Search

PURPOSE Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb–mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC. PATIENTS AND METHODS This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics. RESULTS By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1-6); 49.5% received antiprogrammed death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred in 97 patients (90.7%) and grade b % 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%) including grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit. CONCLUSION In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing.

Purpose: The objective of the study is to propose the immunotherapy progression decision (iPD) score, a practical tool based on patient features that are available at the first evaluation of immunotherapy treatment, to help oncologists decide whether to continue the treatment or switch rapidly to another therapeutic line when facing a progressive disease patient at the first evaluation. Experimental Design: This retrospective study included 107 patients with progressive disease at first evaluation according to RECIST 1.1. Clinical, radiological, and biological data at baseline and first evaluation were analyzed. An external validation set consisting of 31 patients with similar baseline characteristics was used for the validation of the score. Results: Variables were analyzed in a univariate study. The iPD score was constructed using only independent variables, each considered as a worsening factor for the survival of patients. The patients were stratified in three groups: good prognosis (GP), poor prognosis (PP), and critical prognosis (CP). Each group showed significantly different survivals (GP: 11.4, PP: 4.4, CP: 2.3 months median overall survival, P < 0.001, log-rank test). Moreover, the iPD score was able to detect the pseudoprogressors better than other scores. On the validation set, CP patients had significantly worse survival than PP and GP patients (P < 0.05, log-rank test). Conclusions: The iPD score provides oncologists with a new evaluation, computable at first progression, to decide whether treatment should be continued (for the GP group), or immediately changed for the PP and CP groups. Further validation on larger cohorts is needed to prove its efficacy in clinical practice.

Association of high body mass index (BMI) with longer survival has been reported in patients on immune checkpoint inhibitors (ICIs), but results are inconsistent. This 'obesity paradox' is potentially confounded by the effects of BMI change over time and of skeletal muscle depletion.We conducted a secondary analysis of a prospective cohort, including consecutive patients receiving ICI treatment for melanoma (n = 411) and non-small cell lung cancer (NSCLC) (n = 389) in routine care.In the univariable analysis of the entire population, overweight/obesity (BMI ≥ 25 kg/mThe so-called 'obesity paradox', counterintuitive association between high BMI and longer survival, vanished when controlling for confounders, such as type of cancer, and manifestations of depletion (WL and reduced skeletal muscle mass).

Radiological feature impact on survival. Radiological features include progression of target lesions > 20%, progression of non-target lesions > 50% and the emergence of new lesions.

Purpose:The objective of the study is to propose the immunotherapy progression decision (iPD) score, a practical tool based on patient features that are available at the first evaluation of immunotherapy treatment, to help oncologists decide whether to continue the treatment or switch rapidly to another therapeutic line when facing a progressive disease patient at the first evaluation.Experimental Design:This retrospective study included 107 patients with progressive disease at first evaluation according to RECIST 1.1. Clinical, radiological, and biological data at baseline and first evaluation were analyzed. An external validation set consisting of 31 patients with similar baseline characteristics was used for the validation of the score.Results:Variables were analyzed in a univariate study. The iPD score was constructed using only independent variables, each considered as a worsening factor for the survival of patients. The patients were stratified in three groups: good prognosis (GP), poor prognosis (PP), and critical prognosis (CP). Each group showed significantly different survivals (GP: 11.4, PP: 4.4, CP: 2.3 months median overall survival, P < 0.001, log-rank test). Moreover, the iPD score was able to detect the pseudoprogressors better than other scores. On the validation set, CP patients had significantly worse survival than PP and GP patients (P < 0.05, log-rank test).Conclusions:The iPD score provides oncologists with a new evaluation, computable at first progression, to decide whether treatment should be continued (for the GP group), or immediately changed for the PP and CP groups. Further validation on larger cohorts is needed to prove its efficacy in clinical practice.

