AACR 2018: First-line atezolizumab, bevacizumab plus chemotherapy active in non-squamous NSCLC

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AACR 2018: ADDITION OF ATEZOLIZUMAB TO BEVACIZUMAB AND CHEMOTHERAPY IMPROVES PROGRESSION-FREE SURVIVAL IN NON-SQUAMOUS LUNG CANCER

Medical writer: Stijn van den Borne, MSc | Last updated: 10th May 2018 | In: Chemotherapy, ImmunoOncology, Immunotherapy, Lung Cancer, Oncology, Translational Research

Article Keywords

AACR 2018, atezolizumab, carboplatin, chemotherapy, Genentech, Immunotherapy, non-squamous cell lung cancer, NSCLC, Oncology News, paclitaxel, PD-L1, Roche

Patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with first-line atezolizumab (Tecentriq®) plus bevacizumab (Avastin®), carboplatin, and paclitaxel had a 38% reduction of risk for progression disease or death compared with patients treated with bevacizumab and chemotherapy alone. The emerging data of the IMpower150 (NCT02366143) study were presented at the ELCC 2018 and the AACR 2018 conferences.

The IMpower150 study showed that addition of the anti-programmed death 1 ligand (PD-L1) antibody to bevacizumab and platinum-based chemotherapy resulted in a median progression-free survival (PFS) of 8.3 months. Patients treated with bevacizumab plus carboplatin and paclitaxel had a median PFS of 6.8 months (hazard ratio [HR]=0.62; 95% CI, 0.52-0.74; P<0.0001). See the interactive Forest plot (Figure 4) for all results.

“The trial [IMpower150] explored these combinations because atezolizumab’s T-cell mediated cancer cell killing may be enhanced through bevacizumab’s reversal of VEGF-mediated immunosuppression, while the chemotherapy of carboplatin plus paclitaxel may induce immune responses,”

Prof. Martin Reck of the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf in Germany presented the IMpower150 results during the ELCC 2018.

The Phase III IMpower150 randomised 1202 stage IV non-squamous NSCLC patients 1:1:1 to receive atezolizumab plus carboplatin and paclitaxel (ARM A), atezolizumab plus bevacizumab, carboplatin and paclitaxel (ARM B), or bevacizumab plus carboplatin and paclitaxel (ARM C) (Figure 1).

The co-primary endpoints were investigator-assessed PFS in the intention-to-treat (ITT) EGFR wild-type (wt) population, investigator-assessed PFS in the T-effector (T_eff) gene signature high population, and overall survival (OS) in the ITT-wt population.

Roche, the manufacturer of both atezolizumab and bevacizumab, issued a press release in March 2018 stating the OS co-primary endpoint to be positive. The OS results are pending presentation at an upcoming meeting.

Figure 1. IMpower150 (NCT02366143) clinical study design. Presented data during the ELCC and AACR 2018 focussed solely on ARM B and ARM C.

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

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All patients received carboplatin (area under the concentration-time curve [AUC] 6) and paclitaxel (200 mg/m²) on day 1 of every 3 weeks (q3w) for 4 or 6 cycles. Atezolizumab was administered intravenously (IV) at 1200 mg q3w, and IV bevacizumab was given at 15 mg/kg q3w. Maintenance therapy for patients in ARM A was atezolizumab alone, in ARM B bevacizumab plus atezolizumab, and in ARM C bevacizumab alone.

At interim analysis, which was designed to compare arms B and C of the IMpower150, the median follow-up was approximately 15 months. The results in the ITT population are displayed in Table 1 and Figure 2.

**Table 1.** The median PFS, 6- and 12-month PFS rates, and response rates of the ITT population in ARM B (atezolizumab plus bevacizumab, carboplatin and paclitaxel) and ARM C (bevacizumab plus carboplatin and paclitaxel) of the IMpower150 study. DOR: duration of response; ITT: intention-to-treat; PFS: progression-free survival.
	Median PFS	6-mo PFS	12-mo PFS	ORR	CR	PR	median DOR
ARM B	8.3 mo	67%	56%	64%	4%	60%	9.0 mo
ARM C	6.8 mo	37%	18%	48%	1%	47%	5.7 mo

Figure 2. Comparison of the response rates between atezolizumab (ATEZO) plus bevacizumab (BEV), carboplatin and paclitaxel (CP) vs bevacizumab (BEV) plus carboplatin and paclitaxel (CP) in the IMpower150 study. CR: complete response; PD: progression disease; PR: partial response; SD: stable disease.

PD-L1+ ≥50% of TC or ≥10% of IC;
pd-l1 low: TC1/2 or IC 1/2 = ≥1% PD-L1+ TC <50% or ≥1% PD-L1+ IC <10%
PD-L1 negative: TC0 and IC0 = PD-L1+ <1% of TC and IC

Translational Research

The IMpower150 looked at translational components, such as the T_eff gene signature and PD-L1 expression by immunohistochemistry (IHC) with both the SP142 and SP263 assays. The T_eff gene signature is defined by mRNA expression of 3 genes, including PD-L1, CXCL9, and IFNγ. It is a surrogate for both PD-L1 expression and pre-existing immunity.

