab (NIVO) and ipilimumab (IPI) with NIVO plus CTx and CTx alone in advanced NSCLC with no known epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)-sensitising mutations.2Borghaei H et al. J Clin Oncol 2018;36(suppl):Abstr 9001 Previously, the study met its primary efficacy endpoint of improved progression-free survival (PFS) when comparing NIVO+IPI vs CTx in patients with ≥10 mutations/Mb (TMB-high). During ASCO 2018, the positive results of NIVO+CTx vs CTx were reported in patients (N=186) with a <1% tumour PD-L1 level expression.
Finally, in NSCLC of unselected histology, a Phase II trial (NCT02343952) showed that consolidation PEMBRO following concurrent chemoradiation in patients with unresectable stage III NSCLC was associated with 1-year OS of 80.5% and 2-year OS of 68.7% and a median PFS of 15.4 months.3Durm GA et al. J Clin Oncol 2018;36(suppl):Abstr 8500 The primary endpoint, time to metastatic disease or death (TMDD) was not yet reached. Five (5.4%) patients developed Grade 3/4 pneumonitis, and one pneumonitis-related death was reported.
Anti-PD-1 combined with CTx in selected NSCLC histology
The Phase III IMpower150 (NCT02366143) investigated anti-PD-L1 antibody atezolizumab (ATEZO) plus CP (Arm A) vs ATEZO plus CP and bevacizumab (BEV) (Arm B) vs CP plus BEV (Arm C) in 1202 non-squamous NSCLC patients.4Socinski MA et al. J Clin Oncol 2018;36(suppl):Abstr 9002 The interim overall survival (OS) results showed a significant 22% relative risk reduction in the intention-to-treat (ITT) wildtype (WT) OS endpoint when comparing Arm B (N=359) with Arm C (N=337); 19.2 vs 14.7 months, respectively (hazard ratio [HR]=0.78; 95% confidence interval [CI], 0.64-0.96; P=0.016). Several subgroup analysis were performed for Arm B vs C, including the T-effector (Teff)-high vs low population, and different levels of PD-L1 expression on the tumour (TC) and immune cells (IC), but most subgroup analysis still crossed the boundary of confidence in this preliminary interim analysis. No new safety signals were observed.
In the frontline, Stage IV squamous NSCLC setting, ATEZO was combined with CP (Arm A) or C plus nab-paclitaxel (NP) (Arm B) vs CNP (Arm C) in the Phase III IMpower131 study (NCT02367794).5Jotte RM et al. J Clin Oncol 2018;36(suppl):Abstr LBA9000 The addition of ATEZO to CNP (N=343) vs CNP (N=340) significantly increased median progression-free survival (PFS); 6.3 vs 5.6 months (HR=0.72; 95% CI, 0.60-0.85; P<0.001), respectively. Patients subgroups enriched for PD-L1 had better outcomes in an expression-dependent manner. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 68.0% and 56.9% of patients in Arm B and Arm C, respectively. Serious TRAEs were recorded in 20.4% (Arm B) and 10.5% (Arm C).
Another Phase III randomized controlled study in patients (N=560) with metastatic squamous cell NSCLC presented at ASCO2018 was the KEYNOTE-407 study (NCT02775435).6Paz-Ares LG et al. J Clin Oncol 2018;36(suppl):Abstr 105 In a first interim analysis of the study in 204 patients, the addition of anti-PD-1 antibody PEMBRO to CTx (CP or CNP) was associated with an almost double objective response rate (ORR). The investigators reported an ORR of 54.8% ORR (PEMBRO+CTx) vs 35% (CTx). Notably, 35% of patients in the PEMBRO plus CTx arm had a PD-L1 TPS <1%.
