Neoadjuvant Ipilimumab Research Articles

The impact of emotional distress on pathologic response and survival after neoadjuvant combination immune checkpoint blockade (ICB) in high-risk stage III melanoma.

9558 Background: Neoadjuvant ICB has been shown to induce high pathologic response rates in high-risk stage III melanoma, outperforming adjuvant ICB with respect to survival benefit. Biomarkers that have been shown to predict ICB efficacy, including the interferon-gamma (IFN-γ) signature and tumor mutational burden (TMB), do not completely explain why some patients (pts) fail to benefit from neoadjuvant ICB. Emerging evidence in preclinical and clinical studies suggests that emotional distress (ED) negatively affects tumor progression and anti-tumor immune responses, mediated by β-adrenergic and glucocorticoid signaling. Here, we investigate the association between ED prior to neoadjuvant ICB and pathologic response and survival in pts with stage III melanoma treated in the PRADO trial. Methods: PRADO tested neoadjuvant ipilimumab + nivolumab followed by a response-directed surgical and adjuvant treatment regimen in stage III melanoma pts. The European Organization for Research and Treatment of Cancer (EORTC) scale for emotional functioning was used to identify pts with ED, based on established clinically relevant thresholds. Association between ED and pathologic response or survival was assessed using multivariable logistic or Cox regression analysis. Potential effects of ED on the tumor and its microenvironment were examined in baseline tumor biopsies using RNA sequencing. Results: Pts who completed the baseline EORTC questionnaire were included and defined as pts with ED (n = 28) or without ED (n = 60). Baseline characteristics, IFN-γ signature expression and TMB were comparable. Pts with ED showed a trend towards achieving less major pathologic responses (MPR; ≤10% viable tumor) compared to pts without ED (46% vs 65%, p = 0.099). Multivariable analysis showed a significant association between ED and MPR (OR 0.20, p = 0.043) when adjusted for age, sex, IFN-γ signature (OR 9.36, p = 0.002) and TMB (OR 13.21, p = 0.003). Pts with ED also had a significantly lower relapse-free survival (RFS) compared to pts without ED (2-year RFS 74% vs 91%, p = 0.011), and ED at baseline remained associated with relapse in multivariable regression (HR 3.81, p = 0.034) when adjusting for IFN-γ signature (OR 0.34, p = 0.109) and TMB (OR 1.02, p = 0.972). Analyses investigating the relation between ED with β-adrenergic and glucocorticoid signaling and factors representing anti-tumor immune responses are ongoing and will be presented at ASCO. Conclusions: Emotional distress was identified as baseline marker associated with impaired clinical outcomes after neoadjuvant combination ICB in pts with high-risk stage III melanoma. This data warrants further investigation in independent cohorts and into the potential effect of pharmacological and psychosocial interventions, e.g. adrenergic receptor blockade, on the anti-tumor immune response and patient outcomes. Clinical trial information: NCT02977052 .

Revisiting the optimal neoadjuvant immunotherapy regimen in resectable stage III melanoma based on the interferon gamma signature: A pooled analysis.

