Background

Malignant pheochromocytoma and paraganglioma (MPP) is a very rare cancer (annual incidence < 1 per million). Here, we report the first academic randomized double-blind phase II study results assessing Sunitinib efficacy compared to placebo.

Methods

Patients with progressive MPP with 1.5year according to (RECIST) were randomized 1/1 for Sunitinib therapy 37.5 mg/d or Placebo and stratified for SDHB status and line of treatment. Primary endpoint: progression-free survival (PFS) at 12 months according to real-time central review (RECIST 1.1), analyzed every 3 months (ITT). Key secondary endpoints: ORR, response (delay, duration), overall PFS, overall survival, safety (NCI CTCAE v.4). On the basis of a two-step Simon model (alpha 10%, power 90%), we aimed for 74 patients, assuming a PFS improvement at 12 months from 20 to 40%. 11 or more patients out of 37 with no progression at 12 months were expected to conclude that Sunitinib is effective. The placebo group served as an internal control to validate the hypothesis of the Simon design with a 12-m PFS equal to 20%. An IDMC was set up to review the accrual, toxicity, and interim analysis.

Results

78 patients were enrolled (median age, 53 yrs; 59% men). Main characteristics: adrenal/PGL primaries, each 50%; 32% SDHx inherited, 71% secreting, distant lymph node/bone/lung/liver mets, 73%/65%/51%/49%; 60% prior therapy. 39 patients were randomized in each arm. The primary endpoint was met: PFS at 12 months was 35.9% (Sunitinib) vs. 18.9% (Placebo; within the 90%CI confirming the Simon design conclusion). Median PFS was 8.9 (95CI: 5.5-12.7) vs. 3.6 months (3.1-6.1). Reasons for drug discontinuation were AE/tumor progression in 14%/64% (Sunitinib) and 0%/86% (Placebo). 54% patients with Sunitinib vs. 49% with Placebo experienced SAE; most frequent grade 3-4 were asthenia/fatigue (18% vs. 3%) and hypertension (10% vs. 6%).One death occurred in each arm.

Conclusions

After 8 years of enrolment, this first randomized study in the field of MPP provides the highest level of evidence ever reached in this very rare cancer. Sunitinib becomes the first-line option in patients with progressive MPP.

Clinical trial identification

NCT01371201.

Legal entity responsible for the study

Gustave Roussy.

Funding

Pfizer.

Disclosure

E. Baudin: Financial Interests, Personal and Institutional, Advisory Board, research grant and principal investigator: Novartis; Financial Interests, Personal and Institutional, Advisory Board, and research grant: HRA; Financial Interests, Personal and Institutional, Project Lead, Principal investigation: Ipsen; Financial Interests, Personal and Institutional, Advisory Board, research grant (drug supply for trial): AAA; Financial Interests, Personal and Institutional, Research Grant, drug supply for trial: Pfizer; Financial Interests, Personal and Institutional, Advisory Board: Hutchinson Pharma. All other authors have declared no conflicts of interest.

Background

Patients with cancer are at increased risk of severe outcomes from COVID-19. Understanding the impact of SARS-CoV-2 infection and vaccination induced-immunity is an area of unmet need.

Methods

CAPTURE (NCT03226886) is a prospective longitudinal cohort study of COVID-19 vaccine or SARS-CoV-2 infection-induced immunity. SARS-CoV-2 infections were confirmed by RT-PCR and ELISA. Neutralising antibody titres (NAbT) against wild-type (WT) SARS-CoV-2 and variants of concern (VOC; Alpha, Beta, Delta) and SARS-CoV-2 specific T-cells (SsT-cells) were quantified.

Results

118 patients (89% solid malignancy, [SM]) were SARS-CoV-2-positive (median follow-up: 154 days). 85% patients were symptomatic; 2 died of COVID-19. 82% had S1-reactive antibodies, of whom 89% had neutralising antibodies (NAbs); NAbT were lower against all VOCs. While S1-reactive antibody levels declined over time, NAbT remained stable up to 329 days. Most patients had detectable SsT-cells (76% CD4+, 52% CD8+). Haematological malignancy (HM) patients had impaired immune responses that were disease and treatment-specific (anti-CD20), but with evidence suggestive of compensation from T-cells. 585 patients were evaluated following 2 doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after 2 doses were 85% and 54% in patients with SM and HM, respectively. A lower proportion of patients had detectable NAbs against SARS-CoV-2 VOC (Alpha 62%, Beta 54%, Delta 49%) vs WT (84%), with corresponding significantly lower NAbT. Patients with HM were more likely to have an undetectable NAb and had lower NAbT vs solid malignancies to both WT and VOCs. Seroconversion showed poor concordance with NAbTs against VOCs. Prior SARS-CoV-2 infection boosted NAbT including against VOCs. Anti-CD20 treatment was associated with severely diminished NAbTs. Vaccine-induced T-cell responses were detected in 80% of patients, with no differences between vaccines or cancer types.

