Gut microbiota diversity and composition in patients enrolled in the JCOG2007 trial reveal associations with efficacy outcomes and toxicity to chemo-immunotherapy
1O - Exploration of Gut Microbiota Biomarkers in Treatment-Naïve Advanced NSCLC Patients Undergoing Chemo-Immunotherapy: Insights from the Phase III trial, JCOG2007 (NIPPON)
Taiki Hakozaki (Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Japan) presented insights from the phase 3 JCOG2007 (NIPPON) trial regarding the association between gut microbiota diversity and both response to treatment and emergence of serious adverse events (AEs). The randomized (1:1) JCOG2007 trial investigated safety and efficacy of nivolumab + ipilimumab + chemotherapy (NIC) in comparison to pembrolizumab + chemotherapy (PC) in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) and was terminated early due to significant occurrence of treatment-related deaths in the NIC arm (7% of patients). In this biomarker analysis, 270 of 295 patients enrolled were analyzed for gut microbiota composition from baseline stool samples using 16S rDNA sequencing to explore associations with efficacy and toxicity. There was no significant difference in alpha diversity when comparing patients with overall survival (OS) ≥ 12 months to those with OS < 12 months (p=0.84), though there was a significant difference in beta diversity (p=0.004). Differences in specific bacterial genera were identified between these groups, with Fusicatenibacter, Butyricicoccus, and Blautia enriched in patients with OS ≥ 12 months (favorable bacteria). Regarding serious AEs (grade ≥ 4), alpha diversity, but not beta diversity, was lower in patients that exhibited a serious AE than those that did not. The incidence of serious AEs was significantly greater in patients with low alpha diversity (odds ratio [OR] =2.6; 95% CI 1.3 to 5.2) and patients with low abundance of favorable bacteria, which was more exaggerated in the NIC arm. Additionally, OS was longer in patients with high abundance of favorable bacteria and was lower in patients with high abundance of unfavorable bacteria (Prevotellaceae and Oscillibacter), with both effects observed to a greater extent in patients in the NIC cohort. This study revealed distinct differences in gut microbiota between patients that experienced better survival outcomes and less toxicity from chemo-immunotherapy treatment than those that did not in the JCOG2007 trial, indicating a potential for microbiota composition to help guide personalized treatment decisions in the first-line strategies of NSCLC.
Early changes in TIL percentage and PD-L1 expression uncover unique associations to response in the Neo-CheckRay trial
2O - TILs and PD-L1 early dynamics in the randomized Neo-CheckRay phase II trial evaluating neo-adjuvant immuno-radiation and adenosine pathway blockade for early-stage, high risk ER+/HER2- breast cancer (BC)
Alex De Caluwe (Institute Jules Bordet, Brussels, Belgium) presented data on changes to tumor infiltrating lymphocytes (TILs) and PD-L1 expression during treatment and across treatment groups from the randomized phase II Neo-CheckRay trial (NCT03875573). The Neo-CheckRay trial randomized (1:1:1) patients with newly diagnosed, MammaPrint® high risk, ER+ HER2- breast cancer to receive either neo-adjuvant chemotherapy (NACT) + immune modulating stereotactic body radiation therapy (iSBRT) (Arm 1), NACT + iSBRT + durvalumab (Arm 2), or NACT + iSBRT + durvalumab + oleclumab (Arm 3). Biopsies were taken at baseline, at week 6 during neoadjuvant therapy, and at 20 weeks later at surgery. At week 6 biopsy, 5/38 (13.2%) of patients in arm 1, 18/43 (41.9%) of patients in arm 2, and 16/44 (36.4%) of patients in arm 3 had no tumor present. Tumor absence at week 6 biopsy was associated with a significantly greater probability of achieving a pathological complete response (pCR) rate (odds ratio=4.53; 95% CI 1.94 to 10.91) than tumor presence. Within each treatment arm, PD-L1 expression on immune cells increased from baseline to week 6, with more significant increases seen for arm 2 (p<0.01) and arm 3 (p<0.01) than arm 1 (p=0.20). Arms 2 and 3 also exhibited a greater percentage of patients with increased TIL percentage or complete tumor disappearance from baseline to week 6 biopsy than arm 1. Sub-group analysis of patients that had an increase of PD-L1 expression on immune cells from baseline to week 6 revealed a significant benefit of durvalumab vs. no durvalumab treatment, supported by a greater difference in pCR rate (26.5%; 95% CI 11.6% to 41.3%). These data on early dynamics of TIL percentage and PD-L1 expression in luminal B breast cancer patients in the Neo-CheckRay trial reveal that an increase in PD-L1 expression on immune cells during neoadjuvant treatment may result in increased probability of response to neo-adjuvant combination of chemoradiation with immunotherapy, such as durvalumab.