9516 Background: Neoadjuvant anti-PD1 has been shown to be superior to adjuvant administration. Combination of neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) induces even higher pathologic response rates (pRR) and event-free survival (EFS), but at the cost of higher toxicity. We previously showed that the interferon gamma (IFN-γ) signature is associated with a higher pRR after neoadjuvant IPI+NIVO. We hypothesized that IFN-γ high patients (pts) might benefit from less toxic anti-PD1 monotherapy (mono), while IFN-γ low pts might need an escalated regimen with IPI 3mg/kg + NIVO 1mg/kg. Methods: In this pooled analysis, pts with macroscopic nodal melanoma who received neoadjuvant NIVO 1mg/kg + IPI 3mg/kg (IPI3/NIVO1), IPI 1mg/kg + NIVO 3mg/kg (IPI1/NIVO3), sequential IPI 3mg/kg and NIVO 3mg/kg (IPI3>NIVO3), or NIVO mono (240mg; IFN-γ high pts only) from the OpACIN-neo, PRADO and DONIMI trials, were analyzed according to their baseline IFN-γ signature. RNA gene expression from baseline tumor biopsies was analyzed using the Nanostring nCounter platform. The IFN-γ scores were calculated using an algorithm and cut-off previously developed at the NKI and prospectively tested in the DONIMI trial. Results: Baseline tumor material was available from 151 pts (Table). Median follow-up was 42 months for the entire cohort and 19 months for NIVO mono pts. Combined IPI+NIVO in IFN-γ high pts induced similar major pathologic response (MPR) rates compared to NIVO mono in IFN-γ high pts (71% vs 80%, p=0.715), and significantly higher MPR rates compared to IPI+NIVO in IFN-γ low pts (71% vs 45%, p=0.003). At 18-months, EFS rates were 87%, 100% and 73% respectively, and overall survival (OS) rates were 98%, 100% and 96%. Notably, IPI3/NIVO1 seemed to induce a higher MPR rate than IPI1/NIVO3 in IFN-γ low pts (64% vs 41%), which was not statistically significant due to small subgroups. At 36 months, EFS was 91% vs 62% and OS was 91% vs 82%. Conclusions: Neoadjuvant NIVO mono seems to have equal outcomes as IPI+NIVO in IFN-γ high pts. IFN-γ low pts may benefit from IPI+NIVO with higher doses of IPI. Incorporating baseline biomarkers like the IFN-γ signature algorithm in neoadjuvant treatment decisions will optimize the risk-benefit ratio for these pts. [Table: see text]

Neoadjuvant Immunotherapy Increases Event-Free Survival in Melanoma

Neoadjuvant Immunotherapy Increases Event-Free Survival in Melanoma

A Tumor and Immune-Related Micro-RNA Signature Predicts Relapse-Free Survival of Melanoma Patients Treated with Ipilimumab.

Despite the unprecedented advances in the treatment of melanoma with immunotherapy, there continues to be a major need for biomarkers of clinical benefits and immune resistance associated with immune checkpoint inhibitors; microRNA could play a vital role in these efforts. This study planned to identify differentially expressed miRNA molecules that may have prognostic value for clinical benefits. Patients with surgically operable regionally advanced melanoma were treated with neoadjuvant ipilimumab (10 mg/kg intravenously every 3 weeks × two doses) bracketing surgery. Tumor biospecimens were obtained at baseline and surgery, and microRNA (miRNA) expression profiling was performed on the tumor biopsies. We found that an expression profile consisting of a 4-miRNA signature was significantly associated with improved relapse-free survival (RFS). The signature consisted of biologically relevant molecules previously reported to have prognostic value in melanoma and other malignancies, including miR-34c, miR-711, miR-641, and miR-22. Functional annotation analysis of target genes for the 4-miRNA signature was significantly enriched for various cancer-related pathways, including cell proliferation regulation, apoptosis, the MAPK signaling pathway, and the positive regulation of T cell activation. Our results presented miRNAs as potential biomarkers that can guide the treatment of melanoma with immune checkpoint inhibitors. These findings warrant further investigation in relation to CTLA4 blockade and other immune checkpoint inhibitors. ClinicalTrials.gov NCT00972933.

IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma.

Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.

Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial

Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7–43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6–61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129.)

Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials

Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2×ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n= 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3mg/kg q3w; n= 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n= 26) followed by surgery. The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response. Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.

Neoadjuvant ipilimumab plus nivolumab in locally advanced melanoma: A real-world single-centre retrospective study