Conclusions

Patients with HM had blunted humoural responses to infection and vaccination, particularly against VOCs, but preserved cellular responses might contribute to protection. Our results lend support to prioritisation of all cancer patients for further booster vaccination.

Clinical trial identification

NCT03226886.

Legal entity responsible for the study

The Royal Marsden NHS Foundation Trust.

Funding

The Royal Marsden Charity; The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute for Cancer Research (ICR).

Disclosure

All authors have declared no conflicts of interest.

Background

Patients with cancer have an increased risk of complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Vaccination is recommended, but the impact of chemotherapy and immunotherapy on immunogenicity and safety is still unclear.

Methods

This prospective multicenter non-inferiority trial comprises four cohorts: individuals without cancer (A) and patients with solid tumors who were treated with immunotherapy (B), chemotherapy (C) or chemo-immunotherapy (D). Participants received two mRNA-1273 vaccinations 28 days apart. The primary endpoint was SARS-CoV-2 Spike S1-specific IgG serum antibody response, defined as >10 binding antibody units (BAU)/ml 28 days after the second vaccination. We also assessed the virus neutralizing capacity of these antibodies, SARS-CoV-2 Spike-specific interferon-gamma T cell response, and adverse events.

Results

Of the 791 participants enrolled, 743 were evaluable for the primary endpoint in cohort A (n=240), B (n=131), C (n=229) and D (n=143). A SARS-CoV-2-binding antibody response was found in 100%, 99.3%, 97.4%, and 100% of the participants in cohorts A, B, C, and D, respectively. To discriminate between suboptimal and adequate responders, we defined a cut-off level at 300 BAU/ml, based on neutralizing capacity. The antibody response was considered adequate after the first vaccination in 66.0%, 37.1%, 32.5%, and 33.3% of the participants in cohorts A, B, C, and D, respectively. This raised 28 days after the second vaccination to respectively 99.6%, 93.1%, 83.8%, and 88.8% in cohorts A, B, C, and D. Spike-specific T cell responses were detected in 46.7% of suboptimal and non-responders. No new safety signals were observed.

Conclusions

mRNA-1273 vaccination is safe in the patient populations studied. For each cohort, the proportion of patients with a SARS-CoV-2-binding antibody response after two vaccinations is non-inferior compared to individuals without cancer. However, a significant minority lacks an adequate response. Most patients have an antibody concentration increase after the second vaccination. Therefore, an additional booster may turn inadequate into adequate responders.

Clinical trial identification

NCT04715438.

Legal entity responsible for the study

University Medical Center Groningen, the Netherlands.

Funding

ZonMw, The Netherlands Organisation for Health Research and Development.

Disclosure

All authors have declared no conflicts of interest.

Background

Despite treatment with curative intent, up to 60% of patients (pts) with stage I-III NSCLC still experience disease relapse. IMpower010 is the first randomised Phase 3 study to show significant DFS improvement with adjuvant cancer immunotherapy (CIT; atezolizumab [atezo]; anti–PD-L1) after adjuvant chemotherapy in pts with early-stage resected NSCLC (Wakelee ASCO 2021). We explored the sites of relapse and post-relapse treatment (tx).

Methods

Enrolled pts had completely resected stage IB-IIIA NSCLC and ECOG PS 0-1. 1280 pts received up to four 21-day cycles of cisplatin-based chemotherapy (plus pemetrexed, docetaxel, gemcitabine or vinorelbine). 1005 pts were then randomised 1:1 to atezo 1200 mg Q3W (16 cycles or until disease relapse or unacceptable toxicity) or best supportive care (BSC). The DFS primary endpoint was tested hierarchically in PD-L1 TC ≥1% (SP263) stage II-IIIA pts, then in all randomised stage II-IIIA pts and then in ITT stage IB-IIIA pts. Exploratory analyses of relapse sites and post-relapse tx were conducted.

Results

As previously reported, the DFS significance boundary was crossed in PD-L1 TC ≥1% stage II-IIIA (HR [95% CI] 0.66 [0.50, 0.88]) and all randomised stage II-IIIA (HR 0.79 [0.64, 0.96]) pts. In all randomised stage II-IIIA pts, DFS improvement (HR [95% CI]) was seen with increasing PD-L1 expression: TC <1%, 0.97 (0.72, 1.31); TC 1-49%, 0.87 (0.60, 1.26); TC ≥50%, 0.43 (0.27, 0.68). Among PD-L1 TC ≥1% stage II-IIIA pts, 73 (29%) relapsed in the atezo arm vs 102 (45%) in the BSC arm. Sites of relapse and post-relapse tx are shown in the table; further data will be presented, including in all randomised stage II-IIIA and ITT pts.

