Quality-adjusted time without symptoms or toxicity analysis of nivolumab plus chemotherapy versus chemotherapy alone for the management of previously untreated patients with advanced gastric cancer,gastroesophageal junction cancer,or esophageal adenocarcinoma

Background

The phase 3 CheckMate 649 established superior overall survival of nivolumab in combination with chemotherapy (NIVO + chemo) compared with chemotherapy (chemo) alone as a first-line treatment for patients with Her2-negative advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC). This post hoc trial analysis aimed to evaluate the benefit of NIVO + chemo using quality-adjusted time without symptoms or toxicity (Q-TWiST) to further account for quality of life (QoL) in different health states depending on disease progression and treatment toxicity.

Methods

Using data from CheckMate 649, we evaluated the quality-adjusted survival gain associated with NIVO + chemo compared with chemo alone among all randomized patients and repeated similar analyses among those with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5. Relative Q-TWiST gains of ≥ 10% were predefined as clinically important.

Results

In all randomized patients, those receiving NIVO + chemo had a mean Q-TWiST gain of 1.8 (95% CI 0.9, 2.7) months compared with those receiving chemo alone. The relative Q-TWiST gain was estimated to be 12.8%. Patients with PD-L1 CPS ≥ 5 had greater quality-adjusted survival gain from NIVO + chemo with an estimated Q-TWiST gain of 2.8 (95% CI 1.5, 4.1) months, representing a relative gain of 20.6%. Subgroup analyses and sensitivity analyses with various QoL utility values yielded consistent findings in favor of NIVO + chemo compared with chemo alone. Q-TWiST gain from NIVO + chemo increased with longer duration of follow-up.

Conclusions

NIVO + chemo was associated with a statistically significant and clinically important gain in quality-adjusted survival compared with chemo alone among previously untreated patients with advanced GC/GEJC/EAC.

     

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in advanced non-small cell lung cancer: a subanalysis of Asian patients in CheckMate 9LA

International Journal of Clinical Oncology - CheckMate 9LA, a phase 3, randomized, open-label study in first-line advanced non-small cell lung cancer (NSCLC), showed significantly improved overall...     

Apatinib plus S-1 for previously treated,advanced gastric or gastro-oesophageal junction adenocarcinoma: a phase 2, single-arm,prospective study

BackgroundThe current management of advanced gastric or gastro-oesophageal junction adenocarcinoma remains unsatisfactory. We investigated the efficacy and safety of the combination therapy of apatinib and S-1, considering the potential advantage of home-based treatment without hospital admission, in patients with platinum-refractory gastric or gastro-oesophageal junction adenocarcinoma.MethodsIn this open-label, single-arm, phase 2 trial, in each 21-day cycle, eligible patients received apatinib at an initial dose of 500 mg once daily continuously and S-1 at a dose of 40–60 mg twice daily on days 1–14 until the trail was discontinued disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoints were progression-free survival. The secondary endpoints were objective response rates, disease control rates, and safety, and overall survival. This study was registered at ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT04338438","term_id":"NCT04338438"}}NCT04338438.ResultsBetween April 2015 and May 2019, we included 37 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma refractory to first-line platinum-containing therapy. At the data cutoff, the 6-month progression-free survival was 31.5%, the median progression-free survival and overall survival were 4.2 (95% CI: 3.50–4.90) months and 8.2 (95% CI: 4.69–11.71) months, respectively. Of 37 eligible patients, 8 (21.6%) patients reached objective responses, 31 (83.8%) patients reached disease control. Grade 3 or 4 adverse events occurred in 8 (21.6%) patients, including hand-foot syndrome, hypertension, and diarrhea, etc.ConclusionsThe combination of Apatinib and S-1 showed promising efficacy and manageable toxicity as a home-based, second-line therapy in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, especially for the elder patients with poor performance status.Trial Registration{"type":"clinical-trial","attrs":{"text":"NCT04338438","term_id":"NCT04338438"}}NCT04338438.     

