AACR 2018: First-line Nivolumab-Ipilimumab in TMB-high NSCLC

Non-Sponsored Content

AACR 2018: First-Line Nivolumab-Ipilimumab for TMB-High NSCLC

Medical writer: Stijn van den Borne, MSc | Last updated: 21st April 2018 | In: Chemotherapy, ImmunoOncology, Immunotherapy, Lung Cancer, Oncology, Translational Research

Article Keywords

AACR 2018, BMS, Bristol-Myers Squibb, carboplatin, cisplatin, CTLA4, gemcitabine, ipilimumab, nivolumab, non-squamous cell lung cancer, NSCLC, Oncology News, PD-1, PD-L1, pemetrexed, platinum-doublet, squamous cell lung cancer, TMB

First-line nivolumab (OpdivoⓇ) plus ipilimumab (YervoyⓇ) was associated with a more than tripled 1-year progression-free survival (PFS) rate compared to platinum-based chemotherapy for patients with tumour mutation burden (TMB)-high non-small cell lung cancer (NSCLC) in the Phase III CheckMate 227 trial. The results were presented during the 2018 AACR Annual Meeting with simultaneous online publication in the New England Journal of Medicine (NEJM).

“In this study of TMB-high non–small cell lung cancer, we found that nivolumab plus ipilimumab significantly improved progression-free survival compared to chemotherapy,”

~Matthew D. Hellman, MD, Memorial Sloan Kettering Cancer Center

Study Design

The CheckMate 227 (NCT02477826) initially was a multipart study comparing various immunotherapeutic regimens of programmed death 1 (PD-1) inhibitor nivolumab with chemotherapy (Figure 1). Eligible patients had Stage IV or recurrent NSCLC and not received prior systemic treatment. Participants were stratified as squamous NSCLC and non-squamous NSCLC. Subjects with insufficient tissue available for testing of PD-1 ligand (PD-L1) could not participate in the study.

Upon successful study-registration, participants were divided into a low PD-1 ligand (PD-L1) expression-group [PD-L1<1%] and high PD-L1 expression-group [PD-L1≥1%] and randomised to either nivolumab plus ipilimumab, chemotherapy alone, or nivolumab alone. Patients in the PD-L1<1% group and allocated to the nivolumab-arm received concomitant chemotherapy (Figure 1).

Based on the results of the CheckMate 012 and 032 studies, which showed efficacy of nivolumab plus ipilimumab in TMB-high lung cancer, the study was amended to include the co-primary progression-free survival endpoint comparing the immunooncology combination (IO-IO) with chemotherapy in patients with TMB-high (≥10 mutations per megabase [mut/Mb]).

AACR 2018 First-line Nivolumab-Ipilimumab in TMB-high NSCLC front-line immunotherapy for non-small cell lung cancer study design CheckMate 227 NCT02477826

Figure 1. Study design of the CheckMate 227 study. Platinum-doublet chemotherapy was subject to the histological subtype. Patients with non-squamous NSCLC received pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) or carboplatin (area under the concentration-time curve [AUC] 5 or 6), every 3 weeks (q3w) for up to four cycles. Maintenance therapy with pemetrexed 500 mg/m² after chemotherapy or with nivolumab 360 mg q3w plus pemetrexed 500 mg/m² after nivolumab plus chemotherapy was optional. Patients with squamous NSCLC received gemcitabine (1000 or 1250 mg/m²) plus cisplatin (75 mg/m²), or gemcitabine (1000 mg/m²) plus carboplatin (AUC 5) q3w for up to four cycles.

Progression-Free Survival

In patients with TMB-high NSCLC the 1-year PFS rate was 43% for nivolumab plus ipilimumab compared with 13% for platinum-doublet chemotherapy (Figure 2). The median PFS was 7.2 months (nivolumab plus ipilimumab) versus 5.5 months (chemotherapy), a 42% risk reduction for disease progression or death (hazard ratio [HR]=0.58, P<0.001; 97.5%CI, 0.41-0.81).

AACR 2018 First-line Nivolumab-Ipilimumab in TMB-high NSCLC front-line immunotherapy for non-small cell lung cancer PFS CheckMate 227 NCT02477826

Figure 2. Progression-free survival (PFS) for chemotherapy vs ipilimumab plus nivolumab in TMB-high NSCLC, the co-primary endpoint of the CheckMate 227 study (NCT02477826). The combination IO-IO was associated with a 42% reduction of risk for disease progression or death (HR=0.58, P<0.001; 97.5% confidence interval [CI], 0.41-0.81). mPFS: median PFS.

