ABSTRACT
Background: The value of increased HER2 gene copy number (GCN) in NSCLC is unclear. In this study we defined its frequency and characterized a cohort of patients harboring it. Methods: Patients with stage IIIB/IV NSCLC enrolled in the Gustave Roussy MSN study (NCT02105168) between Oct. 2009 and Feb. 2016 were screened by FISH (positivity defined as HER2 GCN to centromeres ratio ≥ 2) and tested for other molecular alterations. Descriptive analyses of clinical-pathological data were performed, progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Results: HER2 FISH tested positive in 22 of 250 screened patients (9%). Median age was 60 years (range 47-80), 68% (n=15) were male, 91% (n=20) were current or former tobacco smokers (median exposure 47 pack-year), 64% (n=14) had adenocarcinoma, 18% (n=4) squamous cell and 18% (n=4) large cell carcinoma. 91% (n=20) had an ECOG PS of 0 or 1. Stage IV with extra-thoracic involvement was the most common clinical presentation (64%, n=14). Overall, 95% of patients (n=21) had 1 or 2 metastatic sites at diagnosis (bone 32%, lung 27%, nodes 18%, liver 18%, brain 18%). In 9 patients (41%) 12 concurrent molecular alterations were detected: 5 KRAS mutation (3 G12C, 1 G12D, 1 G61H), 2 HER2 exon 20 insertion, 1 EGFR exon 19 deletion, 1 BRAF V600E mutation, 1 ALK rearrangement, 1 FGFR1 and 1 MET amplification. 18 patients received first-line platinum-based chemotherapy, with 33% (95% CI 16-56) objective response rate and 83% (95% CI 61-94) disease control rate. After a median follow-up of 28 months (95% CI 23-45), median PFS and OS were 5.9 (95% CI 3.4-11.0) and 15.3 (95% CI 10.3-NR) months, respectively. Median PFS was longer in patients with higher GCN. As further line of treatment, 5 patients received trastuzumab: 4 in combination with chemotherapy and 1 as monotherapy, with 1 stabilization of disease as best response. 3 patients received nivolumab (1 partial response and 1 stable disease) and 3 a targeted therapy (anti ALK, EGFR, BRAF). Conclusions: Increased HER2 GCN was found in 9% of patients with unresectable NSCLC, was not correlated to particular clinical characteristics, but frequently occurred with other molecular alterations. Its clinical actionability and the correlation with protein expression deserve further characterization. Clinical trial identification: NCT02105168. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: M. Tagliamento: Other, Personal, Other, Travel grants: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly;Other, Personal, Writing Engagements, Honoraria as medical writer: Novartis, Amgen. E. Auclin: Financial Interests, Personal, Advisory Board: Amgen, Sanofi. E. Rouleau: Financial Interests, Institutional, Advisory Board: AstraZeneca, Roche, Amgen, GSK;Financial Interests, Institutional, Invited Speaker: Clovis, BMS;Financial Interests, Institutional, Funding, Data base: AstraZeneca. A. Bayle: Non-Financial Interests, Institutional, Other, Principal/Sub-Investigator of Clinical Trials: AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, BicycleTx Ltd, Non-Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi;Financial Interests, Institutional, Other, drug supplied: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. F. Barlesi: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Seattle Genetics, Takeda;Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. D. Planchard: Financial I terests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen;Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen;Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre;Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, EISAI, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. All other authors have declared no conflicts of interest.
