Olanzapine (5 mg) Plus Standard Triple Antiemetic Therapy for the Prevention of Multiple-Day Cisplatin Chemotherapy-Induced Nausea and Vomiting: A Prospective Randomized Controlled Study

Objective A prospective randomized controlled trial was conducted to compare 5 mg olanzapine plus standard triple antiemetic therapy for the prevention of nausea and vomiting induced by multiple-day cisplatin chemotherapy. Methods Patients received 3-day cisplatin-based chemotherapy(25mg/m2/d) were given either 5mg olanzapine quadruple therapy (aprepitant, tropisetron, dexamethasone) or 5mg olanzapine-based triplet therapy. The primary end-point was the complete response(CR) in the overall phase(OP)(0-120h) between quadruple regimen group and triplet regimen group. The secondary end-points were the CR in the acute phase(AP)(0-24h), delayed phase(DP)(25-120h) between two groups. The first time of vomiting was also compared by Kaplan-Meier curves. The impact of chemotherapy induced nausea and vomiting(CINV) on the quality of life was assessed by the Functional Living Index-Emesis(FLIE). Aprepitant-related adverse effects (AEs) was also recorded. Results (1) The primary end-point CR during overall phase was 76.0% (45/59) vs 67.0% (41/61) between the quadruple regimen group and triplet regimen group(P =0.271). The secondary end-point CR during the AP was significantly higher in the quadruple group than in the triple group, which was 100.0%(59/59) vs 93.0%(57/61)(P=0.045). The difference between the groups was especially greater in the delayed phase(quadruple group 76.0% (45/59) vs triple group 67.0%(41/61)(P=0.271)). The rate of patients who achieved total protection in the overall phase was also larger in the quadruple group than in the triple group(28.8% (17/59) vs 23.0%(14/61)(P=0.463)). During the OP, the incidence of no vomiting in quadruple group and triple group was 93.2%(55/59) vs 80.3%(49/61)(P=0.038)respectively.(2) Kaplan-Meier curves of time to first emesis were obviously longer in the quadruple group than in the triple group(P=0.031). According to FLIE, no impact of CINV on daily life was defined as total score of questionnaire >108, this study exhibited identical life quality in quadruple group and the triplet group.(3) The most common aprepitant- and olanzapine-related AEs included sedation, fatigue and constipation. The occurrences between two groups were identical. Conclusion It may been recommended that combined 5mg olanzapine with aprepitant, tropisetron, dexamethasone quadruple therapy for the prevention of multiple-day cisplatin induced nausea and vomiting due to the better CINV control rate and safety.

Safety analysis of the randomized phase II study of FOLFOXIRI plus cetuximab versus FOLFOXIRI plus bevacizumab as the first-line treatment in metastatic colorectal cancer with RAS wild-type tumors: The DEEPER trial (JACCRO CC-13).

86 Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet regimen plus bev or triplet regimen in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or VOLFI trial ( J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as first-line treatment in terms of the DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC (ClinicalTrials.gov Identifier: NCT02515734). The experimental arm with cet was considered to be active if the difference of median DpR was over 12.5% compared with the bev arm, under the conditions of significance level of 0.05 and power of 0.85. Secondary endpoints included the ETS at week 8, progression-free survival, overall survival, secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the safety analysis set (median age 65y, 64% male, PS0/1:91%/9%, left/right primary:83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively, some patients were excluded for the safety analysis due to the violation of inclusion criteria (6 for cet arm and 5 for bev). On the cutoff date of September 2020, median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. The incidence of severe adverse events (AEs) was 25.4% (44/173) for the cet arm and 25.7% (45/175) for the bev arm, respectively. The following AEs of grade 3-4 were observed more frequently in the cet arm compared to the bev arm: oral mucositis (9.2% vs. 2.3%), diarrhea (12.1% vs. 8.0%), dermatitis acneiform (12.1% vs. 0%), and hypomagnesemia (4.0% vs. 0%). The treatment-related death occurred in 2 patients of the cet arm, while no patients in the bev arm. The rate of treatment discontinuation due to AEs of any cause was comparable between the cet and bev arms (7% vs. 9%). Conclusions: This safety analysis indicated that both regimens of m-FOLFOXIRI plus cet or bev were tolerable in RAS wt mCRC patients although some frequent severe AEs were observed. Clinical trial information: UMIN000018217.

A multi-institutional phase Ib/II trial of first-line triplet regimen (Pembrolizumab, Trastuzumab, Chemotherapy) for HER2-positive advanced gastric and gastroesophageal junction cancer (PANTHERA Trial): Molecular profiling and clinical update.