Despite PEMBRO’s significant anti-tumour activity in NSCLC, a Phase II study (NCT02879994) designed to investigate the use of PEMBRO in advanced EGFR-mu+, tyrosine kinase inhibitor (TKI) naïve patients (N=11) with PD-L1 positive NSCLC failed to show efficacy. The majority of patients (73%) had a TPS ≥50% and 64% had sensitising EGFR mutations. Two patient deaths were reported during the study, including one attributable to pneumonitis.7Lisberg EL et al. J Clin Oncol 2018;36(suppl):Abstr 9014
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Figure 1. Data of selected ASCO 2018 NSCLC immunotherapy studies
19del=exon 19 deletion; ALEC=alectinib; ALK=anaplastic lymphoma kinase; ATEZO=atezolizumab; AVE=avelumab; BEV=bevacizumab; C=carboplatin; CIS=cisplatin; CNS=central nervous system; CRIZ=crizotinib; CRT=concurrent chemoradiation therapy; CTx=chemotherapy; DACO=dacomitinib; DLL3=delta-like protein 3; DURVA=durvalumab; EGFR=epidermal growth-factor receptor; ERLO=erlotinib; GEF=gefitinib; IRC=independent review committee; L858R=exon 21 point mutation L858R; LORLA=lorlatinib; MET=metformin; mo=months; Mtn=maintenance; mu+=mutation-positive; NIVO=nivolumab; NP=nab-paclitaxel; NR=not reported; NS=non-significant; NSCLC=non-small cell lung cancer; OLA=olaparib; ORR=overall response rate; OS=overall survival; P=paclitaxel; PD-L1=programmed death ligand 1; PEM=pemetrexed; PEMBRO=pembrolizumab; PFS=progression-free survival; R/M=recurrent/metastatic; ROVA-T=rovalpituzumab tesirine; SCLC=small cell lung cancer; TMB=tumour mutational burden; TPS=PD-L1 tumour proportion score; wt=wild-type.
Recent advances in the treatment of EGFR mutation-positive NSCLC
Several large randomised studies investigated novel strategies for the treatment of NSCLC patients with sensitising EGFR mutations (EGFR-mu+).
Prof Mok and colleagues conducted the Phase III ARCHER 1050 (NCT01774721) study comparing the second-generation EGFR-TKI dacomitinib (DACO) to gefitinib (GEF) in the first-line setting for stage IIIB/IV recurrent NSCLC.8Mok TSK et al. J Clin Oncol 2018;36(suppl):Abstr 9004 All participants (N=452) had EGFR-mu+ (exon 19 del or exon 21 L858R ± exon 20 T790M) disease and no central nervous system (CNS) metastases. DACO significantly improved the median OS (34.1 months) compared to GEF (26.8 months) (P=0.044). The 30-month OS-rate were 56.2% and 46.3% for DACO and GEF, respectively. East-Asian patients on DACO (N=170) had a median OS of 34.2 months vs 29.1 months on GEF (N=176) (not significant [NS]). The investigators concluded that DACO should be considered as a standard treatment option in NSCLC patients harbouring EGFR mutations.
Japanese researchers conducted the pioneer Phase III study comparing GEF with carboplatin (CPT) plus pemetrexed (PEM) vs GEF monotherapy as first-line treatment for patients with advanced EGFR-mu+ NSCLC (NEJ009).9Nakamura A et al. J Clin Oncol 2018;36(suppl):Abstr 9005 The study recruited 344 advanced NSCLC patients harbouring exon 19 deletions and/or exon 21 L858R sensitising mutations. Nakamura et al reported significantly better PFS when adding CTx to GEF when compared to GEF monotherapy; 20.9 months vs 11.2 months, respectively. The median OS was improved as well, 52.2 months for the combination GEF+CTX vs 38.8 months for single-agent GEF. The PFS after the next line of therapy (PFS2), however, was not improved; 20.9 months vs 21.1 months for GEF+CTx vs GEF monotherapy, respectively.