Clinical outcome of patients with Ewing sarcoma family of tumors of bone in Japan: the Japanese Musculoskeletal Oncology Group cooperative study

BACKGROUND: Ewing sarcoma family of tumors (ESFT) of bone is extremely rare in Japan. The objectives of the current study were to assess the clinical outcome and prognostic factors of patients with ESFT of bone in Japan and to compare them between Euro-American and Japanese populations. METHODS: The authors conducted a retrospective analysis of 243 patients who were treated for ESFT of bone in Japan between 1981 and 2003. Local therapy was surgery in 35% of patients, surgery combined with radiotherapy in 40% of patients, radiotherapy alone in 22% of patients, and no local treatment in 3% of patients. All but 3 patients received various regimens of multidrug chemotherapy. RESULTS: The median patient age was 16 years. The primary disease sites were the trunk in 53% of patients and the extremities in 47% of patients. Forty-one patients had metastases at presentation. The median follow-up was 66 months. A univariate survival analysis demonstrated that patients who had metastases at presentation, primary site in the trunk, age >or=16 years, tumor size >or=10 cm, tumor that responded poorly to induction chemotherapy, and local treatment with radiotherapy alone had a significantly worse event-free survival (EFS). A multivariate analysis further verified that the former 3 factors were significant adverse prognostic factors. Of 201 patients with localized disease, 45 patients who received current chemotherapy regimens that included ifosfamide and etoposide had a significantly better 5-year EFS rate (67.6%) compared with other patients. CONCLUSIONS: The clinical outcome of patients with localized ESFT of bone in Japan has improved markedly with the use of current chemotherapy regimens that include ifosfamide and etoposide and has become comparable to the outcomes observed in other major series of Euro-American patients. The prognostic factors are also almost identical.     

Triple negative status is a poor prognostic indicator in Chinese women with breast cancer: a ten year review

Background: Ethnic variation in tumor characteristics and clinical presentation of breast cancer is increasinglybeing emphasized. We studied the tumor characteristics and factors which may influence the presentation andprognosis of triple negative breast cancers (TNC) in a cohort of Chinese women. Methods: A prospective cohortof 1800 Chinese women with breast cancer was recruited in a tertiary referral unit in Hong Kong between1995 and 2006 and was followed up with a median duration of 7.2 years. Of the total, 216 (12.0%) had TNCand 1584 (88.0%) had non-TNC. Their clinicopathological variables, epidemiological variables and clinicaloutcomes were evaluated. Results: Patients with TNC had similar age of presentation as those with non-TNC,while presenting at earlier stages (82.4% were stage 1-2, compared to 78.4% in non-TNC, p=0.035). They werelikely to be associated with grade 3 cancer (Hazard Ratio(HR)=5.8, p<0.001). TNC showed higher chance ofvisceral relapse (HR=2.69, p<0.001), liver metastasis (HR=1.7, p=0.003) and brain metastasis (HR=1.8, p=0.003).Compared with non-TNC group, TNC had similar 10-year disease-free survival (82% vs 84%, p=0.148), overallsurvival (78% vs 79%, p=0.238) and breast cancer-specific mortality (18% vs 16%, p=0.095). However, TNCshowed poorer 10-year stage 3 and 4 specific survival (stage 3: 53% vs. 67%, p=0.010; stage 4: 0% vs. 40%, p= 0.035). Conclusions: Chinese women with triple negative breast cancer do not have less aggressive biologicalbehavior compared to the West and presentation at a later stage results in worse prognosis compared with thosewith non triple negative breast cancer.     