BackgroundNeoadjuvant immune-checkpoint inhibition (neoICI) with ipilimumab and nivolumab has shown high pathologic response rates as well as a long-lasting relapse-free survival in stage III melanoma patients. However, safety and efficacy data from real-world patients is very limited. MethodsStage IIIB-IV (M1a) melanoma patients with macroscopic nodal metastases with or without synchronous non-nodal lesions received combined neoICI with ipilimumab 1 mg/kg and nivolumab 3 mg/kg. Radiological and pathological response as well as relapse-free survival (RFS), event-free survival (EFS), overall survival (OS), melanoma-specific survival (MSS), adverse events (AE) related to neoICI and subsequent therapies were analysed. ResultsBetween November 2018 and October 2021, 23 patients received a combined neoICI. A pathologic response was achieved in 65% (15/23) of the patients, with 43% (10/23) achieving a pathological complete response. At a median follow-up of 22.8 months, median RFS, EFS, OS and MSS have not been reached. At a 3-year landmark, the RFS, EFS, OS and MSS rates were 77.6% (95% CI 60.1–100), 61.8% (95% CI 43.8–87.1), 62.0% (95% CI 42.2–91.0) and 76.7% (95% CI 55.7–100), respectively. Regarding AE, 70% (16/23) had immune-related AE (irAEs) of any grade which were classified as severe (≥ grade 3) irAEs in 13% (3/23) of patients. ConclusionThe combined neoICI with ipilimumab 1 mg/kg and nivolumab 3 mg/kg showed high response rates as well as long lasting relapse-free survival. Besides a promising efficacy, neoICI was well tolerated in our real-world patient cohort with only few high-grade irAEs indicating feasibility of neoICI in a non-trial setting.

6P Response and survival according to the interferon-gamma (IFN-γ) signature and tumor mutational burden (tmb) in the PRADO trial testing neoadjuvant ipilimumab and nivolumab in stage III melanoma

The PRADO trial (n=99) tested different surgical and adjuvant therapy strategies based on the pathologic response after neoadjuvant IPI 1mg/kg and NIVO 3mg/kg in stage III melanoma patients (pts). The pathologic response rate (pRR: ≤50% viable tumor) was 72%, including 61% major pathologic responses (MPR: ≤10% viable tumor). After a median follow-up of 28.1 months, the 2-year (2y) event-free survival (EFS) rate was 80%. Here, we report the response and EFS data of PRADO according to the IFN-γ signature and TMB.

Abstract PR002: Antigen presentation and processing pathway is associated with early relapse after neoadjuvant immune checkpoint blockade (ICB) in dedifferentiated liposarcomas (DDLPS)