Safety and efficacy of nivolumab + concurrent chemoradiotherapy (CCRT) followed by nivolumab ± ipilimumab in patients with locally advanced stage III NSCLC in CheckMate 73L
65O - CheckMate 73L: Phase 3 study comparing nivolumab (N) + concurrent chemoradiotherapy (CCRT) followed by N _ ipilimumab (I) v CCRT followed by durvalumab (D) for previously untreated, locally advanced stage (stg) III NSCLC
Solange Peters (CHUV - Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland) reported results from the randomized phase 3 study, CheckMate 73L (NCT04026412) investigating the safety and efficacy of nivolumab + concurrent chemoradiotherapy (CCRT) followed by nivolumab ± ipilimumab against the current standard of care, CCRT followed by durvalumab, for patients with previously untreated, locally advanced non-small cell lung cancer. A total of 925 patients were randomized (1:1:1) to receive either CCRT + nivolumab followed by nivolumab + ipilimumab (n=287; arm A), CCRT + nivolumab followed by nivolumab (n=320; arm B), or CCRT followed by durvalumab (n=318; arm C). The primary endpoint was progression-free survival (PFS; arm A vs arm C) with secondary endpoints of overall survival (OS), PFS (arm B vs arm C), overall response rate (ORR), and safety. Patient characteristics were well-balanced across the treatment arms, with more than half of the patients having squamous histology, more than 80% had stage IIIA/B NSCLC, a third of patients had PD-L1 < 1%, and a third of patients had PD-L1 ≥ 50%. At a median follow-up of 30.5 months, the median PFS was 16.7 months (95% CI 12.6 to 22.0) for arm A and 15.6 months (95% CI 13.7 to 19.8) for arm C (HR=0.95; 95% CI 0.77 to 1.19; p=0.6460). None of the sub-group analyses showed significant superiority of arm A or C for PFS, including PD-L1 expression. Median OS was 34.6 months (95% CI 26.8 to not reached [NR]) for arm A and 40.2 months (95% CI 30.5 to NR) for arm C (HR=1.12; 95% CI 0.87 to 1.43). Again, similar results were seen for all sub-group analyses. Similar non-superiority of arm B over arm C was seen in PFS and OS analysis. A majority of relapses in all arms happened locally only, at 59% for arm A, 56% in arm B, and 51% in arm C. All adverse events (AEs) and treatment-related AEs (TRAES) were similar between the arms, regardless of grade. However, TRAEs of any grade leading to discontinuation were higher in arm A (22%) than arm B (16%) and arm C (13%). The most common TRAEs across treatment arms (A, B, C), were nausea (29%, 26%, 31%), esophagitis (25%, 26%, 22%), and anemia (35%, 32%, 36%). In comparing adverse events between treatment phases, rates of AEs were similar between CCRT and the consolidation phase for all three arms. Important to note, there were 22 treatment-related deaths, with 10 in the consolidation phase of arm A, 11 in the consolidation phase of arm B, and 1 in arm C. These data reveal no significant benefit of adding nivolumab concurrently with CCRT followed by either nivolumab alone or nivolumab + ipilimumab in comparison to CCRT followed by durvalumab in patients with locally advanced, unresectable NSCLC.