Supplementary Figure from PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon

Supplementary Data from PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair–proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti–PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy.Significance:POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti–PD-1 efficacy in mismatch repair–proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy.See related video: https://vimeo.com/720727355This article is highlighted in the In This Issue feature, p. 1397

Angular error impact on accuracy according to tumor size and depth

Human intratumoral immunotherapy (HIT-IT) is under rapid development, with promising preliminary results and high expectations for current phase III trials. While outcomes remain paramount for patients and the referring oncologists, the technical aspects of drug injection are critical to the interventional radiologist to ensure optimal and reproducible outcomes. The technical considerations for HIT-IT affect the safety, efficacy, and further development of this treatment option. Image-guided access to the tumor allows the therapeutic index of a treatment to be enhanced by increasing the intratumoral drug concentration while minimizing its systemic exposure and associated on-target off-tumor adverse events. Direct access to the tumor also enables the acquisition of cancer tissue for sequential sampling to better understand the pharmacodynamics of the injected immunotherapy and its efficacy through correlation of immune responses, pathologic responses, and imaging tumor response. The aim of this article is to share the technical insights of HIT-IT, with particular consideration for patient selection, lesion assessment, image guidance, and technical injection options. In addition, the organization of a standard patient workflow is discussed, so as to optimize HIT-IT outcome and the patient experience.

Intratumoral injection techniques

Interventional radiology techniques provide excellent local tumor control for small tumors in various organs, but several limitations can hamper the oncological outcomes such as the tumor size or the number of lesions. Technical improvements, optimal patient selection and combination with systemic therapies, including immune checkpoint inhibitors, have been successfully developed to overcome these barriers. In this setting, chemotherapy and targeted therapies aim to diminish the tumor burden in addition to local treatments, while immunotherapies may have a synergistic effect in terms of mechanism of action on the tumor cell as well as the immune environment, with multiple treatment combinations being available. Finally, interventional Rrdiology treatments often increase tumor antigen exposure to the immune system, and thus stimulate a specific antitumor immune response that can act beyond the treated site. Notwithstanding their many benefits, combination treatment may also result in complications, the most feared may be auto-immune-related adverse events. In early studies, several combined therapies have shown promising levels of safety and efficacy, particularly in hepatocellular carcinoma. This review provides a comprehensive and up-to-date overview of results of combined therapies for primary and secondary liver malignancies. Recent advances and future perspectives will be discussed.

Immunosenescence is a progressive remodeling of immune functions associated with a decreased ability of the immune system to set up an efficient immune response, both innate and adaptive, with an increase of highly differentiated T cells at the expense of naive T cells. The incidence and prevalence of most cancers increase with age, which can partly be explained by tumor escape mechanisms and decreased immunosurveillance. Aging is also associated with inflammaging, a low-grade proinflammatory state characterized by an increase in inflammatory mediators. Anti-cancer immunotherapy has profoundly changed the landscape of oncology therapy in the last 10 years. Modern T-cell targeted therapies such as bispecific T cell engagers, CAR-T cells, or immune checkpoint blockers may be theoretically affected by immunosenescence or inflammaging.A bibliographic review through PubMed and Embase was carried out using the following search terms: 'immunosenescence,' 'immunotherapy,' 'inflammaging,' 'bispecific antibodies,' 'CAR-T cells,' 'immune checkpoint blockers,' and 'older patients.'This review explores the potential impact of immunosenescence and inflammaging on anti-cancer immunotherapy and therapeutic strategies that could counter immune senescence. A more dedicated research on immunosenescence biomarkers in future clinical trials is warranted for the development of new, more effective and safer therapies.

