Adjuvant chemotherapy is recommended in high-risk stage II–III colorectal cancer (CC). We examine the effect of daily wheatgrass juice (WGJ) intake in addition to chemotherapy on immune parameters, including IL-6, IL-8, IL-10, IL-12, and white blood cells (WBCs) among CC patients. In a controlled prospective trial, 100 stage II–III CC patients were enrolled. According to patient preference, they were divided into two subgroups, control group and intervention group, 50 patients each, all of whom received the same standard postoperative adjuvant chemotherapy, plus consumption of 60 cc WGJ daily in the intervention group. Blood samples were collected at baseline (T0) and upon treatment termination, 5–6 months later (T1). Cytokine concentrations were assessed using ELISA kits. Anti-inflammatory cytokine IL-10 concentrations were significantly higher in the WGJ group than in the control group at T1. The decline in WBC counts between T0 and T1 was significantly lower in the WGJ group. No significant differences were observed in IL-6, IL-8, and IL-12 concentrations between the study groups. The higher levels of IL-10 and the attenuating of WBC decline during chemotherapy may constitute preliminary evidence of the beneficial effects of WGJ on immune parameters, when given as a supplement to standard care. In light of these preliminary results, WGJ supports immunological parameters during adjuvant chemotherapy. Nevertheless, future studies are needed in order to translate those results to clinical recommendations for cancer survivors.
Abstract Background: ES-SCLC is an aggressive cancer with substantial mortality. Current 1L treatments include anti-PD-(L)1 + etoposide-platinum chemo (EP), but with minimal improvements in OS vs chemo. In the phase 3 KEYNOTE-604 study, pembro + EP significantly improved PFS (P = 0.0023) but not OS vs placebo + EP; ORR was also improved (71% vs 62%). We present data from the phase 2 KEYNOTE-B99 study (NCT04924101) of 1L pembro + investigational agents (MK-4830, anti-ILT4; boserolimab, anti-CD27; or lenvatinib), and EP for ES-SCLC. Methods: In this open-label platform study, patients (pts) were aged ≥18 y with previously untreated histologically or cytologically confirmed stage IV ES-SCLC (per AJCC v8) and ECOG PS 0 or 1. Pts were randomized 1:1:1 to receive MK-4830 800 mg Q3W (35 cycles; arm A), boserolimab 30 mg Q6W (18 cycles; arm B), or lenvatinib 8 mg (induction)/20 mg (maintenance) QD (arm C). All pts received pembro 200 mg Q3W (35 cycles) + etoposide 100 mg/m2 Q3W and cisplatin 75 mg/m2 Q3W or carboplatin AUC 5 mg/mL/min Q3W (4 cycles). Primary endpoints were ORR and PFS at 6 mo, both assessed per RECIST v1.1 by BICR. Secondary endpoints included DOR, PFS, OS, and safety. Results: 122 pts received ≥1 dose of study treatment (arm A, 43; B, 41; C, 38). At data cutoff (Sep 15, 2023), median follow-up was 14.1 (range, 6.1-25.7) mo. ORR was 65%, 71%, and 74% in arms A, B, and C, respectively; median DOR was 6.8, 4.7, and 7.1 mo. 6-mo PFS rates were 45%, 38%, and 54%, respectively (Table). AEs (any cause) occurred in 98% of pts in arm A and all pts in arms B and C; most commonly neutropenia and anemia. Serious AEs occurred in 30%, 37%, and 55%; grade ≥3 AEs in 86%, 83%, and 87% of pts; and grade 5 AEs in 5%, 7%, and 21%, respectively. Conclusions: 1L ES-SCLC treatment with pembro + EP and MK-4830, boserolimab, or lenvatinib was associated with similar antitumor activity as in KEYNOTE-604 with pembro + EP. No new safety signals were identified. TABLE 1. NAND Group A MK-4830 + Pembro + EP(n = 43) Group B boserolimab + Pembro + EP(n = 41) Group C Lenvatinib + Pembro + EP(n = 38) ORR (95% CI), % 65.1 (49.1-79.0) 70.7 (54.5-83.9) 73.7 (56.9-86.6) Median DOR (range), mo 6.8 (2.4-13.9) 4.7 (1.4+ to 16.4+) 7.1 (1.8 to 18.4+) PFS - 6-mo PFS rate (95% CI), % 45.2 (29.9-59.4) 37.8 (22.7-52.7) 54.2 (35.8-69.4) - Median PFS (95% CI), mo 5.5 (4.2-8.3) 5.5 (4.0-6.7) 7.2 (5.4-NR) Median OS (95% CI), mo 15.5 (8.3-NR) NR (13.2-NR) 15.8 (7.2-NR) ‘+’, no PD at the time of last disease assessment. NR, not reached. Citation Format: Delvys Rodríguez-Abreu, Maximillian Hochmair, Byoung Chul Cho, Tibor Csőszi, Talia Shentzer Kutiel, Veronika Müller, Myung-Ju Ahn, Dariusz Kowalski, Michele Maio, Vladimir Moiseyenko, Alejandro Navarro, Jianxin Niu, Andrea S. Fung, Carolin Lips, Heng Zhou, Bin Zhao, Humberto Lara-Guerra, Nir Peled. Results from KEYNOTE-B99: Phase 2 study of first-line (1L) pembrolizumab (pembro) plus investigational agents and chemotherapy (chemo) for extensive-stage small-cell lung cancer (ES-SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT253.