Abstract Background: We evaluated the activity of neoadjuvant ICB in localized resectable DDLPS (n=17) and undifferentiated pleomorphic sarcomas (UPS; n=10). DDLPS and UPS patients were randomized to neoadjuvant nivolumab or ipilimumab+nivolumab, with UPS patients receiving concurrent radiotherapy. We assessed genomic markers of early relapse (progression before surgery or relapse within 52 weeks following surgery) using longitudinally acquired tumor samples. Methods: RNA sequencing (RNAseq) and whole genome sequencing (WGS) were performed on longitudinally acquired samples (baseline biopsies and surgical specimens). Differential gene expression between any two groups of patients (i.e., non-early relapse [non-relapsers] vs early relapse [relapsers]) were selected (fold change&amp;gt;1.5 and p value&amp;lt;0.05). Gene set enrichment analyses (GSEA) of KEGG pathways were performed and a network-based approach used to identify genes/pathways associated with MHC-I. Results: At a median follow-up of 23 months, 12 patients (9 DDLPS, 3 UPS) relapsed, including 7 early relapses (relapsers: 5 DDLPS, 2 UPS). The median relapse-free survival was 22 months in DDLPS patients (6 months in relapsers; not reached [NR] in non-relapsers) and NR in UPS patients. At baseline, the most differentially upregulated pathways in non-relapsers compared to relapsers were “graft versus host disease” (GSEA Normalized Enrichment Score[NES]=2.25; False Discovery Rate[FDR] q= 0.009), “natural killer cell mediated cytotoxicity” (NES=2.17; FDR q=0.009), “antigen processing and presentation” (NES=2.16; FDR q=0.009), “allograft rejection” (NES=1.99; FDR q=0.019) and “B-cell receptor signaling pathway” (NES=1.87; FDR q=0.018). In DDLPS patients, the antigen presentation and processing pathway was the most upregulated pathway in non-relapsers compared to relapsers (NES=2.01; FDR q=0.025) while it was not significantly upregulated in UPS (NES=1.15; FDR q=0.62). When looking at pathways longitudinally, the antigen presentation and processing pathway was significantly upregulated at surgery compared to baseline in DDLPS. As antigen presentation and processing was significantly upregulated in DDLPS patients and associated with relapse, we looked for expressed neoantigens that may be processed and presented. Using WGS, we detected 5712 rearrangements at baseline in DDLPS, of which 230 were found in more than one tumor specimen. We also sought to identify genes associated with MHC-I. We selected genes upregulated during ICB comparing baseline to surgical specimens in DDLPS relapsers and looked at the top 10% of genes associated with MHC-I in order to identify potential therapeutic targets for combination. We identified 41 genes upregulated during ICB and associated with MHC-I in relapsers, for which up to 275 inhibitory compounds were found in drug databases. Conclusion: Antigen presentation and processing is a major driver of response to immunotherapy. Future efforts should focus on identifying which antigens are presented to find synergizing compounds in order to increase the clinical benefit of ICB. Citation Format: Elise F. Nassif, Chia-Chin Wu, Kadir Akdemir, Russell G. Witt, Raymond Traweek, Brandon Cope, Prapassorn Thirasastr, Taylor Tate, Grace Mathew, Shadarra Crosby, Randy Chu, Mohammad Mohammad, Kenna Shaw, Ingram Davis, Khalida Wani, Alexander J. Lazar, Wei-Lien Wang, Sheila Duncan, Ashleigh B. Guadagnolo, Andrew J. Bishop, Valerae Lewis, Justin E. Bird, Keila E. Torres, Kelly K. Hunt, Barry W. Feig, Christopher P. Scally, Ravin Ratan, Shreyaskumar Patel, Robert S. Benjamin, Robert Satcher, Kevin McBride, Wolf H. Fridman, Ignacio Wistuba, Andrew Futreal, Jennifer A. Wargo, Neeta Somaiah, Christina L. Roland, Emily Z. Keung. Antigen presentation and processing pathway is associated with early relapse after neoadjuvant immune checkpoint blockade (ICB) in dedifferentiated liposarcomas (DDLPS) [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR002.

791MO Clinical and tumor characteristics of patients (pts) with recurrence after pathologic response upon neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma

Pathologic (path) response (resp) is an excellent surrogate marker for long-term recurrence-free survival after neoadjuvant (neoadj) IPI + NIVO in stage III melanoma. Few resp pts develop recurrence of disease, and their clinical characteristics and mechanisms of tumor immune escape are unknown.

797P Relapse-free survival (RFS) update and first translational analyses of DONIMI, a study testing personalized neoadjuvant domatinostat, nivolumab (NIVO) and ipilimumab (IPI) in stage III melanoma patients (pts) based on the interferon-gamma signature (IFN-γ sign) algorithm

In stage III melanoma, neoadjuvant (neoadj) IPI + NIVO induces high pathologic response rates (pRR 72-78%), which is associated with long-term RFS. Pts with a low baseline IFN-γ sign are less likely to respond (pRR 55%). Domatinostat (DOM), a class I histone deacetylase inhibitor, increased intratumoral T cell infiltration and the IFN-γ sign expression in melanoma. DONIMI tests neoadj combinations of NIVO ± IPI with DOM stratified according to the IFN-γ sign of baseline biopsies in stage IIIB-D nodal melanoma.

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

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.

OS158 - PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma

OS158 - PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma

Survival data of PRADO: A phase 2 study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma.