Long-term Outcomes with Nivolumab as First-line Treatment in Recurrent or Metastatic Head and Neck Cancer: Subgroup Analysis of CheckMate 141

In the randomized, phase 3 CheckMate 141 trial, nivolumab significantly improved overall survival (OS) versus investigator’s choice (IC) of chemotherapy at primary analysis among 361 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) post-platinum therapy. Nivolumab versus IC as first-line treatment also improved OS among patients with R/M SCCHN who progressed on platinum therapy for locally advanced disease in the adjuvant or primary setting at 1-year follow-up. In the present long-term follow-up analysis of patients receiving first-line treatment, OS benefit with nivolumab (n = 50) versus IC (n = 26) was maintained (median: 7.7 months versus 3.3 months; hazard ratio: 0.56; 95% confidence interval, 0.34-0.94) at 2 years. No new safety signals were identified. In summary, this long-term 2-year analysis of CheckMate 141 supports the use of nivolumab as a first-line treatment for patients with platinum-refractory R/M SCCHN.     

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204)

BackgroundIn patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients.MethodsPatients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months).ResultsSymptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed.ConclusionsNivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02320058","term_id":"NCT02320058"}}NCT02320058.     

多西他赛联合替加氟和顺铂治疗晚期胃癌疗效观察

目的：观察多西他赛联合顺铂、替加氟（DCF1方案）治疗晚期胃癌的疗效和不良反应。方法：采用DCFt方案治疗66例晚期胃癌患者。多西他赛75m／m^2,d1;顺铂75m／m^2,d1;替加氟20mg／kg,静脉滴注d。天,3周1个周期,至少2个周期。结果166例晚期胃癌中,完全缓解（CR）0例,部分缓解（PR）36例（54．5％）,稳定（SD）16例（24．2％）,进展（PD）14例（21．2％）。中位肿瘤进展时间为6．1个月（3．5—11．5个月）,中位总生存期为11．2个月（6．0—14．5个月）。最常见的不良反应为骨髓抑制、消化道反应及可逆性体液潴留,不良反应多为Ⅰ-Ⅱ度,无Ⅳ度不良反应发生。骨髓抑制以自细胞减少为特点,血小板减少及贫血较轻。消化道反应主要表现为恶心呕吐、腹泻便秘。无治疗相关性死亡。结论：DCFt方案是治疗晚期胃癌安全有效的化疗方案。     

Combination of folinic acid, 5-fluorouracil bolus and infusion, and cisplatin (LV5FU2-P regimen) in patients with advanced gastric or gastroesophageal junction carcinoma.

BACKGROUND: Combination chemotherapy with continuous 5-fluorouracil (5-FU) and cisplatin in a monthly regimen is one of the standard treatments for advanced gastric carcinoma. This study evaluated the new LV5FU2-P regimen, designed to improve efficacy and tolerance of the 5-FU plus cisplatin combination. PATIENTS AND METHODS: Forty-three patients with advanced or metastatic gastroesophageal junction or gastric carcinoma were prospectively included in the study. They were treated every 14 days with cisplatin 50 mg/m(2) on day 2 plus folinic acid 200 mg/m(2)/day as a 2-h intravenous (i.v.) infusion on days 1 and 2, plus bolus 5-FU 400 mg/m(2)/day on days 1 and 2, plus continuous 5-FU 600 mg/m(2)/day as a 22-h i.v. infusion on days 1 and 2. Ten patients received a simplified regimen (folinic acid 40 mg/m(2) day 1 + bolus 5-FU 400 mg/m(2) day 1 + continuous 5-FU 2400 mg/m(2) on days 1 and 2 with cisplatin 50 mg/m(2) on day 2). RESULTS: All the patients were assessable for response and 42 for toxicity. One patient achieved a complete response and 15 a partial response, for an overall response rate of 37.2% [95% confidence interval (CI) 22.1% to 52.3%]. The median progression-free survival was 7.2 months (95% CI 5.4-10.9) and the overall survival was 13.3 months (95% CI 10.1-16.4). There were no treatment-related deaths. Hematological and gastrointestinal toxicities were the most common severe toxicities. CONCLUSIONS: LV5FU2-P is an active and well tolerated regimen in the treatment of advanced gastroesophageal junction or gastric carcinomas. It warrants evaluation comparatively with other active regimens.     

