Clinical trialPhase 3Lung cancer

Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC

N Engl J Med · 2018In the WT population: 356 patients in the ABCP group and 336 patients in the BCP group (the number in the ACP group is not stated in the abstract)

Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. N Engl J Med. 2018. 378:2288-2301

Study type: Clinical trial
Study name: IMpower150
Phase: Phase 3
Design: Randomised, open-label trial
Sample size: In the WT population: 356 patients in the ABCP group and 336 patients in the BCP group (the number in the ACP group is not stated in the abstract)
Source: N Engl J Med · 2018
Trial registration: NCT02366143

In plain words

In this study, the immunotherapy drug atezolizumab was added to a combination of bevacizumab and chemotherapy in people with advanced non-squamous lung cancer who had not yet had chemotherapy. This combination lengthened the time the disease stayed under control without getting worse, and it also helped people live longer. The benefit was seen whatever the level of PD-L1, a protein on the tumour cells. The side effects of the combination matched the known side effects of each of the drugs.

Key results

8.3 vs 6.8 months

Progression-free survival (WT population): ABCP vs BCP

HR for disease progression or death 0.62 (95% CI 0.52–0.74); P<0.001

11.3 vs 6.8 months

Progression-free survival (Teff-high WT population): ABCP vs BCP

HR 0.51 (95% CI 0.38–0.68); P<0.001

19.2 vs 14.7 months

Overall survival (WT population): ABCP vs BCP

HR for death 0.78 (95% CI 0.64–0.96); P=0.02

Drugs in this study:Bevacizumab (Avastin)Carboplatin (Paraplatin)Paclitaxel (Taxol)Atezolizumab (Tecentriq)

Dose and schedule cards

Atezolizumab + bevacizumab + paclitaxel + carboplatin (IMpower150)

Metastatic non-squamous NSCLC without EGFR/ALK, first lineCycle length: Every 21 daysOn the page “Atezolizumab (Tecentriq)” · Combination regimens (FDA label)

Metastatic non-squamous NSCLC without EGFR/ALK, first line

Drug	Dose	Route	Schedule
Induction: 4 or 6 cycles
Atezolizumab	1200 mg	IV, first of all	Day 1
Induction
Bevacizumab	15 mg/kg	IV	Day 1
Paclitaxel	175 or 200 mg/m²	IV	Day 1
Carboplatin	AUC 6	IV	Day 1
Maintenance
Atezolizumab + bevacizumab	1200 mg + 15 mg/kg	IV	Day 1

Cycle length: Every 21 days
Duration: 4 or 6 induction cycles, then maintenance until progression or toxicity

Alternative regimen (IMpower130): atezolizumab 1200 mg and carboplatin AUC 6 on day 1 and protein-bound paclitaxel 100 mg/m² on days 1, 8 and 15 every 21 days, for 4 or 6 cycles; then atezolizumab every 3 weeks.

On the page “Atezolizumab (Tecentriq)” · Combination regimens (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1ACP

Induction: atezolizumab 1200 mg IV, then paclitaxel 200 mg/m² (FDA label: 175 or 200 mg/m²) IV and carboplatin AUC 6 IV, all on day 1 of each 21-day cycle, for 4 or 6 cycles. Maintenance: atezolizumab 1200 mg IV day 1 every 21 days until loss of clinical benefit.

2BCP (comparator group)

Induction: bevacizumab 15 mg/kg IV, then paclitaxel 200 mg/m² (FDA label: 175 or 200 mg/m²) IV and carboplatin AUC 6 IV, all on day 1 of each 21-day cycle, for 4 or 6 cycles. Maintenance: bevacizumab 15 mg/kg IV day 1 every 21 days until disease progression, unacceptable toxicity or death.

3ABCP

Induction: atezolizumab 1200 mg + bevacizumab 15 mg/kg IV, then paclitaxel 200 mg/m² (FDA label: 175 or 200 mg/m²) IV and carboplatin AUC 6 IV, all on day 1 of each 21-day cycle, for 4 or 6 cycles. Maintenance: atezolizumab 1200 mg (until loss of clinical benefit) + bevacizumab 15 mg/kg (until disease progression or unacceptable toxicity) IV, day 1 every 21 days.

Source of the regimen details: ClinicalTrials.gov NCT02366143 (dose and schedule of each arm) and the FDA label for Tecentriq (DailyMed, section 14, IMpower150); the full text of the NEJM paper was not available in PMC.

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with stage IV non-squamous NSCLC who had not received chemotherapy for metastatic disease, with ECOG performance status 0 or 1, measurable disease and adequate haematological and organ function, regardless of PD-L1 expression. Patients with EGFR or ALK alterations could enrol after treatment with an appropriate kinase inhibitor but were excluded from the main analysis population (WT).

Exclusion criteria: active or untreated central nervous system metastases, history of autoimmune disease, history of idiopathic pulmonary fibrosis or pneumonitis or evidence of active pneumonitis on CT, clear tumour infiltration into the major thoracic blood vessels or clear cavitation of lung lesions on imaging, prior treatment with immune checkpoint inhibitors, HIV, active hepatitis B or C, and significant cardiovascular disease.

Endpoints

The co-primary endpoints were investigator-assessed progression-free survival (PFS), in both the WT population and the WT population with high expression of an effector T-cell gene signature (Teff-high WT), and overall survival (OS) in the WT population. The ABCP group was compared with the BCP group before the ACP group.

Safety and side effects

According to the abstract, the safety profile of ABCP was consistent with the known risks of each drug. According to the FDA label (393 ABCP versus 394 BCP patients): fatal adverse events in 6% of patients on atezolizumab (including haemoptysis, febrile neutropenia, pulmonary embolism and pulmonary haemorrhage); serious adverse events 44% (most common: febrile neutropenia, pneumonia, diarrhoea and haemoptysis); atezolizumab discontinuation due to adverse events 15% (most common cause pneumonitis, 1.8%) and temporary interruption 48%. Selected grade 3–4 adverse events (ABCP versus BCP): hypertension 9% versus 8%, diarrhoea 6% versus 0.5%, fatigue/asthenia 6% in both groups, nausea 4% versus 2%, decreased appetite 4% versus 0.8%, neuropathy 3% in both groups, proteinuria 3% in both groups and rash 2% versus 0.3%. The overall rate of grade 3 or higher adverse events is not stated in the abstract or the label.

Clinical significance and place in guidelines

According to the abstract, adding atezolizumab to bevacizumab and chemotherapy (carboplatin and paclitaxel) in the first-line treatment of metastatic non-squamous NSCLC improved progression-free survival and overall survival compared with BCP, including in patients with low or negative PD-L1 and patients with liver metastases. The status of drug approvals and the place of this regimen in current guidelines should be checked separately, as they are not stated in the abstract.

Limitations

The study was open-label and progression-free survival was investigator-assessed. The main analyses were done in the WT population, which did not include patients with EGFR or ALK alterations. The ACP versus BCP comparison came after the ABCP versus BCP comparison and its data are not reported in the abstract. Other limitations should be checked in the full text.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.