Newsletter Sign-Up

Do you like our content? Subscribe to our non-intrusive newsletter today! We promise we won’t be spammy.

The evolving role of NK₁ in CINV management

Lung Cancer Update April 2021

Abemaciclib: A review of the evidence through clinical cases

The Role of Patient Blood Management for Inflammatory Bowel Disease

the-evolving-role-of-nk1-in-cinv-management-chemotherapy-induced-nausea-vomiting-akynzeo-nepa-palonosetron-netupitant

16th April 2021

The evolving role of NK₁ in CINV management

8th April 2021

Lung Cancer Update April 2021

Figure 3a. Response rates with nivolumab plus ipilimumab combination in TMB-high NSCLC.

Figure 3b. Response rates with chemotherapy in TMB-high NSCLC.

Objective Response Rate

The nivolumab-ipilimumab combination showed an objective response rate (ORR) of 45.3%. Responses were durable, 68% had an ongoing response after 1 year. In the chemotherapy-arm, the ORR was 26.9% and 25% of responders had an ongoing response at 1 year.

Figure 3a shows the response rates for nivolumab plus ipilimumab in TMB-high NSCLC and Figure 3b the response rates for chemotherapy in TMB-high NSCLC.

Comparison with Overall Population

In the overall population, ipilimumab plus nivolumab was associated with a higher 1-year PFS rate (30.9% vs 17.0%; HR=0.83; 95%CI, 0.72-0.96). However, the median PFS for IO-IO did not significantly differ from chemotherapy: 4.9 vs 5.5 months, respectively. In the subset of participants with TMB-low tumours (<10 mut/Mb), the median PFS was 3.2 months with the IO-IO vs 5.5 months with chemotherapy (HR=1.07; 95%CI, 0.84-1.35).

Overall Survival

At the time of database-lock on January 24, 2018, the overall survival (OS) data were not yet mature. Despite censoring of over 50% of the data points, the preliminary HR for OS in TMB-high patients was 0.79 (95%CI, 56-1.10) favouring the IO-IO combination over chemotherapy.

Cross Over

More than 24% of patients treated with IO-IO nivolumab plus ipilimumab for TMB-high NSCLC continued treatment at the time of database-lock, compared with 3.1% of chemotherapy-treated patients. Notably, 30% of CheckMate 227 patients on chemotherapy were treated with subsequent immunotherapy.

Figure 3a. Response rates with nivolumab plus ipilimumab combination in TMB-high NSCLC.

Figure 3b. Response rates with chemotherapy in TMB-high NSCLC.

Figure 4a. CheckMate 227 TMB analysis as by the FoundationOne companion diagnostic (CDx).

Figure 4b. CheckMate 227 PD-L1 level expression was evenly distributed across the TMB-high (PD-L1<1%: 21%; PD-L1≥1% 79%) and TMB-low groups (PD-L1<1%: 21%; PD-L1≥1% 79%), represented in this figure as total proportions.

Biomarker Analysis

A total of 1004 tissue samples were successfully tested for TMB-analysis by the FoundationOne companion diagnostic (CDx) (Figure 4a). In total, 444 (25.5%) samples of 1739 participants in the CheckMate 227 had ≥10 mut/Mb.

PD-L1 level expression was independent of the TMB-classification and equally distributed across the two TMB subgroups. In the TMB-high subgroup, 21% of the samples tested for PD-L1 were found to have a <1% level expression, and 79% were found to have a PD-L1≥1% level expression. The distribution of PD-L1 <1% and ≥1% level expression was similar in the TMB-low group; 21% and 79%, respectively (Figure 4b).

Subgroup analysis showed that nivolumab plus ipilimumab improved PFS among all patients regardless of PD-L1 expression or histologic (squamous vs non-squamous) subtypes. “This suggests TMB is an important independent biomarker,” commented the authors in the NEJM.

Safety

The safety of nivolumab plus ipilimumab was similar as reported in other trials of the IO-IO combination. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31% of the nivolumab plus ipilimumab-treated patients. In this group, rash, diarrhoea, and anaemia (1.6% each) were the most frequently observed TRAEs. In the chemotherapy-arm, 36% of patients experienced grade 3/4 TRAEs. Treatment discontinuation due to TRAEs occurred more often in the IO-IO combination-group than in the chemotherapy-group: 12% vs 4.9%, respectively.