e23045 Background: Adjuvant chemotherapy is recommended in stage II-III colorectal cancer (CC). Wheatgrass juice (WGJ), has high nutritional values may attenuate chemotherapy adverse events (AE). Extracellular vehicles (EVs) are subcellular membrane blebs that provide information on cellular processes. Aim: To evaluate the incidence of chemotherapy AE and to elucidate the effects of supportive treatment of WGJ on CC patients’ EVs characteristics. Methods: In a prospective trial between 3/2014- 7/2017, 99 patients stage II-III CC, treated with standard adjuvant chemotherapy were enrolled. According to patient preference, they were divided into: control group of 50 (CC-C) patients and intervention group of 49 patients who received chemotherapy plus consumption of daily 60cc frozen WGJ (CC-W). EVs were isolated from the blood samples of 15 healthy controls (HC) and 25 patients from each study group. Blood samples were taken before, during and at the end of chemotherapy, EVs characterized by membrane antigens/cytokine content Results: Study groups were well balanced. Median follow-up time was 15 months. Eleven patients had died at the time of analysis, 3 in the WGJ and 8 in the control ( p= 0.142). 11/50 (22%) and 8/49 (16.3%) had severe diarrhea in the control and WGJ groups, respectively ( p= 0.47). There was no difference between the groups in RFS (HR = 1.19 , p= 0.69). Higher levels of endothelial EVs (CD34 + 41, CD144), indicating vascular injury, were found in CC-C patients- compared to CC-W during and at the end of treatment. Increased EVs thrombogenicity in patients was documented, while EVs thrombogenicity was lowered in CC-W compared to CC-C during or at the end of treatment (TF, P = 0.029; TF/TF-pathway inhibitor (TFPI) ratio, p = 0.008; endothelial protein C receptor 0.005 and annexin-V 0.05). Following treatment, the majority of growth-factors/pro-inflammatory cytokines were found to be lower in CC-W than in CC-C. Conclusions: Daily consumption of WGJ during chemotherapy may reduce vascular damage and thrombogenicity. There was no statistical difference in overall survival. However, the large difference in death rate may relate to other long-standing effects of daily WGJ consumption. Clinical trial information: NCT01991080.