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair–proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti–PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy. Significance: POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti–PD-1 efficacy in mismatch repair–proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy. See related video: https://vimeo.com/720727355 This article is highlighted in the In This Issue feature, p. 1397

Background: SAR441000 is an intratumoral (IT) therapy consisting of a mixture of mRNAs encoding the cytokines IL-12, IFN-α 2b, GM-CSF, and IL-15sushi. SAR441000 is hypothesized to induce a local and systemic immune response with reduced toxicity, and potentially enhance anti-tumor response when combined with checkpoint inhibitors. Methods: We conducted a phase 1 dose escalation and expansion study (NCT03871348) in patients with advanced/metastatic solid tumors to investigate SAR441000 as monotherapy (QW) and in combination with cemiplimab (350mg Q3W). The recommended dose (RD) of SAR44100 in combination with cemiplimab was further investigated to confirm the anti-tumor activity in patients with metastatic melanoma who had previously exhausted all standard of care options and failed treatment with anti-PD-(L)1 therapies. Serum samples and tumor biopsies were collected at baseline and post-treatment to characterize the PK/PD profile, and immune cell tumor infiltration. Tumor assessment was performed per RECIST 1.1 and iRECIST, where ≥1 non-injected lesion was considered as target lesion. Analysis was triggered after the last treated patient underwent their 2nd tumor assessment. Results: 77 patients were treated, 36 in escalation phase (21 in monotherapy, 15 in combination therapy) across eight dose levels (8µg-4000µg) and 41 in expansion phase. No dose limiting toxicities were observed. During escalation phase, 1 patient (6%) achieved confirmed complete response (iCR), 1 (6%) partial response (iPR), and 3 (20%) stable disease (iSD) as per iRECIST in combination therapy. Paired biopsies from the iPR patient showed significant increases in CD3+ and CD8+ immune cells in both injected and non-injected lesions compared to baseline. Increase of peripheral PK and PD (IFN-γ and IP-10) cytokines were observed post-treatment but no clear dose response relationship was established. Based on the overall data, 4000µg was chosen as the RD. During expansion phase, 2 (5%) melanoma patients achieved confirmed iPR and 12 (29%) achieved iSD as best overall response. Although clinically meaningful responses of injected and/or non-injected lesions were observed in 13 (32 %) patients, responses were mostly limited to loco-regional disease and no significant distant non-injected lesion response was seen. Post-treatment biopsies showed increased CD3+ and CD8+ immune cells in approximately 50% and 40% of injected and non-injected tumors, respectively. Most frequent (>10%) related TEAEs observed in expansion phase included injection site pain (26.8%), fatigue, diarrhea, pruritus, and asthenia (each 12.2%). Conclusion: IT with SAR441000 in combination with cemiplimab was generally well tolerated and demonstrated anti-tumor activity and immune cell infiltration in both injected and non-injected tumors. Citation Format: Oliver Bechter, Carmen Loquai, Stephane Champiat, Jean Francois Baurain, Jean-Jacques Grob, Jochen Utikal, Sylvie Rottey, Alfonso Berrocal, Jessica Hassel, Ana Arance, Miguel F. Sanmamed, Marye Boers-Sonderen, Brian Gastman, Christoffer Gebhardt, Brant Delafontaine, Ugur Sahin, Özlem Türeci, Giovanni Abbadessa, Gianfranco Di Genova, Patrick Brueck, Rahul Marpadga, Helen Lee, Céleste Lebbe. A first-in-human, open-label, multicenter study of intratumoral SAR441000 (mixture of cytokine encoding mRNAs), as monotherapy and in combination with cemiplimab in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB198.

BackgroundThe phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.MethodsGSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity.Results138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response.ConclusionsGSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers.Trial registration numberNCT02528357.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines. Furthermore, there are no prospective trial data to inform the management of the distinct presentations of irAEs. Recognizing a need for uniform terminology for the natural history, response to treatment, and patterns of irAEs, the Society for Immunotherapy of Cancer (SITC) convened a consensus panel composed of leading international experts from academic medicine, industry, and regulatory agencies. Using a modified Delphi consensus process, the expert panel developed clinical definitions for irAE terminology used in the literature, encompassing terms related to irAE natural history (ie, re-emergent, chronic active, chronic inactive, delayed/late onset), response to treatment (ie, steroid unresponsive, steroid dependent), and patterns (ie, multisystem irAEs). SITC developed these definitions to support the adoption of a standardized vocabulary for irAEs, which will have implications for the uniform application of irAE clinical practice guidelines and to enable future irAE clinical trials.