References

Hellmann MD et al. N Engl J Med. DOI: 10.1056/NEJMoa1801946.

Hellmann MD et al. Abstract CT077. Presented at 2018 AACR Annual Meeting; April 14-18, 2018.

Figure 4a. CheckMate 227 TMB analysis as by the FoundationOne companion diagnostic (CDx).

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).

Second-line treatment of gastric cancer or cancer of the gastroesophegeal junction: a case study of ramucirumab in Hong Kong

Capivasertib added to fulvestrant improves progression-free survival in advanced breast cancer patients

Calaspargase pegol-mknl (Asparlas®) FDA approved in paediatric and young adult acute lymphoblastic leukaemia (ALL) patients

Fully resorbable synthetic matrix offers improved safety for breast cancer patients undergoing immediate breast reconstruction

Pembrolizumab FDA approved in hepatocellular carcinoma patients pretreated with sorafenib

Lorlatinib FDA approved for metastatic ALK-positive NSCLC

ESMO 2018 HCC ESMO18 Liver Cancer ESMO2018 hepatocellular carcinoma hepatobiliary cholangiocarcinoma BTC

ESMO 2018 HCC: The ESMO18 hepatobiliary cancer track summarised

Pembrolizumab plus chemotherapy approved for metastatic squamous NSCLC

Dr Joanne Chiu HKU management irAE hepatitis manage immune-mediated hepatitis immunotherapy I-O immunooncology immune-induced hepatitis

Management of Immune-Mediated Hepatitis: a Case Report

PARPi talazoparib FDA approved for deleterious gBRCAm HER2‑negative breast cancer

Anti-PD1 sintilimab plus biosimilar bevacizumab receive IND-status by China NMPA

IMpower133: first-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer

Pembrolizumab plus chemotherapy effective in squamous NSCLC

Ipilimumab plus nivolumab for persistent or recurrent ovarian cancer

Brigatinib prolongs PFS compared to crizotinib in ALK-Positive NSCLC

CAR-T axicabtagene ciloleucel granted Orphan Drug designation for B-Cell Lymphoma by the Japan MHLW

PD-1 mAB cemiplimab FDA approved for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC)

JAVELIN Lung 200 avelumab vs docetaxel in patients with pretreated advanced non-small cell lung cancer NSCLC

JAVELIN Lung 200: avelumab vs docetaxel for pretreated NSCLC

Dacomitinib FDA approved for the first-line treatment of metastatic EGFR-mutated NSCLC

©United States Food and Drug Agency US FDA

Duvelisib FDA approved for adult patients with R/R CLL or SLL

©United States Food and Drug Agency US FDA

Duvelisib FDA approved for adult patients with R/R follicular lymphoma

Frontline atezolizumab plus chemotherapy improves PFS in NSCLC

First-line osimertinib vs EGFR-TKI in Asian patients with advanced NSCLC

Early breast cancer treatment in China remains conservative

immuno-oncology I-O treatment for the irAE Rash

©MediPaper Medical Communications Ltd

ImmunoOncology: Dr Oscar Chan on the treatment of irAE rash

Prof Stefan Kasper on I-O in EXTREME-ineligible Head and Neck Cancer I-O in SCCHN with focus on EXTREME-ineligible Patients and the future directions of combination immunotherapy

Prof Stefan Kasper on I-O in EXTREME-ineligible SCCHN

Venetoclax FDA label updated to include Minimal Residual Disease negativity data

Quizartinib receives Orphan Drug designation for FLT3-mutated AML in Japan

Capmatinib plus gefitinib promising in MET-dysregulated NSCLC

CAR-TCR Summit 2018: Preliminary first-in-human data with CAR-Claudin18.2-T in gastric and pancreatic cancer

DRIVER connects cancer patients in China and the United States to the best care

Blood-based TMB-assay predicts response to atezolizumab in NSCLC patients

Plasma TMB predicts response to atezolizumab in NSCLC patients

First-in-Class Oncology Vaccine BIL06v Starts Phase 1 Evaluation

Nivolumab FDA approved for patients with metastatic small cell lung cancer (SCLC)

Pembrolizumab and atezolizumab USPIs updated by FDA

Nivolumab FDA approved for patients with metastatic small cell lung cancer (SCLC)