“In the OAK study, the T_eff gene signature appeared to be a more sensitive biomarker of PFS benefit for monotherapy atezolizumab versus docetaxel than PD-L1 IHC expression.”

~Mark A. Scozinski, MD of the Florida Hospital Cancer Institute in the United States presented the IMpower150 results during the AACR 2018.

Figure 3. Comparison of the response rates between atezolizumab (ATEZO) plus bevacizumab (BEV), carboplatin and paclitaxel (CP) vs bevacizumab (BEV) plus carboplatin and paclitaxel (CP) in the T_eff-high EGFR-wt subpopulation of the IMpower150 study. CR: complete response; PD: progression disease; PR: partial response; SD: stable disease.

**Table 2.** The median PFS, 6 and 12-month PFS rates, and response rates of the T_eff-high EGFR-wt population in ARM B (atezolizumab plus bevacizumab, carboplatin and paclitaxel) and ARM C (bevacizumab plus carboplatin and paclitaxel) of the IMpower150 study. DOR: duration of response; ITT: intention-to-treat; PFS: progression-free survival; wt: wild-type.
	Median PFS	6-mo PFS	12-mo PFS	ORR	CR	PR	median DOR
ARM B	11.3 mo	72%	57%	69%	5%	64%	11.2 mo
ARM C	6.8 mo	46%	18%	54%	2%	52%	5.7 mo

Median PFS in the T_eff-high cohort, a co-primary endpoint, was 11.3 months (95% CI, 9.1-13.0) when atezolizumab was added to bevacizumab plus the platinum-doublet, compared to 6.8 months (95% CI, 5.9-7.4) with bevacizumab and platinum-doublet chemotherapy alone (HR=0.51; 95% CI, 0.38- 0.68; P<0.0001). The 6-month and 12-month PFS-rates for the T_eff-high subgroup are displayed in Table 2. Additionally, Figure 3 shows the response rates in T_eff-high patients with EGFR-wt status. Finally, Figure 4 shows PFS outcomes and odds ratio (Forest plot) for different subgroups in the study.

Figure 4. Forest plot for median PFS in different subgroups of the IMpower150 study. The study showed that the T_eff gene signature enriches for PFS similarly to PD-L1 IHC, including biomarker-negative patients.

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

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Legend by Figure 4 and Table 3

ALK: anaplastic lymphoma kinase; ATEZO: atezolizumab; BEV: bevacizumab; CP: carboplatin + paclitaxel; EGFR: epidermal growth-factor receptor; IC: immune cells; IHC: immunohistochemistry; mo: months; ITT: intention-to-treat; PD-L1: programmed death ligand 1; PFS: progression-free survival; TC: tumour cells; wt: wild-type.

**Table 3.** Algorithm for PD-L1 staining by SP142, the companion diagnostic (CDx) IHC for atezolizumab
	PD-L1 level expression (TC/IC coding)	PD-L1 level expression (%)
PD-L1 high	TC3 or IC3	≥50% PD-L1+ TC or ≥10% PD-L1+ IC
PD-L1 low	TC1/2 or IC1/2	≥1%-49% PD-L1+ TC or ≥1%-9% PD-L1+ IC
PD-L1 negative	TC0 and IC0	PD-L1+ <1% of TC and IC

Safety

The incidence of any adverse events (AEs), including serious AEs and immune-related AEs (irAEs), was similar between treatment arms. Moreover, the occurrence of treatment-related serious AEs (SAEs) was comparable; addition of atezolizumab to bevacizumab plus chemotherapy in ARM B was associated with 25% treatment-related SAEs vs 19% for bevacizumab plus chemotherapy in ARM C.

Roche noted that no new safety signals were identified when adding atezolizumab to the bevacizumab/chemotherapy combination and that the safety of the PD-L1 inhibitor combination appeared consistent with the known safety profile of the individual drugs.

Common atezolizumab-related side effects.

References

Reck M, et al. ESMO IO 2017 [LBA_PR1]

Reck M, et al. Ann Oncol 2017;28(11)

Reck M, et al. ELCC 2018 [134PD]

Kowanetz M & Socinski M, et al. AACR 2018 [CT076]

Roche. IMpower150 Media Release (2018, March 26). [Press release]

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).

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First-line atezolizumab, bevacizumab plus chemotherapy active in non-squamous NSCLC - MediNews Asia says:

24th May 2018 at 12:13 AM

Patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with first-line atezolizumab (Tecentriq®) plus bevacizumab (Avastin®), carboplatin, and paclitaxel had a 38% reduction of risk for progression disease or death compared with patients treated with bevacizumab and chemotherapy alone. The emerging data of the IMpower150 (NCT02366143) study were presented at the ELCC 2018 and the AACR 2018 conferences.

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