BackgroundThis phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).MethodsEmactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.ResultsOverall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.ConclusionEmactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

Background Early phase clinical trials usually include patients with advanced disease who have failed standard therapies. Early palliative care for these patients has shown to improve quality of life and even survival. PALLIA 10 score (ranging from 1 to 10) is a tool developed by the French Palliative Care Society to identify the best time to introduce palliative care. Methods We assessed the PALLIA 10 score and other prognostic factors (age, ECOG, Royal Marsden Hospital (RMH) score, LDH and albumin levels, number of prior systemic treatments and metastatic sites) in patients enrolled in phase I trials at Gustave Roussy Cancer Center prospectively during 2 periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the PALLIA 10 score was done during 15 days by a member of the palliative care unit in C2. A PALLIA 10 > 3 motivated a dedicated palliative care consultation. Results From July 1st 2018 to November 1st 2018 (C1) and from December 1st 2020 to April 16th 2021 (C2), a total of 86 patients were assessed in C1 and 302 in C2. No difference was observed between the two cohorts regarding prognostic factors. Median PALLIA 10 was also similar and very low (median 1, range 1-5 in C1 and 1-8 in C2). On C1 and C2, 12% and 5% of patients had a dedicated palliative consultation. Overall, 77% and 74% of patients in C1 and C2 were still alive beyond 3 months after discontinuation of the trial (p=0.78), followed by at least one subsequent treatment in 63% and 70% of pts. In C2, assessment of PALLIA 10 score was significantly different between palliative care physician (median 5, range 3-8), phase I physician (median 1, range 1 -6) and phase I nurse (median 3, range 1-8) (p

Purpose: Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumors is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials.Patients and methods: On-purpose tumor biopsies from pts with metastatic solid tumors enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using Whole Exome Sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumor board. Clinical characteristics and outcome were collected.Results: Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumors. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumor samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1 – 10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p < 0.001). Outcome was not correlated with the presence of EGA.Conclusions: Epigenetic alterations occur frequently in metastatic solid tumors. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analyzed in molecular profiling studies.

ObjectivePhase I clinical trials usually include patients with advanced disease who have failed standard therapies and should benefit from early palliative care. We try to assess whether PALLIA 10, a score developed in France to help identify patients who might benefit from a palliative care referral, could be used in a phase I department trial.MethodsWe assessed PALLIA 10 score and other prognostic factors in patients enrolled in phase I trials at Gustave Roussy Cancer Center prospectively during two periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the PALLIA 10 score was done in C2 by a palliative care specialist and a nurse.ResultsFrom 1 July 2018 to 1 November 2018 (C1) and from 1 December 2020 to 16 April 2021 (C2), 86 patients were assessed in C1 and 302 in C2. Median PALLIA 10 was very low in both cohorts (median 1, range 1–5 in C1 and 1–8 in C2). On C1 and C2, 12% and 5% of patients had a dedicated palliative consultation. In C2, assessment of PALLIA 10 score was significantly different between palliative care physician (median 5, range 3–8), phase I physician (median 1, range 1–6) and phase I nurse (median 3, range 1–8) (pConclusionMedian PALLIA 10 score was low when assessed by the phase I physician, which suggests the need for a better tool and appropriate clinician’s education to implement early palliative care in clinical practice and trials.