In the Phase II GOAL study (NCT01513174), GEF monotherapy was compared with combination therapy of GEF and olaparib (OLA) in 182 treatment-naïve stage IV NSCLC patients harbouring EGFR-sensitising mutations.10Campelo RG et al. J Clin Oncol 2018;36(suppl):Abstr 9012 The median PFS in patients with exon 19del and/or exon 21 L858R EGFR mutations was 10.4 months for GEF vs 12.8 months for the combination GEF+OLA. The response rate were 68% vs 78% for GEF vs GEF+OLA, respectively. Analysis of translational components, including PFS related to BRCA1 mRNA and 53BP1 and EZH2 as possible modulators of BRCA1, may provide further insights on subgroups that benefit more from the novel combination.
Furuya et al reported the preliminary results of BEV plus erlotinib (ERLO) in 226 CTx-naïve EGFR-mutated non-squamous NSCLC patients in the randomised Phase III NEJ026 study (UMIN000017069).11Furuya N et al. J Clin Oncol 2018;36(suppl):Abstr 9006 Preliminary results indicated higher median PFS for the combination BEV+ERLO (16.9 months) vs single-agent ERLO (13.3 months) (P=0.0157). The investigators reported a significant increase in haemorrhage, proteinuria, and hypertension in the BEV+ERLO arm. Low-grade pneumonitis was observed in five patients on ERLO. No pneumonitis was reported in the combination arm and no treatment-related deaths occurred.
A survival follow-up analysis of the Japanese open-label randomised Phase II JO25567 study (JapicCTI-111390) comparing ERLO plus BEV to ERLO monotherapy as first-line treatment in 152 CTx-naïve Stage IIIb/IV EGFR mutation–positive non-squamous NSCLC patients, revealed no major difference in PFS between the two arms.12Yamamoto N et al. J Clin Oncol 2018;36(suppl):Abstr 9007 The median OS was non-significant: 47.0 months for BEV+ERLO vs 47.4 months for ERLO. The 5-year OS-rate was 41% for BEV+ERLO and 35% for ERLO single-agent. Around 85% of patients in both arms received post-study treatments.
A randomised Phase II study (NCT03071705) investigated the addition of metformin (MET) to an EGFR tyrosine kinase inhibitor (TKI).13Arrieta Rodriguez OG et al. J Clin Oncol 2018;36(suppl):Abstr 9013 Adding MET to the EGFR-TKI was associated with a significantly improved PFS of 14.0 months compared to 10.0 months for the EGFR-TKI alone. Moreover, adding MET to the EGFR-TKI led to significant improvements in ORR of 67.4% vs. 47.5% and median OS 27.2 months vs. 19.0 month, all for MET+EGFR-TKI vs EGFR-TKI respectively.
Figure 2. Data of selected ASCO 2018 NSCLC studies in patients with EGFR-sensitising mutations
19del=exon 19 deletion; ALEC=alectinib; ALK=anaplastic lymphoma kinase; ATEZO=atezolizumab; AVE=avelumab; BEV=bevacizumab; C=carboplatin; CIS=cisplatin; CNS=central nervous system; CRIZ=crizotinib; CRT=concurrent chemoradiation therapy; CTx=chemotherapy; DACO=dacomitinib; DLL3=delta-like protein 3; DURVA=durvalumab; EGFR=epidermal growth-factor receptor; ERLO=erlotinib; GEF=gefitinib; IRC=independent review committee; L858R=exon 21 point mutation L858R; LORLA=lorlatinib; MET=metformin; mo=months; Mtn=maintenance; mu+=mutation-positive; NIVO=nivolumab; NP=nab-paclitaxel; NR=not reported; NS=non-significant; NSCLC=non-small cell lung cancer; OLA=olaparib; ORR=overall response rate; OS=overall survival; P=paclitaxel; PD-L1=programmed death ligand 1; PEM=pemetrexed; PEMBRO=pembrolizumab; PFS=progression-free survival; R/M=recurrent/metastatic; ROVA-T=rovalpituzumab tesirine; SCLC=small cell lung cancer; TMB=tumour mutational burden; TPS=PD-L1 tumour proportion score; wt=wild-type.