218 Background: We report the updated clinical data and molecular profiling results of a multi-institutional phase Ib/II trial of triple combination (pembrolizumab, trastuzumab, and chempotherapy) as first line therapy for HER2 positive advanced gastric and gastroesophageal junction (AGC/GEJ) cancer. (PANTHERA trial; NCT02901301). Methods: Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m2 bid D1-14, and Cisplatin 80mg/m2 D1 every 3 weeks was selected as recommended phase II dose. The primary endpoint for phase II was ORR per RECIST v1.1. Secondary endpoints included PFS, OS, DOR, safety, and predictive biomarker analysis by targeted NGS. Results: At the time of data lock on Aug 31, 2020, total of 43 patients were treated with median follow up of 18.2 months, and 3 patients remained on the treatment, and 6 patients finished 2-year treatment without progression. ORR was 76.7% (CR 16.3%, PR 60.5%, conversion surgery 4.6%) with 26 pts (56.6%) showing more than 50% of tumor burden reduction. Median PFS was 8.6 months (95% CI 7.2-16.5) and median OS was 19.3 months (95% CI 16.5-NR). There were no MSI-H/dMMR or EBV-positive pts. No patient discontinued pembrolizumab because of immune-related adverse events. Clinical features including PD-L1 status (55.3% of pts ≥ CPS 1 and 13.2% of pts ≥ CPS 10 among available 38 pts), metastatic organ or baseline tumor burden was not related to the survival. Ninety-eight tumor tissues from 39 pts (paired tumor tissues from 22 pts) were analyzed with targeted NGS. Although every pts were HER2 IHC-positive, baseline HER2 amplification by NGS was related to the survival ( HER2 amp (n=8) vs HER2 non-amp (n=23); mPFS, not reached vs 7.7 months, P=0.0178; mOS, not reached vs 17.9 months, P=0.044) but no other signaling pathways predicted pts’ survival. HER2 mutations including L869R or D769H were related to the acquired resistance. High TMB showed a tendency toward better survival (mPFS; High (n=7) vs Low (n=24) TMB, 22.0 vs 8.2, P=0.2835) due to small number of patients. Updated immune markers and serial NGS analyses will be presented. Conclusions: First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) showed promising efficacy based on HER2 amplification by NGS regardless of PD-L1 status in AGC/GEJ cancer. Correlative biomarkers found from NGS study need to be validated through on-going phase III Keynote-811 study. Clinical trial information: NCT02901301. [Table: see text]

Management of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Novel Therapies in Routine Clinical Practice in Germany