Introduction: SOT101 (previously SO-C101), a fusion protein of IL-15 and the IL-15 receptor α sushi+ domain, was investigated in an open-label, multicenter, dose-escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced tumors (NCT04234113). Here we report an update on the safety and efficacy of the combination treatment. Methods Dose escalation followed a standard 3+3 design. Objectives were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The evaluation period for dose-limiting toxicities in each dose step was 21 days. The RP2D was defined as the MTD or a dose below, considering pharmacokinetic and pharmacodynamic parameters. The study is ongoing (data cut-off 26 January 2022). Results: Twenty-one patients with a median of 2 (range 1-6) lines of previous systemic therapies were treated with 1.5, 3.0, 6.0, 9.0, and 12.0 μg/kg of SOT101 subcutaneously in combination with pembrolizumab. The MTD was not yet reached at the ongoing dose level 12.0 µg/kg, which is the RP2D in SOT101 monotherapy. The most common treatment-emergent adverse events were transient and included pyrexia, chills, injection site reaction, anemia, transaminase elevation, vomiting, and lymphopenia. One dose-limiting toxicity with rash, hypotension, and oliguria was reported at 6.0 µg/kg. The event resolved within 2 days and the patient continued with SOT101 at a lower dose. No treatment-related death was reported. One patient achieved a confirmed complete response (CR): mesothelioma at 9.0 µg/kg, on treatment 20 weeks with CR. This patient was immune checkpoint blocker (ICB)-naïve. Four patients achieved a partial response (PR): thyroid gland carcinoma at 3.0 µg/kg, ICB-naïve, on treatment 61 weeks with PR; skin squamous cell carcinoma at 6.0 µg/kg, ICB-relapsed, with PR and disappearance of target lesions, then fluctuating lesions, and on treatment 46 weeks with significant clinical benefit; skin melanoma at 6.0 µg/kg, ICB-relapsed, on treatment 41 weeks with PR; cervical melanoma at 9.0 µg/kg, ICB-pretreated, discontinued treatment after 8 weeks while still on PR. Five patients had confirmed stable disease (SD): anal squamous cell carcinoma (anal SCC) at 1.5 µg/kg, gastric cancer at 3.0 µg/kg, cervical cancer at 6.0 µg/kg, liver cancer at 6.0 µg/kg, and colorectal cancer at 9.0 µg/kg, with 1 patient (anal SCC) having a long-lasting SD over 40 weeks. In this heavily pretreated population, the observed preliminary clinical benefit rate was 63%. Conclusions: SOT101 in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals were reported in ICB-naïve and ICB pre-treated patients, including ICB-resistant tumors. Citation Format: Stephane Champiat, Aurelien Marabelle, Vladimir Galvao, Patricia LoRusso, Peter Grell, Philippe Cassier, Carlos Gomez-Roca, Iphigenie Korakis, Aung Naing, Lenka Palova Jelinkova, Irena Adkins, Ulrich Moebius, Richard Sachse, Sascha Tillmanns, David Bechard, Joachim Kiemle-Kallee, Elena Garralda. SOT101, an IL-2/IL-15 Rβγ superagonist, in combination with pembrolizumab in patients with advanced solid tumors: Interim safety and efficacy results from the AURELIO-03 dose escalation trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT040.