Early phase trial evidence for advanced anaplastic lymphoma kinase-positive NSCLC
The Phase Ib/II JAVELIN Lung 101 study (NCT02584634) assessed the efficacy of anti-PD-L1 with avelumab (AVE) when used in combination with ALK-inhibtors crizotinib (CRIZ) or lorlatinib (LORLA) for patients with advanced NSCLC.14Tsang-Shaw A et al. J Clin Oncol 2018;36(suppl):Abstr 9008 In total 40 pre-treated patients enrolled in the study, 12 ALK-negative patients received AVE+CRIZ and 28 ALK-positive patients received AVE+LORLA. The combination ALK+CRIZ was associated with Grade ≥3 adverse events (AEs) in 7 (58.3%) ALK-negative patients including five (41.7%) dose-limiting toxicities (DLTs). Fifteen (53.6%) ALK-positive patients had Grade ≥3 AEs when receiving AVE+LORLA. However, no DLTs were reported. The confirmed ORR was 16.7% in ALK-negative patients receiving AVE+CRIZ with two patients having a partial response (PR). In ALK-positive patients, the ORR was 46.4%, counting 12 PRs and one complete response (CR).
Another Phase 1b study (NCT02013219) by Kim et al. in ALK-positive patients investigated the addition of anti-PD-L1 drug ATEZO to ALK-inhibitor alectinib in 21 treatment-naïve patients with ALK-positive advanced NSCLC.15Kim DW et al. J Clin Oncol 2018;36(suppl):Abstr 9009 The trial did not exclude patients with known brain metastases. Grade 3 AEs occurred in 62% of patients and no Grade 4 and 5 AEs or DLTs were reported. The investigators reported an ORR of 81% and a median PFS of 21.7 months.
Trial updates on treatments for other lung cancers
The Phase II KEYNOTE-158 trial, a basket trial in 11 tumour types (NCT02628067), included the evaluation of PEMBRO in 107 patients with advanced small-cell lung cancer (SCLC).16Chung HC et al. J Clin Oncol 2018;36(suppl):Abstr 8506 The ORR was 18.7% for all patients, 35.7% for PD-L1-positive patients, and 6.0% for PD-L1-negative patients. The median PFS was 2.0 months for the whole cohort, 2.1 months in patients with PD-L1-positive disease, and 1.9 months in patients with PD-L1-negative disease. Finally the median OS was 9.1 months for all patients, 14.6 months for those found positive for the PD-L1 biomarker, and 7.7 months in patients found not to express PD-L1. TRAEs were reported in 63 patients (59%), including one Grade 5 pneumonia.
The Phase II, open-label, single-arm, TRINITY study (NCT02674568) was carried out to query the anti-tumour activity and safety of rovalpituzumab (ROVA-T) in 199 Delta-like 3 protein-expressing SCLC patients who had failed at least two prior systemic therapies, including treatment with platinum-based CTx.17Carbone DP et al. J Clin Oncol 2018;36(suppl):Abstr 8507 DLL3-positive was defined as ≥25% DLL3 expression by immunohistochemistry. Patients whose tumour expressed ≥75% DLL3 were classified as DLL3-high. By independent review committee (IRC) the 188 patients who received ROVA-T in the 3rd-line had an ORR of 18% (DLL3-high; N=85) and 17% (DLL3-positive; N=103). The complete benefit rate (CBR) in this population was 71% in DLL3-high and 65% in DLL3-positive. Moreover, 305 patients received ROVA-T in the ≥3rd-line. The investigators reported an ORR of 14% (DLL3-high; N=140) and 14% (DLL3-positive; N=165) and a CBR by IRC of 75% and 71% for DLL3-high and DLL3-positive, respectively. Grade ≥3 TRAEs were thrombocytopenia (15%), photosensitivity (7%), pleural effusion (7%), and fatigue (5%).