110 Background: Single agent selinexor, an oral selective inhibitor of nuclear export (SINE), showed activity against heavily pretreated CRC with RAS mutations (mut) or wildtype (wt) in 2 clinical studies. In preclinical studies, selinexor showed superior potency in KRAS mut over wt with improved activity in combination with PD-1/PD-L1 blockade. A phase 1b study (NCT02419495) showed the safety and antitumor activity of combined selinexor and a PD-1/PD-L1 inhibitor. This phase 1/2 open-label study is evaluating selinexor with pembrolizumab in patients with microsatellite instability (MSI)-stable CRC. Methods: The study enrolled patients with advanced/metastatic CRC who progressed after prior chemotherapy (1-3 lines for RAS wt, 1-2 for RAS mut) and are ineligible for anti-PD-1/PD-L1 therapy. Patients received weekly oral selinexor 80 mg and pembrolizumab 200 mg IV every 3 weeks. Antitumor activity, safety and tolerability were assessed. Results: Thirty-four patients, median age 57.5 years, male 59%, RAS mut 53%, median prior lines 2, are enrolled. At data cutoff (1-SEP-21) median treatment duration was 57 days (range: 1-246) and 25 patients were evaluable for response. Best response was stable disease in 8/13 patients with RAS mut CRC (62%) and in 3/12 patients with RAS wt CRC (25%). Median overall survival (months) has not been reached for the overall population (95% CI: 6.3, NE), for RAS mut (95% CI: 7.6, NE), and for the RAS wt (95% CI: 6.1, NE). Median progression-free survival is 3.0 and 1.4 months for patients with CRC with RAS mut and wt, respectively (p=0.04; HR: 0.43 [959% CI: 0.18, 1.01]). Thirty patients (88%) discontinued therapy, mostly due to progressive disease (44%). The most common treatment-emergent adverse events (TEAEs) (total; Grade ≥3) were nausea (77%; 3%), vomiting (41%; 0%), fatigue (41%; 12%), decreased appetite (35%; 0%), diarrhea (32%; 0%). Nine patients (26%) had serious treatment-emergent adverse events. Conclusions: Combined selinexor with pembrolizumab demonstrated higher disease control rates and prolonged overall survival in patients with chemotherapy-refractory advanced/metastatic CRC with RAS mut vs RAS wt tumors. These patients would not have been eligible for anti-PD-1 mAb therapy because their tumors were not MSI-high, suggesting that the combination may be active in RAS mut CRC. Therapy was well tolerated with no unanticipated adverse events. Further investigation of this combined treatment is warranted, particularly in patients with CRC with RAS mut. Clinical trial information: NCT04256707.
8631 Background: Immune-Checkpoint inhibitors (ICI) have transformed the treatment of solid tumors, specifically in cutaneous melanoma, clear cell renal cell carcinoma (ccRCC) and non-small cell lung cancer (NSCLC). Despite these advances, resistance to ICI eventually occurs in many patients. Recent reports have found that patients showing poor response to ICI are characterized by a reduced gut microbiome diversity, suggesting that the gut microbiome might affect immune activation by ICI. BMC128 is a live bacterial consortium of 4 bacterial strains designed to induce anti-tumor immune function when given in conjunction with ICI. These strains were identified by analyzing microbiome data obtained from NSCLC and ccRCC patients presenting varied responses to ICI, using a proprietary computational discovery platform enabling high-resolution functional microbiome analysis. In pre-clinical studies, treatment with BMC128 potentiated the efficacy of ICI in breast cancer and melanoma mouse models, reducing tumor volume, increasing the number of responders, and demonstrating an increase in infiltrating immunocytes: CD4, CD8 and NK cells. The aim of this study was to assess the safety and tolerability of BMC128 in combination with nivolumab. Methods: 12 patients with ccRCC, cutaneous melanoma and NSCLC-adenocarcinoma (EGFR/ALK wild-type) (6, 1 and 5 patients, respectively), who previously progressed on PD1/PDL-1 inhibitors were recruited to this FIH open label phase 1 study. Patients were treated with a daily oral dose of BMC128 4*10 8 live cells/ strain in combination with nivolumab 480mg q4weeks. The study treatment consisted of 4 stages: depletion with antibiotics, induction with BMC128 monotherapy, combination treatment, and nivolumab monotherapy. Results: No SAEs related to BMC128 were reported throughout the duration of the study. Two patients exhibited minor AEs that were potentially associated with BMC128. At the current time point, 4 out ofthe first 8 patients in the study showed SD and sustained benefit beyond the first imaging timepoint, following the combination treatment. Altogether demonstrating clinical benefit for a total of 16 weeks (2 patients), 24 weeks (1 patient), and 68 weeks (1 patient). Conclusions: BMC128 has demonstrated an excellent safety profile and preliminary beneficial clinical effect. A phase 2 study to investigate the efficacy of BMC128 is planned to be initiated in late 2024. Clinical trial information: NCT05354102 .