Background: γ9δ2 T cells are part of the innate-like immune response to malignancies and have the ability to bridge to the adaptive immune response via cytokine release (e.g., IFNγ and TNFα). Butyrophilin 3A is a novel checkpoint molecule required to activate γ9δ2 T cells highly expressed on immune and malignant cells, and the target of a monoclonal antibody ICT01. ICT01 induces activation/migration of γ9δ2 T cells from the blood to induce immune remodeling of the tumor microenvironment at doses ≥700 μg being tested in the ongoing EVICTION clinical trial (NCT04243499) (AACR 2021, CT034). In vitro studies showed that ICT01 induces upregulation of PD-1 on γ9δ2 T cells and that the combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale for evaluating this combination. Methods: EVICTION is an ongoing Phase 1/2a, international, open-label trial with Group C assessing ICT01 (IV Q3W) plus pembrolizumab (200mg IV Q3W) in patients with bladder cancer, HNSCC, melanoma, or NSCLC who failed ≥1 CPI. Pharmacodynamic activity was monitored by immunophenotyping and cytokine level analysis. Tumor biopsies (baseline, Day 28) were used for immunohistochemistry of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling. Efficacy evaluations by i/RECIST 1.1 were conducted every 8 weeks. Results: Five Group C patient cohorts have been enrolled and treated with ICT01 doses of 700μg, 2mg, 7mg, 20mg or 75mg (n=30) plus pembrolizumab, with the 200mg ICT01 cohort enrolling currently. To date, no DLTs have been observed with the combination. First-dose fever and chills (Grade 1/2) were the most common AEs that increased in frequency up to 75mg (100%, n=6), without any increase in severity, and rarely recur with subsequent dosing. ICT01+pembrolizumab induced trafficking of >95% of circulating γ9δ2 T cells within 30 min post ICT01 (≥700 μg), which was sustained for 21 days at 75mg. Transient, dose-dependent increases in serum cytokines at 30 min (TNFα) or 4h (IFNγ) post-dose were correlated with baseline γ9δ2 T cell counts and returned to baseline by 24 hrs post dose. Baseline γ9δ2 T cell count also correlated with increases in tumor infiltration of γδ, CD3, and CD8 T cells, confirming the ability to remodel the TME, and the potential to select/enrich patients with higher baseline γ9δ2 T cell counts. Sixteen patients (9/16 pembro-experienced, 5/16 received >1 prior CPI) were efficacy-evaluable at ≥Week 8 by RECIST1.1 at ICT01 doses up to 20 mg, with an observed disease control rate of 44% including 3 confirmed PRs beyond 6 months: bladder (2mg), melanoma (2mg), NSCLC (7mg). The Ipi/Nivo-refractory melanoma patient with PR also achieving a CR on their non-target lesion brain metastasis at 6 months. Data from the 75 and 200mg cohorts will be presented. Conclusion: The immune remodeling of the TME by ICT01-activated γ9δ2 T cells is associated with clinical benefit in CPI-experienced patients when used in combination with pembrolizumab. The selection of patients with higher baseline γ9δ2 T cells may improve the response profile to this novel therapeutic combination in CPI-failure patients, which will be tested in the Phase 2a portion of EVICTION starting in Q2 2022. Citation Format: Stephane Champiat, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, Catrin List, Katrin Wetzko, Leo Ruhnke, Elena Garralda, Vladimir Galvão de Aguiar, Patricia LoRusso, Nuria Kotecki, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iché, Céline Leparquier, Daniel Olive, Paul Frohna. ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT188.