Preliminary results from the Phase II DREAM study (ACTRN12616001170415) in 54 CTx-naïve patients with malignant pleural mesothelioma (MPM) revealed that the addition of durvalumab (DURVA) to first-line cisplatin (CIS) plus PEM was tolerable and effective.18Nowak AK et al. J Clin Oncol 2018;36(suppl):Abstr 8503 In the initial 31 evaluable patients the 6-month PFS-rate by modified RECIST (mRECIST) was 71%. Furthermore, the investigators reported an ORR of 61% (mRECIST) and 53% when using immune-response criteria (iRECIST). Grade ≥3 AEs were reported in 31 patients (57%) and immune-related AEs (irAEs) occurred in 19 patients (35%), including two Grade 3 irAEs.
Figure 3. Data of selected ASCO 2018 lung cancer studies in ALK-positive immunotherapy, small cell lung cancer, and malignant pleural mesothelioma
19del=exon 19 deletion; ALEC=alectinib; ALK=anaplastic lymphoma kinase; ATEZO=atezolizumab; AVE=avelumab; BEV=bevacizumab; C=carboplatin; CIS=cisplatin; CNS=central nervous system; CRIZ=crizotinib; CRT=concurrent chemoradiation therapy; CTx=chemotherapy; DACO=dacomitinib; DLL3=delta-like protein 3; DURVA=durvalumab; EGFR=epidermal growth-factor receptor; ERLO=erlotinib; GEF=gefitinib; IRC=independent review committee; L858R=exon 21 point mutation L858R; LORLA=lorlatinib; MET=metformin; mo=months; Mtn=maintenance; mu+=mutation-positive; NIVO=nivolumab; NP=nab-paclitaxel; NR=not reported; NS=non-significant; NSCLC=non-small cell lung cancer; OLA=olaparib; ORR=overall response rate; OS=overall survival; P=paclitaxel; PD-L1=programmed death ligand 1; PEM=pemetrexed; PEMBRO=pembrolizumab; PFS=progression-free survival; R/M=recurrent/metastatic; ROVA-T=rovalpituzumab tesirine; SCLC=small cell lung cancer; TMB=tumour mutational burden; TPS=PD-L1 tumour proportion score; wt=wild-type.
REFERENCES
- Lopes G et al. J Clin Oncol 2018;36(suppl):Abstr LBA4
- Borghaei H et al. J Clin Oncol 2018;36(suppl):Abstr 9001
- Durm GA et al. J Clin Oncol 2018;36(suppl):Abstr 8500
- Socinski MA et al. J Clin Oncol 2018;36(suppl):Abstr 9002
- Jotte RM et al. J Clin Oncol 2018;36(suppl):Abstr LBA9000
- Paz-Ares LG et al. J Clin Oncol 2018;36(suppl):Abstr 105
- Lisberg EL et al. J Clin Oncol 2018;36(suppl):Abstr 9014
- Mok TSK et al. J Clin Oncol 2018;36(suppl):Abstr 9004
- Nakamura A et al. J Clin Oncol 2018;36(suppl):Abstr 9005
- Campelo RG et al. J Clin Oncol 2018;36(suppl):Abstr 9012
- Furuya N et al. J Clin Oncol 2018;36(suppl):Abstr 9006
- Yamamoto N et al. J Clin Oncol 2018;36(suppl):Abstr 9007
- Arrieta Rodriguez OG et al. J Clin Oncol 2018;36(suppl):Abstr 9013
- Tsang-Shaw A et al. J Clin Oncol 2018;36(suppl):Abstr 9008
- Kim DW et al. J Clin Oncol 2018;36(suppl):Abstr 9009
- Chung HC et al. J Clin Oncol 2018;36(suppl):Abstr 8506
- Carbone DP et al. J Clin Oncol 2018;36(suppl):Abstr 8507
- Nowak AK et al. J Clin Oncol 2018;36(suppl):Abstr 8503
Disclaimer
This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).
© Copyright 2018 MediPaper Medical Communications Ltd. – ASCO 2018 NSCLC Track – #ASCO18 Lung Cancer
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© Copyright 2018 MediPaper Medical Communications Ltd. – ASCO 2018 NSCLC Track – #ASCO18 Lung Cancer
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