Pembrolizumab plus pemetrexed-platinum approved for use in the 1st-line treatment of metastatic non-squamous NSCLC

Pembrolizumab plus pemetrexed-platinum FDA approved for first-line treatment of metastatic non-squamous NSCLC

Talazoparib in advanced breast cancer patients with a germline BRCA1/2 mutation

CheckMate 032 Nivolumab ipilimumab metastatic esophagogastric cancer

CheckMate 032: Nivolumab +/- ipilimumab for metastatic esophagogastric cancer

Lenvatinib FDA approved for 1st-line treatment of HCC

©Alex011973 / 123RF Stock Photo

Pan-EGFR TKI pirotinib has commenced into Phase II clinical testing in China

FDA approved lusutrombopag (Mulpleta, Shionogi Inc.) for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. More Information. July 31, 2018.

FDA approved mogamulizumab for adult patients with relapsed or refractory CTCL

Lusutrombopag FDA approved for thrombocytopenia in adult chronic liver disease patients

Ribociclib FDA label updated to include pre- and perimenopausal women

Iobenguane I-131 FDA approved for rare adrenal neuroendocrine tumours

T790M osimertinib nsclc brain metastasis CNS metastases Osimertinib in patients With T790M-Positive Advanced Non-Small-Cell Lung Cancer and brain metastases AURA3

Osimertinib in patients with T790M-positive advanced non-small cell lung cancer and brain metastases (AURA3)

Anti-PD1 with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma

Ivosidenib FDA approved for relapsed or refractory acute myeloid leukemia

FDA approved enzalutamide (XTANDI, Astellas Pharma US, Inc.), for patients with castration-resistant prostate cancer (CRPC). More Information. July 13, 2018

Filgrastim-aafi FDA approved as Filgrastim Biosimilar

Ribociclib FDA label updated to include pre- and perimenopausal women

Enzalutamide FDA approved for castration-resistant prostate cancer (CRPC)

EBV pembrolizumab gastric cancer - MSI-H pembrolizumab gastric cancer - CPS pembrolizumab gastric cancer - MSI, EBV, CPS predict pembrolizumab outcome in gastric cancer

EBV, MSI, and CPS predict pembrolizumab outcome in gastric cancer

Ipilimumab plus nivolumab FDA approved for MSI-H and dMMR pre-treated mCRC

Combination encorafenib plus binimetinib for unresectable/metastatic BRAF V600E or V600K-positive melanoma FDA approved

ASCO 2018 nsclc immunotherapy ASCO18 lung cancer pembrolizumab avelumab nivolumab duravalumab ipilimumab osimertinib dacomitinib lorlatinib crizotinib alectinib keytruda KEYNOTE CheckMate JAVELIN IMpower

ASCO 2018 NSCLC: The ASCO18 Lung Cancer Track Summarised

FDA has limited the use of Tecentriq and Keytruda for patients with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing therapy. More Information. June 19, 2018

FDA limits use of atezolizumab and pembrolizumab in urothelial carcinoma

ASCO 2018 breast cancer TNBC MBC ABC ASCO18 PHEREXA D-CARE ABCSG-18 ASTRRA TEXT SOFT MONARCH-2 MONALEESA-3 SANDPIPER BOLERO-6 TOPACIO KEYNOTE-162 TONIC TOPACIO GeparNeuvo

ASCO 2018 Breast Cancer: The ASCO18 breast cancer track summarised

Bevacizumab in combination with carboplatin and paclitaxel FDA approved for several types of gynaecological cancers

FDA approved pembrolizumab for 3rd-line PMBCL in adult and pediatric patients

FDA approved pembrolizumab for chemotherapy-refractory r/m cervical cancer with PD-L1 CPS ≥1

ASCO18 ASCO 2018 HCC hepatocellular carcinoma liver cancer pembrolizumab KEYTRUDA atezolizumab TECENTRIQ PD-1 PD-L1 immunecheckpoint immunotherapy ramucirumab cabozantinib KEYNOTE-224 SCRUM-Japan GI-SCREEN CELESTIAL REACH-2

ASCO 2018 HCC: The ASCO18 hepatocellular cancer track summarised

FDA approves venetoclax in 2nd-line for patients with CLL or SLL

FDA approved biosimilar pegfilgrastim to decrease the chance of febrile neutropenia in patients with non-myeloid cancers on myelosuppressive chemotherapy

