950O - Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable lung cancer: The INCREASE trial

Background

Neoadjuvant chemoradiotherapy (CRT) and surgery is a treatment option for patients with locally advanced stage non-small cell lung cancer (NSCLC) with limited mediastinal lymph node metastases. Pathological complete response (pCR) correlates with improved survival but is achieved in only approximately 30% of patients after CRT. Neo-adjuvant ipilimumab plus nivolumab (IPI-NIVO) can modulate the tumor microenvironment and may increase pathological responses. In a phase II study (INCREASE, EudraCT-Nr: 2019–003454-83), we studied the addition of IPI-NIVO to CRT.

Methods

This single-arm, prospective phase II trial aimed to enroll 26 evaluable patients with (borderline) resectable, T3-4N0–2 NSCLC. Enrolment commenced in Feb 2020. The primary end-point was pCR. A prespecified pCR threshold of 60% was tested against the historical rate of 30% with CRT alone. Co-primary end-points were safety and major pathological response (MPR), i.e., a residual viable tumor cells percentage of 10% or less. On day 1, platinum-doublet concurrent CRT, IPI 1 mg/kg IV and NIVO 360 mg flat dose IV were administered, followed by NIVO (360 mg flat dose IV) after 3 weeks. Radiotherapy consisted of 50-60 Gy in once-daily doses of 2 Gy, followed by a resection 6 weeks after the last dose of radiation.

Results

To date, pCR was achieved in 15 out of 24 (63%) patients who underwent surgery. The MPR rate was 79%. Toxicity of adding IPI-NIVO to CRT was acceptable (Grade 3-4 treatment-related adverse events 56%). No patient suffered delay in surgery due to the neoadjuvant treatment. No treatment-related deaths occurred. Neoadjuvant treatment enhanced the activation of CD4+ and CD8+ effector and memory subsets in peripheral blood and increased the expression of proliferation markers on CD8+ T cells in tumor-draining lymph nodes.

Conclusions

Our results indicate that adding IPI-NIVO to neoadjuvant CRT is safe, provides deep pathological responses and enhances T cell activation. These data support further research using this combination in locally advanced NSCLC planned for CRT followed by surgery, and support use of such strategies in patients presenting with an inoperable NSCLC.

Clinical trial identification

EudraCT 2019–003454-83; Netherlands Trial Register NL8435

Editorial acknowledgement

Legal entity responsible for the study

Amsterdam UMC, Vrije Universiteit Medical Center, Department of Pulmonology

Funding

Bristol Myers Squibb (BMS)

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, Novartis, Takeda, Xcovery, Loxo, Eli Lilly, Roche, Janssen, GSK, Roche. D. Oprea-Lager: Financial Interests, Institutional, Research Grant: Janssen. 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. T. Radonic: Financial Interests, Institutional, Advisory Board: Roche, Takeda. S. Senan: Financial Interests, Institutional, Advisory Board: Varian Medical Systems, ViewRay, AstraZeneca, BeiGene, Roche, MSD; Financial Interests, Institutional, Research Grant: Varian Medical Systems, ViewRay, AstraZeneca, BMS. All other authors have declared no conflicts of interest.