Background: BI 765063 (OSE-172) is a humanised IgG4 monoclonal antibody which binds selectively to the V1 allele of Signal Regulatory Protein α [SIRPα] blocking the SIRPα/CD47 “don't eat me” pathway. Preclinical studies showed that SIRPα blockage led to macrophage and T-cell recruitment into tumor xenografts, and induced upregulation of chemokines, cytokines and adaptive immune function genes in human tumor explants (Gauttier et al., 2020). The goal of the biomarker analyses was to characterize the BI 765063 impact on peripheral blood immune cells (PBMCs) and the tumor microenvironment (TME). Methods: Fifty patients (26 V1/V1, 24 V1/V2) received BI 765063 IV from 0.02 mg/kg to 36 mg/kg every 3 weeks. Paired tumor biopsies were collected before and 2 weeks after first BI 765063 infusion. PBMCs were collected before, then 4 h, 1, 14, and 21 days after first infusion. BI 765063 receptor occupancy (RO) was determined on peripheral CD14+ monocytes. Immunophenotyping of PBMCs was performed by flow-cytometry. TME was analysed with a Brightplex® IHC panel including CD8+ T-cells, CD68+ macrophages, SIRPα, CD47, and PD-L1. Tumor gene expression profiling was performed using the Pan Cancer Immune gene set. Results: BI 765063 full RO saturation was achieved at trough levels (C2D1, pre-dose) in V1/V1 patients treated with doses of 6 mg/kg and higher, while V1/V2 patients showed a more heterogeneous RO ranging from 40-80%, reaching an apparent saturation at ≥ 12 mg/kg. An increase of activated CD80+/CD14+ and CD40+/CD14+ monocytes in PBMCs was observed at 24 h post-treatment in both, V1/V1 and V1/V2 patients. In paired tumor biopsies, IFNγ, MHCII antigen presentation gene pathways, and CCL7 transcripts appeared to be upregulated at C1D15 in patients with a systemic exposure of ≥ 100 µg/ml. One patient with hepatocellular carcinoma (HCC) and liver and lung metastases treated with BI 765063 monotherapy at 24 mg/kg achieved partial response (Champiat et al., ASCO, 2021). Baseline tumor biopsy of that patient showed that 66% of HCC tumor cells were CD47+ and 87% of CD68+ macrophages were SIRPα+. Furthermore, high levels of CD8+ T-cells were observed at baseline. At C1D15 increased CD68+ macrophage infiltration, sustained CD8 T-cell tumor accumulation and higher PD-L1 CPS (48% at baseline vs 75% at C1D15) were observed. Analysis of paired tumor biopsies in other patients showed that often, increased levels of tumor CD68+ macrophages were accompanied by CD8+ T-cell infiltration. Conclusion: This early biomarker analysis in patients with a wide range of solid tumors and treated with the first-in-class SIRPa inhibitor BI 765063 show encouraging signs of potentially mode-of-action related changes, both in peripheral blood and the TME. These early signals will be further evaluated in similar samples from the ongoing expansion cohorts in more homogeneous patient populations. Citation Format: Stephane Champiat, Philippe A. Cassier, Nuria Kotecki, Carlos Gomez-Roca, Aurélien Marabelle, Armelle Vinceneux, Christiane Jungels, Mabrouk Elgadi, Ralph Graeser, Thomas Vandewalle, Isabelle Girault, Nina Salabert-Le Guen, Nicolas Poirier, Bérangère Vasseur, Dominique Costantini, Claudia Fromond, Jean-Pierre Delord. Biomarker analyses from the Phase I clinical trial of the first-in-class SIRPa immune checkpoint inhibitor BI765063 in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1993.

2502 Background: SOT101 (previously SO-C101) is a fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. Synergistic effects of SOT101 and an anti-programmed cell death protein 1 antibody have been validated in various tumor mouse models inducing a protective memory response. Methods: In this phase 1 study, safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of increasing doses of SOT101 administered subcutaneously were investigated in patients (pts) with advanced solid tumors as monotherapy (Part A) and in combination with pembrolizumab every 3-week cycle (Part B). Dose escalation followed a standard 3+3 design. Data cut-off was 26 January 2022. Results: Overall, 51 pts were treated: 30 in Part A monotherapy at 0.25 to 15 μg/kg SOT101 and 21 in Part B combination therapy (Tx) at 1.5 to 12 μg/kg SOT101. The median (range) number of previous lines of Tx was 3 (1-9) in Part A and 2 (1-6) in Part B. In Part A, 19 (63.3%) pts had previous check-point inhibitor (CPI) Tx, of whom 9 (30 %) were refractory, 5 (16.7%) relapsed. In Part B, 11 pts (52.4%) had previous CPI Tx, and the outcome was 9 (42.9%) pts relapsed, 1 (4.8%) refractory. The most common treatment-emergent adverse events (TEAEs) were transient, and included pyrexia, chills, lymphopenia, anemia, transaminase elevation and vomiting. Most TEAEs were ≤ Grade 2. No treatment-related death was reported. For both monotherapy and combination Tx, the recommended phase 2 dose of SOT101 was determined to be 12 μg/kg. In Part A, in 13 pts at 6 to 12 μg/kg SOT101, the observed clinical benefit rate was 38%. A partial response (PR) was confirmed in 1 pt with skin squamous cell carcinoma, CPI refractory, PR duration 46 days (d), on treatment 154 d. Four pts (all CPI pretreated) had stable disease (SD), range 33-183 d. Final median duration on treatment was 84 d, range 43-183 d. The median duration of clinical benefit was 190 d. In Part B, the observed clinical benefit rate across all SOT101 doses was 63%. A complete response (CR) was confirmed in 1 pt with mesothelioma, CPI naïve, starting at the first tumor assessment, and the pt is ongoing in cycle 5. Three pts, 2 CPI pretreated, had a PR, range 51-232 d, 2 ongoing with PR, and 1 Tx discontinuation while still on PR. Five pts, 3 CPI pretreated, had SD, range 92-340 d, 2 ongoing with SD. The 3 CPI pretreated pts had SD range 41-340 d, 1 pt ongoing. The preliminary median duration on combination Tx was 113 d, range 7-429 d. The preliminary median duration of clinical benefit was 131 d. Conclusions: SOT101 as monotherapy and in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals with one ongoing CR and several long-lasting PRs were reported in CPI-naïve and CPI pretreated pts, including CPI-resistant tumors. Clinical trial information: NCT04234113.