9501 Background: In the OpACIN-neo study, 2 cycles neoadjuvant (neoadj) IPI 1mg/kg + NIVO 3mg/kg (I1N3) have been identified as most favorable dosing scheme with a pathologic response rate (pRR) of 77% and 20% grade 3-4 irAEs. After 24.6 months median follow-up (FU), the 2-year (2y) RFS was 96.9% for patients (pts) with pathologic response versus 35.5% for non-responders (&gt;50% viable tumor; pNR). These data raised the question whether therapeutic lymph node dissection (TLND) could be safely omitted in pts achieving a major pathologic response (MPR; ≤10% viable tumor) in their index node (ILN; largest LN metastasis at baseline), and if additional adjuvant (adj) therapy could improve the outcome of pNR pts. Methods: PRADO is an extension cohort of the phase 2 OpACIN-neo study aiming to confirm the pRR and safety of neoadj I1N3 and to test response-driven subsequent therapy. Pts with stage III melanoma were included to receive 2 cycles neoadj I1N3 after marker placement in the ILN. ILN resection was planned at week 6. Pts that achieved MPR in the ILN did not undergo TLND; pts with partial response (pPR; &gt;10 – ≤50% viable tumor) underwent TLND; and pts with pNR underwent TLND and received adj NIVO or dabrafenib plus trametinib (D+T) for 52 weeks ±radiotherapy (RT). Primary endpoints were pRR in the ILN and RFS at 2y. The 2y RFS rates were calculated using a Kaplan Meier based method. Results: Between Nov 2018 and Jan 2020, 99 patients were enrolled and treated with at least 1 cycle of neoadj I1N3. We previously showed a pRR of 72% (95% CI 62 - 80), including 60 (61%) pts with MPR and 11 (11%) pts with pPR. TLND omission in MPR pts resulted in significant reduced surgical morbidity and improved quality of life. There were 27 non-responders of whom 6 developed distant metastasis before ILN resection. Of the other 21 pNR pts, 7 received adj NIVO, 10 adj D+T, 3 no adj therapy, and 1 was lost to FU. After a median FU of 27.9 months (data cutoff Jan 31, 2022), the estimated 2y RFS rate for MPR pts was 93.3% (95% CI 87.2 – 99.9), with 4/60 pts developing a regional relapse. Distant metastasis-free survival (DMFS) was 100%. Of the 11 pPR pts, 4 developed a relapse (all distant), resulting in a 2y RFS and DMFS rate of 63.6% (95% CI 40.7 – 99.5). The 2y RFS rate of the pNR pts was 71.4% (95% CI 54.5 – 93.6), and DMFS 76.2%. At data cutoff, relapse occurred in 2/7 pNR pts with adj NIVO and 3/10 with adj D+T. Final data cutoff is planned mid Feb, 2022. Conclusions: MPR pts in whom TLND was omitted showed a 2y RFS rate of 93.3% and DMFS of 100%, indicating that the ILN procedure and omitting adj therapy could become a safe approach in these pts. Adj systemic therapy in pNR pts seems to improve RFS as compared to historic control (OpACIN-neo), thus should be considered in this unfavorable pNR group. The DMFS rate of 63.6% observed in the pPR group advocates the consideration of adj therapy also for this subgroup in the future. Clinical trial information: NCT02977052.

The interferon-gamma (IFN-y) signature from baseline tumor material predicts pathologic response after neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma.