Background: To better understand the clinical practice in Germany with respect to the rapidly evolving treatment landscape, we aim to describe the characteristics and treatment patterns of patients (pts) with relapsed/refractory multiple myeloma (RRMM) in Germany. Methods: In a national retrospective medical chart review including consecutive pts treated for RRMM in participating hospitals/centers and practices across Germany between Oct 2017 and Jun 2018, the following data were extracted from Oct 2019 to Feb 2020: pt demographics, disease characteristics, treatment history at MM diagnosis and at initiation of RRMM therapy, and distance to care. Physician's assessment of response to therapy and minimal residual disease (MRD) testing were also collected. Because this analysis was not powered to compare between regimens or lines of therapies, results are purely descriptive. Results: Physicians from 47 participating centers extracted 484 pt charts, that included 214 pts (44%) in 2nd line of therapy (2L), 160 (33%) in 3rd line (3L) and 110 (23%) in 4th line and beyond (4L+) (Figure 1). Half of the participating centers were office-based (52%) and 40% were hospitals. Results are summarized in Table 1 and regimens described by line of therapy in Figure 2: Among the 2L subgroup (N=214), median age was 72 years and the majority (73%) of pts had an ECOG status of 0-1 at 2L initiation. About one-third (31%) of pts had had a transplant. Carfilzomib (CFZ) or daratumumab (Dara)-based regimens were mainly used in 2L pts (40% and 41%, respectively). Among the 87 Dara pts, the triplet regimen Dara, lenalidomide (LEN) and dexamethasone (DRd) was used in more pts (58%) than the triplet with Dara, bortezomib (BTZ) and dexamethasone (DVd, 15%). Among the 85 CFZ pts, nearly half (47%) received the triplet regimen CFZ, LEN and dexamethasone (KRd) and 38% of CFZ pts received the doublet of CFZ and dexamethasone (Kd). Among the remaining 42 pts in 2L, other LEN use was described in 35 pts and BTZ in 7 pts. For 107 pts who completed 2L, median treatment duration was 8 months (9 months for CFZ pts; 8.5 months for Dara pts; 6 months for LEN pts). Where response was available (n=191/214), a complete response (CR) or very good partial response (VGPR) was achieved by 64% of pts, including 73% of Dara pts (n=53/73), 62% of CFZ pts (n=48/78), and 53% of LEN pts (n=18/34). 149 ptssteoprotective drugs at 2L initiation, mainly intravenous zoledronate (ZA, 44%) and subcuteaneous denosumab (Dmab, 42%). In the 3L subgroup (N=160), median age was 72 years. Over half (58%) of pts had an ECOG status of 0-1 at 3L initiation. Most 3L pts received Dara (51%, n=81) or CFZ (35%, n=57), and a further 9% (n=15) of 3L pts received other LEN combinations. In 3L, CFZ was more often used as a doublet (54% Kd vs. 28% KRd); Dara was mainly given in triplet regimens (23% DRd, 17% DVd vs. 12% Dara mono). For 118 pts who had completed 3L at time of data extraction, median treatment duration was 10 months (10 months for both CFZ and Dara pts, 7 months for LEN pts). Where response was available (n=139), CR/VGPR was achieved by 55% of pts in 3L, including 64% of Dara pts (n=46/72) and 41% of CFZ pts (n=20/49). Osteoprotective drugs (51% Dmab, 36% ZA) at 3L initiation were given in 69% (n=111) of pts. In the 4L+ subgroup (N=110), median age was 74 years. A high percentage (64%) of pts had an ECOG status ≥2 at 4L initiation. Over half (52%, n=57) received Dara, mostly as monotherapy (70% Dara; 9% DRd, 2% DVd), followed by CFZ in 26% (n=28) and pomalidomide (POM) in 16% (n=18) of pts in 4L+. For 97 pts who completed 4L at time of data extraction, median treatment duration was 8 months (9 months for both CFZ and Dara pts, 7 months for POM pts). Where response was available (n=106), 39% of pts achieved a CR/VGPR, including 46% of Dara pts (n=25/55) and 36% of CFZ pts (n=10/28). At 4L initiation, 66% (n=72) of pts were receiving osteoprotective drugs (51% Dmab, 40% ZA). Conclusion: This chart review indicates that pts with RRMM who underwent a MM therapy between Oct 2017 and Jun 2018 in routine practice across Germany, mostly received combination regimens with novel agents irrespective of the line of therapy. Lenalidomide is still often combined with novel agents. Patterns of treatment regimens differed by line of therapy and are adapted as disease progresses and ECOG status increases. Disclosures Steinmetz: Amgen; BMS, Celgene, Novartis; Janssen-Cilag; Omnicare, Vifor: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Alexion, Amgen, Bayer, BMS, Boehringer, Celgene, Janssen-Cilag, Novartis, Omnicare, Sanofi, Takeda: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; DGHO, ESMO, DGPM, BNHO, NIONo: Other: Memberships; Alexion, Accord Healthcare, Amgen; Ariad, Bluebird Bio, BMS, Boehringer, Celgene, Hexal-Sandoz, Novartis; Janssen-Cilag; Omnicare, Oncopeptides, Otsuka, Pfizer, Sanofi, Shire, TAD, Takeda, Vifor: Consultancy; Accord Healthcare, Amgen, Celgene, Novartis, Vifor: Research Funding. Singh:Amgen Ltd, UK: Current Employment. Milce:Amgen: Research Funding; Kantar Health, France: Current Employment. Haidar:Kantar Health, France: Current Employment; Amgen: Research Funding. Rieth:Amgen GmbH, Germany: Current Employment; Amgen: Current equity holder in private company. Lebioda:Amgen GmbH, Germany: Current Employment; Amgen: Current equity holder in private company.

A regimen with caplacizumab, immunosuppression and plasma exchange prevents unfavorable outcomes in immune-mediated TTP

The anti-von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on post-marketing surveillance. We treated 90 iTTP patients with a compassionate frontline "triplet regimen" associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared to 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs. 12.2% in historical patients (p=0.01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs. 44%, p<0.01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36, p<0.01), with fewer TPE sessions and lower plasma volumes (p<0.01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 days vs. 22 days, p <0.01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant non-major hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the three processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

Prospective, multicentre, single-arm phase II trial of pembrolizumab combined with carboplatin and pemetrexed in elderly patients with advanced, non-squamous non-small cell lung cancer

IntroductionTriplet regimen of carboplatin or cisplatin with pemetrexed and pembrolizumab is a standard treatment for patients with advanced, chemo-naïve, non-squamous non-small cell lung cancer. However, subgroup analysis for patients aged ≥75 years indicated that elderly patients who received the triplet regimen may have had shorter survival times than if they had chemotherapy alone (HR of 2.09). Treatments in the elderly are not always as effective or safe as for non-elderly patients, so there remains concern over whether the triplet regimen can be widely used in the elderly.Methods and analysisThis is a single-arm, prospective, multicentre phase II study. The primary endpoint is set as the overall response rate according to Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints are progression-free survival, disease control rate and safety. This trial will enrol 22 patients.Ethics and disseminationThis study was approved by the Wakayama Medical University Central Review Board on 2 December 2019 (approval number: W-32). Patients have been enrolled since February 2020. As the study will complete accrual in January 2022, results will be submitted for publication in peer-reviewed medical journals within 2023 and international scientific meetings. This study will provide significant information on whether the triplet regimens are clinically beneficial to elderly patients.Trial registration numberJapan Registry of Clinical Trials (jRCTs051190095).

