Abstract 1020P
Background
Primary and acquired resistance to anti-programmed cell death 1 therapy (anti-PD-1) is an important unmet need in non-small cell lung cancer (NSCLC), especially in patients with a low or negative PD-L1 tumors. We hypothesized that the combination of ipilimumab, nivolumab and medium dose radiotherapy (IPI-NIVO and mRT) could overcome resistance to anti-PD-1. In this study, we studied the safety and efficacy of IPI-NIVO and mRT, in metastatic NSCLC patients who progressed on chemotherapy and anti-PD-1.
Methods
This single-arm, prospective phase II trial aimed to enroll 30 evaluable metastatic NSCLC patients with disease progression after chemo and anti-PD-1. Patients with low (1-49%) and negative (<1%) PD-L1 expressing tumors were included. Co-primary end-points were safety, disease control rate (DCR) and objective response rate (ORR), measured on non-irradiated tumor lesions. The study tested a prespecified ORR threshold of 10%, comparable with the ORR of standard-of-care chemo in the 2nd line and beyond. On day 1, IPI 1 mg/kg Q6W and NIVO 240 mg Q2W was given for 6 weeks, followed by IPI 1 mg/kg Q6W and NIVO 360 mg Q3W until disease progression or unacceptable toxicity. Radiotherapy was given using 3 fractions of 8Gy on days 8, 10 and 12 to a max of 4 tumor sites, at least 1 measurable lesion was not irradiated. Treatment related frequencies for activated CD4+ and CD8+ effector and memory subsets in peripheral blood and tumor biopsies were analyzed.
Results
To date, an ORR was achieved in 9 out of 31 (29%) patients in the intention-to-treat population. Stable disease was seen in another 26% as best response. No ORR difference was seen between tumors with negative (N=15) vs low PD-L1 (N=16). The toxicity of the combination of IPI-NIVO and mRT was acceptable (Grade 3-4 treatment-related adverse events were 31%). No treatment-related deaths occurred.
Conclusions
Our results indicate that the combination of IPI-NIVO and mRT is safe and well tolerated. In patients with both low and negative PD-L1 expressing tumors, resistant to anti-PD-1 therapy, IPI-NIVO and mRT achieved substantial tumor responses. These data support further research using this combination in metastatic NSCLC after disease progression on chemo-immunotherapy.
Clinical trial identification
EudraCT: 2020-001097-29; Netherlands Trial Register: NL8857.
Editorial acknowledgement
Legal entity responsible for the study
Amsterdam UMC, Vrije Universiteit Medical Center, Department of Pulmonology.
Funding
Bristol Myers Squibb.
Disclosure
I. Bahce: Financial Interests, Institutional, Advisory Board: BMS, Boehringer Ingelheim, AstraZeneca, Roche, Pfizer, Takeda, MSD; Financial Interests, Institutional, Research Grant: BMS, Boehringer Ingelheim, AstraZeneca. F.L. Schneiders: Financial Interests, Institutional, Research Grant: ViewRay. S. Hashemi: Financial Interests, Institutional, Advisory Board: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, MSD, Roche, Loxo, Eli Lilly, Janssen, GSK, Novartis, Takeda, Xcovery. H. Daniels: Financial Interests, Institutional, Advisory Board: Olympus, Fujifilm. T. Radonic: Financial Interests, Institutional, Advisory Board: Roche, Takeda. T.D. de Gruijl: Financial Interests, Institutional, Advisory Board: Lava Therapeutics, DCPrime, Macrophage Pharma; Financial Interests, Personal, Advisory Board: Partner Therapeutics; Financial Interests, Personal, Stocks/Shares: LAVA Therapeutics; Financial Interests, Personal, Invited Speaker, Patent: Immunoglobulins binding human Vγ9Vδ2 T cell receptors; P31885NL00: Lava Therapeutics; Financial Interests, Personal, Invited Speaker, Single domain antibodies targeting CD1d; P32016NL00; EP16715360.0-1412: LAVA Therapeutics; Financial Interests, Personal, Invited Speaker, Patent: Novel bispecific antibodies for use in the treatment of haematological malignancies. WO/2020/060406, PCT/NL2019/050625: Lava Therapeutics; Financial Interests, Personal, Invited Speaker, Patent: Novel CD40 binding antibodies; WO/2020/159368; PCT/NL2020/050051: LAVA Therapeutics; Financial Interests, Personal, Invited Speaker, Patent: Recombinant replication competent viruses comprising a coding region for glycogen synthase kinase- (GSK3) and methods of killing aberrant cells. WO/2020/046130, PCT/NL2019/050562: ORCA Therapeutics; Financial Interests, Institutional, Invited Speaker, Research funding from Idera Pharmaceuticals for an investigator-initiated clinical trial (INTRIM) on the intra-dermal administration of IMO-2125 CpG in early-stage melanoma;: Idera Pharmaceuticals; Financial Interests, Institutional, Research Grant, Contract research with Macrophage Pharma Inc.”Pre-clinical testing of the immune modulating effects of MPL-5821 in the tumor microenvironment”: Macrophage Pharma; Non-Financial Interests, Leadership Role, Member of the Board of Directors: SITC, Society for the Immunotherapy of Cancer (SITC); Non-Financial Interests, Advisory Role, Member of the grant review committee: MRA; Non-Financial Interests, Advisory Role, Member of their scientific grant reviewing committee: KWF; Non-Financial Interests, Institutional, Product Samples, Provision of Durvalumab for a clinical trial: AstraZeneca; Non-Financial Interests, Institutional, Product Samples, Provision of nivolumab for clinical trials: BMS; Non-Financial Interests, Institutional, Product Samples, Provision of Pembrolizumab for clinical trials: Merck; Non-Financial Interests, Member: AACR. S. Senan: Financial Interests, Personal, Advisory Board, Ad boards on SCLC and NSCLC: AstraZeneca; Financial Interests, Personal, Advisory Board, Panel to assess treatment toxicity: MSD; Financial Interests, Personal, Advisory Board, NSCLC ad Board (ended in 2021): BeiGene; Financial Interests, Personal, Advisory Board, Adjudication of lung toxicity in non-metastatic lung cancer: MSD; Financial Interests, Personal, Advisory Board, Advisory board: Roche; Financial Interests, Institutional, Research Grant, Funded PhD studentship to study patterns of care in stage III lung cancer, and funding for a trial to evaluate a PD-L1 PET tracers in stage III NSCL undergoing treatment: AstraZeneca; Financial Interests, Institutional, Funding, Funded trials evaluating (i) preoperative induction chemo-immune-radiotherapy in stage III NSCLC, and (ii) evaluating radiotherapy and dual IO following progression after first-line chemo-IO in stage IV nsclc: BMS; Financial Interests, Institutional, Funding, Co-PI of an institutional trial evaluating a palliative radiotherapy workflow: Varian Medical Systems; Financial Interests, Institutional, Funding, Co-PI of an institutional trial evaluating immune effects of ablative radiotherapy of adrenal metastases: ViewRay Inc; Non-Financial Interests, Leadership Role, Coordinating investigator for an international phase III trial evaluating adjuvant immunotherapy in limited-stage SCLC (ADRIATIC study): AstraZeneca. All other authors have declared no conflicts of interest.