ABSTRACT
Background: Immune Checkpoint Blockade (ICB) is moving from metastatic to curative setting in different diseases including NSCLC. While for metastatic disease radiological endpoints are currently the standard surrogate marker of benefit from ICBs, based on RECIST or PERCIST criteria, in neoadjuvant setting they often underestimate the response and then pathological response (PR) criteria were developed to evaluate Major PR (MPR), defined as ≤10% viable tumor cells after neoadjuvant treatment, and PR, defined as less than 50% residual tumor cells. Anyway, a non-invasive approach to determine the response to treatment is still an unmet need. Methods: PRINCEPS was a phase 2 clinical trial including limited-stage (IB-IIIA) NSCLC patients who received one administration of atezolizumab before surgery. 18-F FDG PET was performed within 28 days and after 15-22 days from atezolizumab. Surgery was performed at day 22-29 from atezolizumab. PET derived parameters including MTV and TLG was extracted by experienced nuclear physicians. Results: 30 patients were enrolled, all received A and underwent surgical resection after a median of 23 days. MPR was identified in 4, pPR in 8 tumors. Paired PET were available for 28 pts. Mean time from A to PET was 18 days (IQR 3.5). Total TLG and MTV reduction was not correlated with percentage of pPR (p=0.117 and p=0.843, respectively). Reduction of MTV (Pearson correlation 0.509, p=0.006) and TLG (Pearson correlation 0.562, p=0.002) in the primary tumor were strongly correlated with pPR, while no correlation was observed between percentage of pPR and variation in tumor diameters by RECIST criteria (-0.24, p=0.2) nor metabolic response (-0.12, p=0.55). The appearance of metabolically active hilar and mediastinal, non-pathological lymph nodes (LN) was noted in 12/28 patients, and specifically in. 2 out of 4 MPR and 5 out of 8 pPR. A trend toward an higher pPR was observed with LN appearance (mean 52% reduction in pts with LN appearance vs 29% without, p 0.061), probably reflecting immune activation. LN appearance was associated with hyperplasia and histiocytosis in resected, non-metastatic LNs. Conclusions: PET is able to early detect tumor response in localized NSCLC patients treated with ICBs in neoadjuvant setting. Clinical trial identification: NCT02994576. Legal entity responsible for the study: Institut Gustave Roussy. Funding: Roche. Disclosure: N. Chaput-Gras: Financial Interests, Personal, Advisory Board, Strong-Iopredi Scientific Advisory Board: AstraZeneca;Financial Interests, Institutional, Invited Speaker, Educational Session On Immune Cell Death: Servier;Financial Interests, Institutional, Expert Testimony, Expertise On Immune Cell Death Biomarkers: Servier;Financial Interests, Personal, Invited Speaker: Cytune Pharma;Financial Interests, Institutional, Research Grant, Research grant to identify immune biomarkers associated to clinical response in patients treated with agonistic mAbs: GSK;Financial Interests, Institutional, Research Grant, Preclinical studies in mice: GSK;Financial Interests, Institutional, Research Grant, Immune profiling of Head & Neck tumors: Sanofi. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen;Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen;Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre;Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Resea ch Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. J. Remon Masip: Financial Interests, Personal, Invited Speaker: Roche, Pfizer, MSD, Boehringer-Ingelheim;Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Janssen, Takeda, Sanofi;Financial Interests, Personal, Expert Testimony: Ose Immunotherapeutics;Non-Financial Interests, Principal Investigator, PI of PECATI trial in Thymic malignancies endorsed by a grant by MSD: MSD;Non-Financial Interests, Other, Co-PI of APPLE trial (EORTC-1525): AstraZeneca. F. Barlesi: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda;Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. All other authors have declared no conflicts of interest.
ABSTRACT
Background: The COVID-19 pandemic deeply threatens the rigorous conduct of clinical trials, notably by delaying site initiation visits, patient enrolment, treatment administration, trial-associated procedures, and data monitoring. Unlike most other medical specialties, clinical trials are an integral part of patient care in oncology. Limiting access to clinical trials therefore results in a loss of chance for patients. Methods: In this retrospective single-center study, we collected clinical trial-specific items (including patient-related or trial management-related items) during the first pandemic wave (March– June 2020) and lockdown (March 17th-May 11th) at Gustave Roussy, and compared them to those of the same period in 2019. Results: In March 2020, 84 phase I (P1) and 210 phase II/III (P2/3) trials were open. During the first pandemic wave, 21 (25%) P1 and 20 (9%) P2/3 trials were temporarily halted, following a unilateral sponsor decision in virtually all cases;all but one were industry-sponsored. Despite this, all important metrics of the P1/2 trial activity remained similar to those of 2019, including the number of patients referred for inclusion (599 vs 620), inclusion consultations (215 vs 247), patients starting treatment (130 vs 130), Internal Review Board (IRB) submissions (14 vs 16), and site initiation visits (11 vs 15), all in 2020 vs 2019, respectively. The impact of the first lock-down was more marked on P2/3, with 152 patient inclusions (vs 346 in 2019), 125 randomizations (vs 278), 43 IRB submissions (vs 50) and 34 site initiation visits (vs 40). However, in parallel, 475 patients were included in three “COVID and cancer” trials. Among the 443 P1 and 2851 P2/3 patients, 198 and 628 COVID-19 PCR were performed internally, and five and 15 (2.5%) were positive, respectively. One patient with a community-based COVID-19 died after transfer in intensive care. Conclusions: Cancer clinical trials can, and must be maintained despite challenges brought by COVID-19. Sharing experiences and retrospectively evaluating the impact on patients’ safety and cancer-related outcomes will be critical to durably improve the clinical trials conduct and to anticipate at best challenges brought by future similar crises. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.