Targeting HER2 in combination with anti-PD-1 and chemotherapy confers a significant tumor shrinkage of gastric cancer: A multi-institutional phase Ib/II trial of first-line triplet regimen (pembrolizumab, trastuzumab, chemotherapy) for HER2-positive advanced gastric cancer (AGC).

3081 Background: Combining anti-PD-1 agent and trastuzumab has shown synergy in HER2 positive preclinical cancer models. We first report the result of a multi-institutional phase Ib/II trial of triple combination (pembrolizumab, trastuzumab, and chempotherapy) as first line therapy for HER2 positive AGC. (PANTHERA trial; NCT02901301). Methods: Pembrolizumab 200mg IV D1, Trastuzumab 6mg/kg (after 8mg/kg load) D1, Capecitabine 1000mg/m2 bid D1-14, and Cisplatin 80mg/m2 D1 every 3 weeks was selected as recommended phase II dose. The primary endpoint for phase II was ORR per RECIST v1.1. Secondary endpoints included PFS, OS, DoR, safety, and molecular analysis by targeted NGS. Results: Total of 43 patients were treated with median follow up of 16.1 months, and 11 pts remained on the treatment (treatment duration range: 1.4 to 24 months). There was significant tumor shrinkage of 95.3% with 54.6% median depth of response, with 76.7% ORR (CR 16.3%, PR 60.5%, conversion surgery 4.6%), and 97.7% DCR. Median PFS was 8.6 months (95% CI 7.2-22.0) and median OS was 18.4 months (95% CI 17.9-NA). Subsequent chemotherapy was given to 83.3% of 30 progressed pts. There were no MSI-H/dMMR or EBV-positive pts. PD-L1 status (57.1% of pts ≥ CPS 1 and 14.3% of pts ≥ CPS 10 among 35 pts), metastatic organ or baseline tumor burden was not related to the survival. Treatment-related AE (≥G3) occurred in 32 pts (74.4%) including 17 pts (39.5%) with neutropenia G3-4. Immune-related AEs (≥G3) occurred in 4 pts (10%). Ninety-six tumor tissues from 32 pts (paired tumor tissues from 25 pts) were analyzed with targeted NGS. TMB (median 12.7 mut/MB with range of 9.45-16.71) was not related to the PD-L1 expression or survival. Conclusions: First-line triplet regimen (Pembrolizumab, Trastuzumab, and Chemotherapy) confers a significant tumor shrinkage for HER2 positive AGC, regardless of PD-L1 status. Phase III Keynote-811 study (NCT03615326) is ongoing based on the protocol of this study. Clinical trial information: NCT02901301 . [Table: see text]

Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).

4039 Background: In the BEACON CRC study, the triplet regimen of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) significantly improved overall survival (OS, HR:0.52, P < 0.0001) and objective response rates (ORR, 26% vs 2%, P < 0.0001) in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) compared with current standard of care. This analysis focuses on the patient-reported quality of life (QOL) assessments from this study. Methods: The BEACON CRC study was a randomized, open-label, 3-arm, phase 3 global study which evaluated triplet (ENCO+BINI+CETUX) or doublet (ENCO+CETUX) vs. investigator’s choice of irinotecan + CETUX or FOLFIRI + CETUX in pts with BRAFV600E mCRC. QOL assessments (secondary endpoints in the trial) included the EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The primary assessment for the QOL variables was the time to definitive 10% deterioration. The study is ongoing. Results: 665 pts were randomly assigned to receive either triplet (n = 224), doublet (n = 220), or control (n = 221). Reduction in the risk of QOL deterioration was an estimated 45% (HR 0.55, 95% CI: 0.43, 0.70) and 52% (HR 0., 9485% CI: 0.38, 0.62) in EORTC QLQ C30 and FACT C assessments, respectively, in favor of the triplet regimen over control. For the doublet vs. control, reduction in risk of QOL deterioration was an estimated 46% (HR 0.54, 95% CI: 0.43, 0.69) and 54% (HR 0.46, 95% CI: 0.36, 0.59) in EORTC QLQ C30 and FACT C, respectively in favor of the doublet. Similar results were observed in EuroQol 5D 5L and PGIC assessments. There were no overall differences in QOL between triplet and doublet across the 4 instruments. Conclusions: In BEACON CRC, triplet and doublet demonstrated substantial improvement in patient-reported QOL assessments over the current standard of care in pts with BRAFV600E-mutant metastatic CRC whose disease had progressed after 1 or 2 prior regimens. Clinical trial information: NCT02928224 .