Combining pembrolizumab with stereotactic body radiotherapy for patients with unresected stage I/II non-small-cell lung cancer in KEYNOTE-867
117O - Stereotactic Body Radiotherapy (SBRT) With Pembrolizumab (pembro) for Unresected Stage I/II Non-Small-Cell Lung Cancer (NSCLC): The Randomized, Double-Blind, Phase 3 KEYNOTE-867 Study
Andreas Pircher (Landeskrankenhaus - Universitaetskliniken Innsbruck, Innsbruck, Austria) highlighted the first-interim and final analysis of the randomized, phase 3 KEYNOTE-867 trial, investigating the safety and efficacy of combining pembrolizumab with stereotactic body radiotherapy (SBRT) for patients with unresected stage I/II non-small-cell lung cancer (NSCLC). This trial enrolled 448 patients and randomized (1:1) them to receive either SBRT + pembrolizumab (n=227) or SBRT + placebo (n=221). The primary endpoint was event-free survival (EFS) with secondary endpoints including overall survival (OS), time to death or distant metastases, and safety/tolerability. Efficacy was evaluated in all randomized patients; safety was evaluated in all randomized patients that received at least 1 dose of the study treatment. Baseline characteristics were balanced between the treatment arms; for both groups, median age was 73 years, more than 80% of patients were medically inoperable, and about 7% to 8% of patients had ECOG performance status of 2. The study did not meet the primary endpoint. At a median follow-up of 20.6 months, no significant difference in EFS was observed, with median EFS of 31.2 months (95% CI 22.5 to 39.1) for the pembrolizumab arm and 28.3 months (95% CI 19.8 to 33.1) for the placebo group (HR=0.92; 95% CI 0.69 to 1.24; p=0.29). No significance in EFS was seen in any of the sub-group analyses, including ECOG performance status, smoking history, histology, and reasons for not receiving surgery. Findings suggested a potential benefit in EFS of pembrolizumab over placebo in younger patients (< 65 years), however, this was not significant (HR=0.44; 95% CI 0.18 to 1.24). Though not formally tested, OS favored the placebo arm (median OS not reached) over the pembrolizumab arm (median OS 54.7 months). Additionally, there were no significant differences in OS across sub-group analyses. Notably, the combination of pembrolizumab + SBRT resulted in more treatment-related adverse events (TRAEs) than placebo + SBRT (73.5% vs. 50%, respectively), which was maintained in grade 3–5 TRAEs (20.4% vs. 3.7%, respectively). There were also more treatment discontinuations (15.9% vs. 2.3%) and treatment-related deaths (2.2% vs. 0%) in the pembrolizumab arm than the placebo arm. A similar trend was seen for immune-related adverse events, with more grade 3–5 events in the pembrolizumab group (9.3%) than the placebo group (0.9%), with the most common grade ≥ 3 toxicity being pneumonitis. Analysis from this study reveal that the addition of pembrolizumab to SBRT led to higher rates of toxicity and did not improve survival outcomes for patients with unresected stage I/II NSCLC.
Thursday, Dec. 12, 2024
Inupadenant, an A2AR antagonist, promotes B cell and TLS maturation in tumors
174MO – The A2AR antagonist inupadenant promotes humoral responses in patients
Dr. Hussein Shehade (iTeos therapeutics, (Gosselies, Belgium) presented data on the effects of inupadenant on antibody secreting cells in tertiary lymphoid structures (TLS). Tumors often express high levels of adenosine, which is known to inhibit immune responses by binding to the A2A receptor (A2AR) and inhibiting T cell activation. Inupadenant targets the A2AR to inhibit this interaction and improve T cell responses, however antibody secreting cells have also demonstrated A2AR expression and this study examined the interplay between inupadenant and those antibody secreting cells. In two phase I studies (NCT03873883, NCT05117177), tumor and blood samples were collected from patients with various types of end-stage cancer who were treated with inupadenant monotherapy. Tumor samples were analyzed via spatial transcriptomics and revealed higher expression of immunoglobulin G and other markers indicative of antibody secreting cells in the TLS fraction, indicating a mature TLS. Similarly, Nanostring and Simoa analysis in the blood examined CXCL13 expression, which is associated with TLS formation by recruiting B cells, found a slight but consistent increase. In conjunction, patients who experienced a response (non-progressors) to inupadenant therapy demonstrated increased B cell signatures, while those who experienced disease progression did not. These data demonstrate that not only does inupadenant drive changes in T cell activation for cellular responses, but it also appears to promote B cell and TLS maturation in the tumors for humoral responses. Ongoing work will further examine the role of this mechanism in the clinical setting for patient populations.