9539 Background: Neoadjuvant IPI + NIVO induces high pathologic response rates (pRR) of 74-78% in macroscopic stage III melanoma. Pathologic response ( &lt; 50% viable tumor) is strongly associated with improved relapse-free survival (RFS); the previous OpACIN-neo study demonstrated a 2-year RFS of 96.9% in patients (pts) with pathologic response, whereas the 2-year RFS in non-responders was 35.5%. These data highlight the need for baseline biomarkers predictive for response and survival. Here, we present the predictive value of the 10-gene IFN-y expression signature algorithm (based on Ayers et al.) for pathologic response and relapse in a cohort of melanoma pts treated with neoadjuvant IPI + NIVO. Methods: Baseline tumor biopsies from lymph node metastases of stage III melanoma pts were used for IFN-y signature assessment. Pts were treated with a maximum of two cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg in the OpACIN-neo (arm B) and PRADO studies. RNA expression analysis was conducted using the nCounter® PanCancer Immune Profiling panel on the NanoString Flex machine (NanoString Technologies), which is clinically applicable due to its fast turn-around-time (two days). An IFN-y signature gene expression score (IFN-y score) was calculated using a NKI-developed algorithm. Association between IFN-y score and pathologic response or event-free survival (EFS) was examined by logistic regression and Cox analyses. The optimal cutoff between a high and low IFN-y score was defined based on a summary receiver operating characteristic (sROC) curve. Results: In total, 103 pts treated in the OpACIN-neo and PRADO studies had baseline tumor material available. Median age was 56 years, 62% was male, and 52% had a high baseline IFN-y score. The pRR of the total cohort was 70% (72/103 pts), including 56% (58/103) major pathologic response (MPR, 0-≤10% viable tumor) and 14% (14/103) partial responses (pPR, 10-≤50% viable tumor). 30% (31/103 pts) had no pathologic response. After a median follow-up of 25.2 months, 26 pts (25.2%) developed a melanoma relapse. The IFN-y score was significantly associated with response (OR 1.061, p &lt; 0.001) and relapse (OR 0. 974, p = 0.029). The pRR was 89% (48/54) in pts with a high IFN-y score versus 49% (24/49) in those with a low IFN-y score (p &lt; 0.001). Pts with a high IFN-y score were also less likely to develop a relapse (11% [6/54] versus 41% [20/49], p = 0.001). Conclusions: Pts with a high IFN-y score in pre-treatment biopsies are more likely to respond to neoadjuvant IPI + NIVO with favorable EFS. A rapid gene expression analysis enables the IFN-y score to be used in daily clinical practice to identify pts who might qualify for treatment escalation or de-escalation. The DONIMI study [NCT04133948] currently investigates different neoadjuvant treatment combinations in stage III melanoma pts based on their intratumoral IFN-y score.

Neoadjuvant ipilimumab and nivolumab in combination with paclitaxel following anthracycline-based chemotherapy in patients with treatment resistant early-stage triple-negative breast cancer (TNBC): A single-arm phase 2 trial.

602 Background: We examined the efficacy and safety of neoadjuvant ipilimumab and nivolumab combined with paclitaxel following suboptimal response to anthracycline-based chemotherapy in patients with early-stage TNBC. Methods: This single arm multicentre phase 2 study enrolled 34 patients in 8 sites. Patients were aged ≥18 years with previously untreated stage 3 TNBC and were required to have ≥15mm of tumor remaining or 10mm of tumor with one positive lymph node after 4 cycles of anthracycline-based therapy. A suboptimal response subset at baseline was defined as &lt; 50% reduction in tumor volume after initial anthracycline-based chemotherapy. Patients received neoadjuvant ipilimumab 1mg/kg IV 6 weekly for 2 doses and nivolumab 240mg every 2 weeks for 6 doses, with weekly paclitaxel at 80mg/m2 for 12 weeks, followed by surgery. Nivolumab (480mg 4-weekly) continued post operatively for further 9 months. Primary endpoint was pathological complete response (pCR) in breast and axilla, with secondary endpoints pCR in the suboptimal responders, pCR in PD-L1 positive patients (≥1% by SP142 assay), clinical response in the breast (ORR by RECIST), event-free (EFS) and overall survival (OS). Results: Between December 2018 and April 2020, 34 patients were enrolled, 33 were evaluable for the primary endpoint. Median age was 46.6yrs. At diagnosis, all patients were clinical stage III (AJCC v8), 16/34 (47%) were node positive, 8/31 (26%) were PD-L1 positive. At study entry (following anthracycline-based chemo), the median tumor size by ultrasound was 28mm (12-62). 16/33 (48%) were considered suboptimal responders. The pCR rate (ypT0ypN0) was 24.2% (95% CI, 11.09-42.26) in all evaluable, 37.5% [3/11] in PD-L1+ and 23% [5/22] in PD-L1- patients. In patients with suboptimal anthracycline response (&lt; 50% tumor reduction), the pCR rate was 18.8% (95% CI, 8.52-75.51) (3/16). ORR in the breast was 57.6% (19/33) in all evaluable patients and 43.7% (8/20) in the suboptimal responders. The number of patients with residual cancer burden (RCB) class 0,1,2,3 was 8 (24%), 1 (3%), 19 (57.5%) and 5 (15%) respectively. With 14 months median follow up, 12-months EFS was estimated at 85% and OS 94%. For patients with pCR vs non-pCR, the hazard ratio (HR) for EFS was 0.62, 12 mo EFS was 100% vs 75%. In the neoadjuvant phase, 15/33 (45%) patients experienced at least one grade 3-4 adverse event. Most common immune-related event was grade 1 or 2 pneumonitis 9/33 (27%), which generally occurred with fever after the first dose of ipilimumab, and resolved. There was one case of grade 3 colitis. Conclusions: In these high risk patients, the addition of ipilimumab and nivolumab to neoadjuvant paclitaxel resulted in promising ORR and pCR rates, regardless of PD-L1 status. Rates of low grade pneumonitis were high. Follow up continues. Clinical trial information: ACTRN12617000651381.