Conclusions

At this interim DFS analysis, relapse rate was higher in the BSC vs atezo arm, but there was no clear difference in pattern of relapse between the arms among pts with relapse. Post-relapse CIT use was higher in the BSC arm. Table: LBA9

PD-L1 TC ≥1% stage II-IIIA population

Clinical trial identification

NCT02486718.

Editorial acknowledgement

Medical writing assistance for this abstract was provided by Kia C. E. Walcott, PhD, of Health Interactions Inc and funded by F. Hoffmann-La Roche, Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

E. Felip: Financial Interests, Institutional, Research Grant: Grant for Oncology Innovation (GOI); Financial Interests, Institutional, Research Grant: Fundación Merck Salud; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Other, Honoraria: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Beigene; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Other, Honoraria: Eli Lilly; Financial Interests, Personal, Advisory Board: F. Hoffmann-La Roche; Financial Interests, Personal, Other, Honoraria: F. Hoffmann-La Roche; Financial Interests, Personal, Advisory Board: Glaxo Smith Kline; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Other: Janssen; Financial Interests, Personal, Advisory Board: Medical Trends; Financial Interests, Personal, Other, Honoraria: Medscape; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Other, Honoraria: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Other, Honoraria: Merck Serono; Financial Interests, Personal, Other, Honoraria: Peervoice; Financial Interests, Personal, Advisory Board: Peptomyc; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Other, Honoraria: Springer; Financial Interests, Personal, Advisory Board: Syneos Health; Financial Interests, Personal, Other, Honoraria: Springer; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Other, Honoraria: Touch Medical; Non-Financial Interests, Personal, Leadership Role, President-Elect (2021-2023) of Spanish Society of Medical Oncology (Not compensated): SEOM (Spanish Society of Medical Oncology); Non-Financial Interests, Personal, Leadership Role, Member of the ESMO Nominating Committee and Compliance Committee (Not compensated): ESMO (European Society of Medical Oncology); Non-Financial Interests, Personal, Leadership Role, Member of the Scientific Committee (Not compensated): ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Personal, Leadership Role, Member of the Board of Directors and the Executive Committee (2017 – September 2021): IASLC (International Association for the Study of Lung Cancer); Financial Interests, Personal, Member of the Board of Directors, Independent member of the Board. (Personal fees received): GRIFOLS. E. Vallieres: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Oncocyte; Financial Interests, Personal, Advisory Role: Olympus. C. Zhou: Financial Interests, Personal, Invited Speaker: Roche China; Financial Interests, Personal, Speaker’s Bureau: Lily China BI Sanofi C-Stone Qilu Hengrui Innovent Biologics LUYE Pharma TopAlliance Bioscience Inc Amoy Diagnoistics. H. Wakelee: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Daiichi Sankyo, Blueprint, Mirati, Helsinn; Financial Interests, Personal, Invited Speaker: Fishawack Facilitate LTD, Medscape, Research to Practice, MJH Holdings, Axis Medical Education, Nexus Oncology; Financial Interests, Personal, Writing Engagements: UpToDate; Financial Interests, Personal, Other: Curio Science; Financial Interests, Institutional, Other, Local PI: ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, BMS, Clovis Oncology, Novartis, Seagen, Xcovery; Financial Interests, Institutional, Other, Coordinating PI: Celgene; Financial Interests, Institutional, Other, Steering Committee Member: Genentech/Roche, Merck; Non-Financial Interests, Personal, Officer, President-Elect: International Association for the Study of Lung Cancer (IASLC); Non-Financial Interests, Personal, Leadership Role, Executive Committee: ECOG-ACRIN. H. Sakai: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical Co; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical Co. H. Saito: Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers, Chugai Pharmaceutical. N. Kislov: Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca, Eisai, EMD Serono, Exelixis, MSD, Genentech/Roche, GlaxoSmithKline, Ipsen Novartis, Pfizer, Nektar, Lilly; Financial Interests, Personal, Invited Speaker: Biocad, Ipsen, Roche. M. Reck: Financial Interests, Personal, Other, Honoraria for Lecture and Consultancy: AbbVie, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi; Financial Interests, Personal, Other, Personal Fees: Celgene; Financial Interests, Institutional, Research Grant: Roche/Genentech; Non-Financial Interests, Personal, Other, Non-financial support: Roche/Genentech; Financial Interests, Personal, Other, Honoraria for Consultancy: Mirati. V.A. McNally: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Personal, Stocks/Shares: Roche. Q. Zhu: Financial Interests, Personal, Full or part-time Employment: Genentech. B. Ding: Financial Interests, Personal, Full or part-time Employment: Genentech. E. Bennett: Financial Interests, Personal, Full or part-time Employment: Genentech. B. Gitlitz: Financial Interests, Personal, Full or part-time Employment: Genentech. N.K. Altorki: Other, Institutional, Research Grant: NCI, DoD, AZ LLC, Jannsen. All other authors have declared no conflicts of interest.