A ctDNA Tumor Fraction of greater than 5% is associated with better outcomes following ICB plus chemotherapy compared to ICB alone in advanced non-small cell lung cancer
4MO – Role of ctDNA Tumor Fraction to select immunotherapy based regimens in Advanced Non-small Cell Lung Cancer
Dr. Filippo G. Dall'Olio (Institut Gustave Roussy, Villejuif, France) presented his findings on the role of ctDNA tumor fractions (TF) to inform therapy decisions in advanced non-small cell lung cancer (aNSCLC). This analysis utilized patient data from the de-identified Flatiron Health-Foundation Medicine clinico-genomic database, which holds data of over 20,000 patients, 820 of which were eligible for outcome analysis in this study. Patients chosen for analysis received immune checkpoint blockade (ICB) and F1L/F1LCDx and had specimen collection less than or equal to 60 days prior to the start of therapy. The intended outcome was to determine whether ctDNA TF was a significant marker for response to ICB plus chemotherapy rather than ICB alone with outcome measurements of real-world overall survival (rwOS) and real-world PFS (rwPFS). Patient stratification showed that higher ctDNA TF was correlated with younger age, sex, squamous histology, CNS and liver involvement, and patients with high ctDNA TF were also more likely to have received ICB plus chemotherapy treatment. Interestingly, even when adjusted for confounding factors such as CNS and liver involvement, a high ctDNA TF was a prognostic for poor survival outcomes. At a cutoff of 5% ctDNA TF, a significant benefit in the use of ICB plus chemotherapy over ICB monotherapy was observed. For patients with expression of greater than 5% ctDNA TF, rwOS was 8.3 months versus 3.4 months for those treated with ICB alone (HR 0.55; 95% CI 0.37 to 0.79; p = 0.001). Similarly, rwPFS was 4.6 months versus 2.3 months for ICB chemo vs ICB alone, respectively (HR 0.51; 95% CI 0.33 to 0.78; p=0.0002). In addition to this prognostic data, the ctDNA TF was correlated to an increase in cell cycle gene expression, demonstrating its biological relevance. These data provide a promising prognostic biomarker for patients with aNSCLC, where 5% or more ctDNA TF would inform a combination therapy rather than a monotherapy for improved outcomes.
A2A-005 trial finds optimal dose of Inupadenant when used in combination with doublet-chemotherapy and shows promising early preliminary clinical activity in patients with non-small cell lung cancer
120MO – Inupadenant Combined with Chemotherapy in Patients with Non-Squamous NSCLC Progressing On or After Immune Checkpoint Inhibitor Therapy: Results from Dose-Finding Part of the A2A-005 Trial
Dr. Kristof Cuppens (Jessa Ziekenhuis, Hasselt, Belgium) presented the results from the phase I/II trial dose-finding trial A2A-005 (NCT05403385). This trial examined dose, safety, and preliminary efficacy of Inupadenant, an A2A receptor (A2AR) antagonist, in combination with doublet-chemotherapy for the treatment of patients (n=36) with non-squamous non-small cell lung cancer (NSCLC) who have received at least one prior line of anti–PD-L1 therapy and have experienced progression. Currently, the preferred regiment following first-line progression is platinum-based doublet chemotherapy, however this treatment induces adenosine which has immunosuppressive properties through signaling with A2AR on T cells. By targeting this receptor in combination with platinum doublet chemotherapy, the purpose was to prevent the immunosuppressive side effect driven by chemotherapy-induced adenosine release. The dose cohorts included 40mg, 60mg, and 80mg, with expansion in the 40mg and 80mg cohort. In both expanded cohorts, no new safety signals were observed, and no treatment-related deaths occurred. All TEAEs were in line with expectations following doublet chemotherapy. Efficacy outcomes were promising, with an ORR for all cohorts of 63.9%, and when grouped by dose the ORR for the 40mg cohort was 53.3% while the ORR for 80mg cohort was 73.3%. At a minimum follow up of 6 months for all patients, the median PFS for the 40mg cohort was 5.6 months, while the 80mg cohort PFS was not yet reached. As a results 80mg was defined as the optimal dose of Inupadenant when administered in combination with carboplatin and pemetrexed. These data demonstrate safety and early preliminary clinical activity of Inupadenant in combination with doublet-chemotherapy. This study is ongoing.