EA2201: An ECOG-ACRIN phase II study of neoadjuvant nivolumab plus ipilimumab and short course radiation in MSI-H/dMMR rectal tumors.

TPS3644 Background: Trimodality therapy including chemoradiation, chemotherapy and surgical resection is standard for patients with T3-4 and/or node-positive (N+) rectal adenocarcinomas. Pathologic complete response (pCR) rates after neoadjuvant chemoradiation approach 15% in all-comers and 27% in patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) rectal cancer. Additionally, preclinical data suggest that hypofractionated radiation (large dose per fraction) may enhance immunogenicity. Given high response rates to immunotherapy in MSI-H/dMMR early stage and metastatic colorectal cancer (CRC), we hypothesized that neoadjuvant nivolumab plus ipilimumab and short course radiation in locally advanced MSI-H/dMMR rectal cancer (LARC) would result in increased pCR rates. Methods: EA2201 (NCT04751370) is an NCTN phase II clinical trial for patients with treatment-naïve locally advanced (T3-4Nx or TxN+) rectal adenocarcinoma that is dMMR or MSI-H. Patients receive nivolumab (480 mg) and ipilimumab (1 mg/kg) every 28 days for 2 cycles, followed by short course radiation (5 Gy x 5 fractions; total 25 Gy) and an additional 2 cycles of nivolumab and ipilimumab prior to disease reassessment and TME. The primary endpoint is pCR at TME. Secondary endpoints include 5-year disease-free survival, overall survival, treatment-related toxicities, and sphincter preservation rate for low-lying tumors. This study has a single-arm, two-stage design; a pCR rate of 50% or more will be taken as evidence of promising activity in this patient population. We plan to enroll 31 patients, with accrual currently ongoing. Clinical trial information: NCT04751370.

Neoadjuvant nivolumab, ipilimumab, and celecoxib in MMR-proficient and MMR-deficient colon cancers: Final clinical analysis of the NICHE study.

3511 Background: The combination of PD-1 and CTLA4 blockade has changed the treatment landscape for several cancer types. Although this treatment is highly effective in metastatic mismatch-repair deficient (dMMR) colorectal cancers, metastatic MMR-proficient (pMMR) tumors do not respond. The NICHE study was the first neoadjuvant immunotherapy study in colon cancer (CC) to show impressive responses in 100% of dMMR ( n= 20) and 27% of pMMR ( n= 15) CC. In contrast, pathologic response to neoadjuvant chemotherapy using standard of care folfox is approximately 5% in dMMR tumors. Here we present the final efficacy data for the original NICHE study cohorts. Methods: Patients with non-metastatic, resectable dMMR or pMMR CC were treated with a single dose of ipilimumab 1mg/kg and two doses of nivolumab 3mg/kg and underwent surgery within 6 weeks. In addition, patients with pMMR tumors were randomized to receive celecoxib. The primary endpoints were safety and feasibility, and secondary endpoints included pathologic response rate and disease-free survival in 30 patients with dMMR and 30 with pMMR tumors. Pathologic response was defined as 50% or less viable tumor rest (VTR), and major pathologic response (MPR) as &lt;10% VTR. Results: Thirty patients with pMMR and 32 with dMMR tumors were evaluable for the efficacy analyses. In the pMMR cohort, pathologic response was observed in 9/30 (30%, 95% CI 14-46%) patients, consisting of 7 MPR (including 3 pathologic complete responses {pCR}) and 2 partial responses. Four out of 9 pMMR responders had received celecoxib. Five patients received adjuvant chemotherapy. At a median follow-up of 25 months (IQR 12-35 months), 3 patients (all non-responders) in the pMMR group had disease recurrence. In the 32 patients with dMMR tumors, pathologic response was observed in 100% of patients, with 31/32 MPR (97%, 95% CI 91-100%) and one partial response. Pathologic complete response was observed in 22/32 (69%, 95% CI 53-85%) patients. None of the patients in the dMMR cohort had disease recurrence. Surgery was delayed in one patient with a pMMR tumor due to myositis. Grade 3 immune-related adverse events were observed in 12% of patients, consistent with our previous report on the primary endpoint. There were no grade 4 immune-related AEs nor unexpected surgical complications. Conclusions: These data confirm our previously published results of the NICHE study, with responses to neoadjuvant nivolumab plus ipilimumab in 30% of pMMR and 100% of dMMR CC in the completed original cohorts. Validation of the dMMR responses in a large group of dMMR patients is ongoing and has the potential to change current practice. Clinical trial information: NCT03026140.