BackgroundSO-C101 (IL 15/IL-15Rα sushi + domain fusion protein) was investigated in a multicenter, open-label, dose escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic tumors (NCT04234113). Synergistic effects of SO-C101 and an anti-programmed cell death protein 1 (PD-1) antibody have been validated in various tumor mouse models inducing a protective memory response.MethodsThe combination part of the study follows a classical 3+3 dose escalation design. Study objectives are to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The evaluation period for dose-limiting toxicities in each dose step is 21 days. The RP2D is defined as MTD or a dose below, taking into consideration pharmacokinetic and pharmacodynamic parameters.The study is ongoing (data cut-off 21 June 2021).ResultsA total of 12 patients with a median of 2 (range 1–6) lines of previous systemic therapies were treated at SO-C101 dose levels 1.5 µg/kg (3 patients), 3.0 µg/kg (3 patients), and 6.0 µg/kg (6 patients) together with 200 mg of pembrolizumab. One dose-limiting toxicity of grade (G) 3 cytokine release syndrome (CRS) was observed in one patient at 6.0 µg/kg. The MTD has not yet been reached.Of the treated patients, 2 had long-term stable disease (anal squamous cell carcinoma patient at 1.5 µg/kg, duration 25 weeks; gastric carcinoma patient at 3.0 µg/kg, duration 14 weeks) and 3 achieved a partial response (thyroid gland cancer patient at 3.0 µg/kg, target lesion decrease by 36%; skin squamous cell carcinoma patient at 6.0 µg/kg, target lesion decrease by 40%; and melanoma patient at 6.0 µg/kg, target lesion decrease by 58%). The patients with skin squamous cell carcinoma and melanoma had previously progressed on anti-PD-1 therapy, while the patient with thyroid cancer was anti-PD-1 naïve.The most common study drug-related adverse events were lymphopenia, local injection site reactions, transaminase increase, fever, chills as well as CRS-related symptoms (all mainly G1 or G2 and resolved). The only study drug-related adverse event >G2 that occurred in more than one patient was lymphopenia. No treatment-related death was reported.ConclusionsAlthough the MTD of SO-C101 in combination with pembrolizumab has not been reached yet, clinical efficacy signals were already observed in 5 patients. Available safety data indicate good tolerability. SO-C101 in combination with pembrolizumab has already shown the potential to provide an additional clinical benefit to patients with solid tumors.Trial RegistrationNCT04234113Ethics ApprovalThis study was approved by the FDA (IND 140011) and by the Ethics Boards of participating institutions