The addition of anti-IL8 to combination nivolumab plus ipilimumab therapy in patients with melanoma did not reach primary and secondary endpoints
121MO – Anti–IL-8 (BMS-986253) in combination with nivolumab (NIVO) plus ipilimumab (IPI) in patients (pts) with advanced melanoma: final analysis from the randomized part 2 of the phase 1/2 CA027-002 study
Dr. Matteo Simonelli (Humanitas Cancer Center, Pieve Emanuele, Italy) presented the negative results from the final analysis of the phase I/II trial CA027-002 (NCT03400332). Part 2 of this trial examined the efficacy of the fully human Anti–IL-8 (BMS-986253) in combination with nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of patients with advanced melanoma who were resistant to PD-(L)1 blockade. The current standard of practice is NIVO plus IPI, and low IL-8 levels correlate with an improved response to treatment, therefore the purpose was to investigate whether targeting of IL-8 would drive improved responses to NIVO plus IPI treatment. Part 1 of this trial demonstrated that IL-8 alone and in combination with NIVO was well tolerated and had promising durable tumor activity, with similar rates of treatment-related adverse events (TRAEs). However, in this part 2 which was a randomized double-blind study followed up for 5 years demonstrated no significant difference in the objective response rate (ORR), duration of response (DOR), or progression-free survival (PFS) between treatment arms. Notably, of the responders there was a trend towards a greater complete response (CR) in the anti–IL-8 plus NIVO plus IPI group (5 CR) compared to the NIVO plus IPI group (1 CR). In summary, while the addition of anti–IL-8 to NIVO plus IPI does not worsen the safety profile, this trial failed to meet primary and secondary endpoints for efficacy, and therefore this trial supports further use of NIVO plus IPI in patients with advanced melanoma who progress on or after anti–PD-(L)1 monotherapy.
The oncolytic virus ORCA-010 shows promising hot-to-cold tumor conversion in preliminary trial
176MO – ORCA-010 Oncolytic Therapy: Inducing Tumor-Specific Immune Responses and Activation of Tumor Microenvironment in Treatment-Naïve Prostate Cancer
Dr. Tanja D. De Gruijl (Cancer Center Amsterdam, Amsterdam, Netherlands) presented a promising update regarding the oncolytic virus, ORCA-010, which is a modified adenovirus that has enhanced cancer cell infection, selectively replicates in cancer cells, and exhibits enhanced viral release and spread. In this phase I/IIA trial, ORCA-010 was examined for safety and efficacy in early-stage prostate cancer. In phase I, dose escalation was performed with three cohorts subjected to intra-prostate injection of 1x1011, 5x1011, or 15x1011 viral particles (vp). All doses demonstrated mild side effects (grade 2 or below). Flow cytometry analysis of peripheral blood at two weeks post-injection showed Ki67+ CD8+ T cells indicative of proliferation. Ex vivo restimulation of T cells with overlapping tumor antigens showed positive intracellular staining for IFN gamma and TNF alpha in CD8+ T cells, demonstrating that there was tumor-specific T cell reactivity. In the phase IIA portion of the trial, 12 patients received two injections of 1.5x1012 vp spaced two weeks apart. At the one-year follow up, biopsy samples revealed that the tumor microenvironment (TME) had gone from cold to hot, as shown by an increase in CD4+ and CD8+ T cells, as well as T cells that expressed PD-1 and granzyme B, while regulatory T cells (defined by FOXP3) remained relatively low. These data suggest both expansion of proliferating T cells in the peripheral blood and an increase in T cell infiltration into the tumor, as well as an increase in effector T cells with functional abilities. In summary, intratumoral delivery of the oncolytic virus ORCA-010 is safe and appears to drive conversion of tumors from immune deserts to favorable immune environments, and as such should be further explored in the clinical setting as a therapeutic option for early-stage prostate cancer.