IMPower150 Reck Socinski ELCC AACR 2018 firstline atezolizumab bevacizumab chemotherapy non-squamous nsclc

bravajulia / 123RF Stock Photo

FDA approved osimertinib for the 1st-line treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutations positive metastatic non-small cell lung cancer (NSCLC)

NCT02578680 Keynote189 AACR 2018 pembrolizumab chemotherapy nsclc NEJM Leena Gandhi

krishnacreations / 123RF Stock Photo

FDA granted accelerated approval to blinatumomab for the treatment of adult and paediatric patients with B-cell precursor ALL in first or second complete remission with MRD ≥0.1%

Making sense of 1st-line immunotherapy in non-small cell lung cancer (NSCLC)

manuela schmidinger sutent sunitinib ae management manuela schmidinger manuela schmidinger sutent sunitinib side-effect management sutent sunitinib toxicity management Sutent Sunitinib AE management toxicity management side-effect management sorafenib pazopanib axitinib regorafenib vandetanib cabozantinib lenvatinib bevacizumab VEGFR VEGF renal cell carcinoma RCC kidney cancer renal cell cancer schmidinger

Achieving Long-Term Survival in the First-Line Treatment of Metastatic Renal Cell Carcinoma; A Balancing Act of Efficacy and Side-Effects

2016 pancreatic cancer awareness month IMM-101 plus Gemcitabine medipaper medical communications medical writer hire healthcare writers hong kong

Trackbacks & Pingbacks

Addition of a CTLA-4–Targeted Therapy to a Checkpoint Inhibitor in Ovarian Cancer | MediPaper says:

7th October 2018 at 12:13 AM

[…] Copyright 2018 MediPaper Medical Communications Ltd. – Ipilimumab plus nivolumab for persistent or recurrent ovarian […]

Log in to Reply
Plasma-TMB predicts response to atezolizumab in NSCLC patients says:

31st August 2018 at 12:30 PM

[…] multiple studies have linked a high-TMB to improved outcomes with immune-checkpoint inhibitors. A less invasive diagnostic method, such as […]

Log in to Reply
Making sense of 1st-line immunotherapy in non-small cell lung cancer (NSCLC) says:

31st July 2018 at 11:04 PM

[…] results of the Phase III CheckMate 227 show that the combination of nivolumab and ipilimumab improves PFS when compared with chemotherapy […]

Log in to Reply
ASCO 2018 NSCLC: The ASCO18 Lung Cancer Track Summarised says:

25th June 2018 at 10:30 PM

[…] meeting. This year, encouraging results with combinations therapies were presented, including CheckMate 227 with nivolumab (NIVO), IMpower131 and IMpower150 studies with atezolizumab (ATEZO), and KEYNOTE-042 […]

Log in to Reply
Approved Immune-Checkpoint Inhibitors and Immunotherapies per 23-APR-2018 says:

1st June 2018 at 4:49 PM

[…] /wp-content/uploads/2018/04/US-FDA-approved-CAR-t-cell-BiTE-DAR-T-cell-CD19-Immunotherapies-blinatumomab-axicabtagene-ciloleucel-tisagenlecleucel.jpg 1000 1500 Stijn van den Borne, MSc /wp-content/uploads/2018/04/MediPR-MediPaper-Medical-Communications-Ltd-Healthcare-Writers-Medical-Writers-Medical-Writer-Agency-Hong-Kong-Medical-Writing-Services-Solutions-Quote-醫學寫作-香港-醫學作家香港-medical-PR-medical-public-relations-e1523021883812.png Stijn van den Borne, MSc2018-05-02 10:00:352018-05-24 09:36:21US FDA approved CAR-T cell and BiTE immunotherapy – Updated 2-May-2018Hywards / 123RF Stock Photo […]

Log in to Reply
First-line Nivolumab-Ipilimumab in TMB-high NSCLC - MediNews Asia says:

24th May 2018 at 12:16 AM

First-line nivolumab (OpdivoⓇ) plus ipilimumab (YervoyⓇ) was associated with a more than tripled 1-year progression-free survival (PFS) rate compared to platinum-based chemotherapy for patients with tumour mutation burden (TMB)-high non-small cell lung cancer (NSCLC) in the Phase III CheckMate 227 trial. The results were presented during the 2018 AACR Annual Meeting with simultaneous online publication in the New England Journal of Medicine (NEJM).

Log in to Reply

Want to join the discussion?
Feel free to contribute!