95O - Atezolizumab plus ipatasertib shows promise in extending survival for patients with PI3K/AKT/PTEN-altered advanced solid tumors: An exploratory analysis of the ROME trial

Background

The ROME trial demonstrated the superiority of target treatment (TT) over the standard of care (SoC) in patients (pts) with advanced cancers harboring various actionable genomic alterations. In this exploratory analysis we report the mutational landscape and clinical outcomes of a subgroup of pts with PTEN/PIK3CA alterations.

Methods

A centralized next-generation sequencing analysis was conducted on tissue and liquid biopsies from pts with treatment-resistant cancers (≤2 prior lines of therapy). After MTB discussion, pts bearing mutations deemed actionable by at least one drug available in the trial were randomized to receive TT or SoC. Pts with glioblastoma (GBM) and PTEN alterations or pts with PTEN/PIK3CA alteration and high TMB were proposed by MTB to receive atezolizumab plus ipatasertib. Due to the exploratory nature of the analysis, statistical significance was not determined.

Results

Among 400 randomized pts, 99 harbored alterations in the PIK3CA/AKT/PTEN pathway. 24 received indication to ipatasertib + atezolizumab as TT. 22 pts had GBM, 1 ovarian cancer and 1 prostate cancer. The most commonly altered gene in the pathway was PTEN (12 deletions and 11 mutations, 4 pts had both), followed by PIK3CA (5 mutations, 2 pts had concomitant PTEN alterations). TERT was the most common altered gene outside the pathway (16 pts, 67%), then CDKN2A (14 pts, 58%) and EGFR (13 pts, 54%). The median number of pathogenic alterations was 7 per patient (range 1 – 13). 12 pts were randomized to SoC and 12 to TT. Median PFS was 3.1 months in TT arm compared to 2.7 months in SoC (HR 0.54, 95% CI 0.21-1.38). Median OS was 8.1 months in TT arm vs 7.2 months in SoC (HR 0.47, 95% CI 0.17 - 1.29). TT arm had an higher 9-month (45% vs 11%) and 12-month (24% vs 0%) OS rate compared to SoC arm, respectively.

Conclusions

This exploratory analysis of patients with specific actionable alterations identified a subgroup with poor prognosis cancers who may benefit from TT with atezolizumab plus ipatasertib. The observed improvements in PFS and OS, particularly the substantial difference in 9- and 12-month OS rates, warrant further analysis and investigation in larger, prospective studies.

Clinical trial identification

NCT04591431, 2020-10-19.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione per la Medicina Personalizzata.

Funding

Fondazione per la Medicina Personalizzata.

Disclosure

A. Botticelli: Financial Interests, Personal, Advisory Board: Eli Lilly, Daichii, Gilead, MSD, Seagen, Novartis, Pfizer, Pfizer, Roche; Financial Interests, Personal, Invited Speaker: Gilead, BMS; Financial Interests, Personal, Principal Investigator: Gilead, AstraZeneca. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Astellas, GSK, Takeda, Bayer, Rottapharm, Beigene, Nimbus Therapeutics, Helion; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GSK, Roche, Servier, Amgen, Bristol Myers Squibb, Incyte, Lilly, Merck Serono, MSD, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb; Non-Financial Interests, Personal, Member of Board of Directors, Italian No-Profit Oncology Research Foundation supporting academic Clinical trials: GONO Foundation. G. Lombardi: Financial Interests, Personal, Advisory Board: Janssen, Braun, Helath4U; Financial Interests, Personal, Invited Speaker: Bayer, Orbus, Novartis, Servier; Financial Interests, Institutional, Invited Speaker: Bayer SpA. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Advisory Board, Advisory Board: Menarini, Gilead; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Personal, Leadership Role, Until the end of 2024: EUSOMA; Non-Financial Interests, Personal, Advisory Role, Member of the Scientific Council, Patient advocacy association: Europa Donna; Non-Financial Interests, Personal, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Personal, Officer, Editor of Chief of ESMO Open: ESMO; Non-Financial Interests, Personal, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Personal, Officer, ESMO Open Editor in Chief: ESMO. S. Scagnoli: Financial Interests, Personal, Invited Speaker: Eli Lilly, Roche, Novartis, Daichii, AstraZeneca, Pfizer; Financial Interests, Personal, Advisory Board: Eli Lilly. S. Pisegna: Financial Interests, Personal, Invited Speaker: Eli Lilly, Daichii, Pfizer, AstraZeneca, Novartis, GSK, Gilead; Financial Interests, Personal, Advisory Board: Ipsen, Gentili, Seagen; Financial Interests, Personal, Writing Engagements: Daichii. S. Verkhovskaia: Financial Interests, Personal, Invited Speaker: Novartis. C. Cremolini: Financial Interests, Personal, Advisory Board: Roche, MSD, Pierre Fabre, Nordic Pharma, Takeda, Lilly, AstraZeneca; Financial Interests, Personal, Invited Speaker: Bayer, Servier, Merck Serono, Amgen; Financial Interests, Personal, Expert Testimony: Amgen; Financial Interests, Institutional, Invited Speaker: Roche, Bayer, Servier, Merck, Seagen, Hutchinson, GSK, Tempus, Pfizer. E. Capoluongo: Financial Interests, Personal, Advisory Board: Roche. U. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Eisai, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Merck; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi, Roche. P.F. Conte: Financial Interests, Personal, Advisory Board, advisory board for Alpelisb trial: Novartis; Financial Interests, Institutional, Research Grant: Merch Kga; Non-Financial Interests, Personal, Advisory Role, Chairman of EDMC of two trials: Pfizer. P. Marchetti: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Role: MSD, Gilead, Daiichi, BMS, Genentech, Novartis, Amgen, Merck Serono, Pierre Fabre, and Incyte, Novartis, Incyte, Amgen, Pierre Fabre. All other authors have declared no conflicts of interest.