Abstract Background: Anti-PD-L1 plus chemotherapy is a recommended first-line (1L) treatment option for ES-SCLC. However, most patients (pts) relapse and effective second-line (2L) treatment options are limited. Pembrolizumab (pembro) has demonstrated antitumor activity in previously treated ES-SCLC. The KEYNOTE-B98 study (NCT04938817) evaluated pembro in combination with investigational agents as 2L therapy for anti-PD-(L)1-refractory ES-SCLC. We present initial results from this study. Methods: This randomized, phase 1b/2, multicenter, open-label, platform study enrolled adult pts with confirmed ES-SCLC (stage IV per AJCC v8.0) that progressed ≤12 wk of last anti-PD-(L)1 dose given as part of 1L platinum-based therapy, measurable disease per RECIST v1.1, and ECOG PS of 0-1. Pts were randomized 1:1:1:1 to: (A) MK-1308A (coformulation of quavonlimab [anti-CTLA4] 25 mg + pembro 400 mg) Q6W, (B) MK-1308A Q6W + lenvatinib 20 mg QD, (C) MK-1308A Q6W + MK-4830 (anti-ILT4) 800 mg Q3W, and (D) MK-4280A (coformulation of favezelimab [anti-LAG3] 800 mg + pembro 200 mg) Q3W. A safety lead-in was performed for the first 21 days of treatment in cohort C in ≤10 pts evaluable for dose-limiting toxicities (DLTs), followed by efficacy evaluation. Pts in safety lead-in were not randomized. Primary endpoints were safety (DLTs in safety lead-in phase, AEs, and discontinuations due to AEs) and ORR per RECIST v1.1 by BICR. Secondary endpoints were PFS and DOR per RECIST v1.1 by BICR. Results: 76 pts received ≥1 dose of study treatment: cohort A, n = 19; B, n = 20; C, n = 17; D, n = 20. Median follow-up at data cutoff (Jul 3, 2023) was 12.9 (range, 5.9-21.8) mo. During safety lead-in, 1 pt had a DLT of grade 3 arthralgia. Treatment-related AEs (TRAEs) occurred in 12 pts (63%; grade 3/4, n = 2, 11%) in cohort A, 17 (85%; grade 3/4, n = 6, 30%) in cohort B, 12 (71%; grade 3/4, n = 1, 6%) in cohort C, and 15 (75%; grade 3/4, n = 4, 20%) in cohort D; none were grade 5. 1 pt (5%) in cohort A, 3 (15%) in cohort B, 0 in cohort C, and 2 (10%) in cohort D had TRAEs that led to treatment discontinuation. Confirmed ORR (95% CI) was 5% (0%-26%; 1 PR) in cohort A, 25% (9%-49%; 5 PR) in cohort B, 0% (0%-20%) in cohort C, and 0% (0%-17%) in cohort D. Median (range) DOR was not reached (9.4+ to 9.4+ mo) in group A and 3.9 (2.0-3.9) mo in group B. Median (95% CI) PFS was 1.4 (1.2-2.6) mo, 3.9 (1.7-5.3) mo, 1.2 (0.8-1.4) mo, and 2.6 (1.4-4.0) mo in cohorts A-D, respectively. Conclusions: In the KEYNOTE-B98 study of anti-PD-(L)1-refractory ES-SCLC, no new safety signals were identified for the pembro-based combinations investigated. Modest antitumor activity was observed with MK-1308A ± lenvatinib, but no activity for MK-1308A + MK-4830 or for MK-4280A. This study provided proof-of-concept for the feasibility of platform trials in 2L ES-SCLC. Further investigation of new compounds and combinations is needed in this population. Citation Format: Alejandro Navarro, Myung-Ju Ahn, James Stevenson, Nir Peled, Talia Shentzer Kutiel, Florian Huemer, Dong-Wan Kim, Maria Jove Casulleras, Adnan Khattak, Dariusz Kowalski, Natasha B. Leighl, Filippo de Marinis, Carolin Lips, Jiaxin Niu, Mo Huang, Bin Zhao, Hazem El-Osta, Taofeek Owonikoko. Results from KEYNOTE-B98: A phase 1b/2 study of pembrolizumab plus investigational agents in patients with anti-PD-(L)1-refractory extensive-stage small-cell lung cancer (ES-SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT256.