Preliminary results from a phase Ib study of neoadjuvant ipilimumab plus nivolumab prior to liver resection for hepatocellular carcinoma: The PRIME-HCC trial.

4093 Background: Early-stage hepatocellular carcinoma (HCC) can be treated with liver resection (LR), but up to 70% of patients experience relapse within two years after surgery. Despite their established use in advanced disease, immune checkpoint inhibitors (ICPI) are still under investigation in the peri-operatory setting. Methods: PRIME‐HCC is a phase Ib study investigating safety and bioactivity of the nivolumab (3 mg/kg, day 1 and day 22) plus ipilimumab (1mg/kg, day 1 only) combination (Nivo+Ipi) prior to LR in early-stage HCC. The primary safety analysis assessed treatment-related adverse events (trAE) and delays to surgery. Secondary endpoint included objective response rate (ORR) by RECIST v1.1 and pathologic response rate on resection specimens. Results: At data censoring on the 27th of January 2022, 17 patients were enrolled, of whom 82% (n = 14) were male, with a median age of 64 years (range 47-76). Performance status was 0 in 88% of patients (n = 15) according to the Eastern Cooperative Oncology Group scale. Liver cirrhosis was found in 65% (n = 11) of the patients, mostly secondary to viral hepatitis (41%, n = 7). All patients were Child-Pugh A, with 53% (n = 9) classified as albumin-bilirubin (ALBI) grade 2, and the rest grade 1. Median tumour diameter was 3.4 cm (interquartile range [IQR] 2.4-4.0), and the median number of liver nodules was 1 (range 1-3). Any-grade trAEs were reported by 73% of the patients receiving at least one dose of treatment (n = 11, tot n = 15). Four patients (27%) reported grade 2 trAEs including hypothyroidism (n = 2), diarrhoea (n = 1), and fatigue (n = 1), and one (7%) grade 3 ALT/AST elevation. After a median follow-up of 6.3 months (IQR 1.9-23.0), no deaths had occurred. One patient had experienced relapse 20.8 months after treatment commencement, and he achieved partial response to subsequent treatment with atezolizumab plus bevacizumab. Median time to LR from screening was 2.5 months (IQR 2.3-3.2). Only one patient had a surgery delay due to liver function worsening (ICPI-unrelated) and experienced disease progression 12.4 months post-screening. One patient was found to have cholangiocarcinoma (CCA) on LR specimen and was excluded from efficacy analyses. Of the 13 patients with an available radiological assessment, ORR was 23%, with two partial responses and one complete response. Disease control rate was 92%, with one patient with mixed HCC/CCA histology showing primary progression. Of the nine pathologically evaluable patients, seven (78%) achieved a pathological response, including two (22%) complete responses. Conclusions: Nivo+Ipi can be safely administered in the neoadjuvant setting for HCC and does not delay LR. The combination demonstrates promising evidence of anti-tumour efficacy in terms of radiological and pathological response. Clinical trial information: NCT03682276.