First-line panitumumab plus docetaxel and cisplatin in advanced gastric and gastro-oesophageal junction adenocarcinoma: results of a phase II trial

Clinical and Translational Oncology - Panitumumab is extensively used for RAS-WT metastatic colorectal cancer. This study assessed the efficacy and safety of panitumumab plus first-line...     

改良DOC联合DDP和5-FU一线治疗晚期胃癌及胃食管结合部癌的临床观察

目的 探讨多西他赛(docetaxel,DOC)联合顺铂(DDP)和5-氟尿嘧啶(5-FU)一线治疗晚期胃癌和胃食管结合部癌的临床疗效和不良反应.方法 回顾性分析80例晚期胃癌及胃食管结合部癌患者,接受改良双周DCF方案化疗;具体为多西他赛37.5 mg/m2第1、8天静脉滴注;顺铂20 mg/m2第1-2、8-9天静脉滴注;5-氟尿嘧啶1.0 g/m2第1、8天用药,每次微泵持续静脉滴注48小时,21天为l周期,治疗≥2周期,分析其疗效和不良反应.结果78例患者接受平均4.7周期(2-11周期)的改良双周DCF方案的化疗,均无化疗相关性死亡,总有效率为35.9％ (28/78);疾病控制率为78.2％ (61/78),中位疾病进展时间为5.0月(95％ CI:4.3-5.7月),中位生存时间8.9月(95％ CI:6.8-11.0月);1年的生存率33.3％(26/78).结论 对于不能耐受3周方案的晚期胃癌及胃食管结合部癌患者,采用改良双周DCF方案一线治疗疗效肯定且不良反应可耐受,值得临床进一步应用.     

Efficacy of ramucirumab combination chemotherapy as second-line treatment in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction after exposure to checkpoint inhibitors and chemotherapy as first-line therapy

FOLFOX plus nivolumab represents a standard of care for first-line therapy of advanced gastroesophageal cancer (aGEC) with positive PD-L1 expression. The efficacy of second-line VEGFR-2 inhibition with ramucirumab (RAM) plus chemotherapy after progression to immunochemotherapy remains unclear. Medical records of patients with aGEC enrolled in the randomized phase II AIO-STO-0417 trial after treatment failure to first-line FOLFOX plus nivolumab and ipilimumab were retrospectively analyzed. Patients were divided into two groups based on second-line therapy: RAM plus chemotherapy (RAM group) or treatment without RAM (control group). Eighty three patients were included. In the overall population, progression-free survival (PFS) in the RAM group was superior to the control (4.5 vs 2.9 months). Responders (CR/PR) to first-line immunochemotherapy receiving RAM containing second-line therapy had prolonged OS from start of first-line therapy (28.9 vs 16.5 months), as well as second-line OS (9.6 vs 7.5 months), PFS (5.6 vs 2.9 months) and DCR (53% vs 29%) compared to the control. PD-L1 CPS ≥1 was 42% and 44% for the RAM and the control, respectively. Patients with CPS ≥1 in the RAM group showed better tumor control (ORR 25% vs 10%) and improved survival (total OS 11.5 vs 8.0 months; second-line OS 6.5 vs 3.9 months; PFS 4.5 vs 1.6 months) compared to the control. Prior exposure to first-line FOLFOX plus dual checkpoint inhibition followed by RAM plus chemotherapy shows favorable response and survival rates especially in patients with initial response and positive PD-L1 expression and has the potential to advance the treatment paradigm in aGEC.     

First-line cetuximab plus capecitabine in elderly patients with advanced colorectal cancer: clinical outcome and subgroup analysis according to KRAS status from a Spanish TTD Group Study

Single-agent cetuximab is safe and active in elderly patients with advanced colorectal cancer (CRC). A cetuximab–capecitabine combination has not previously been tested in elderly patients with advanced CRC.

Material and Methods.

Sixty-six patients with advanced CRC were treated with cetuximab as a 400 mg/m² i.v. infusion followed by 250 mg/m² i.v. weekly plus capecitabine at a dose of 1,250 mg/m² every 12 hours. After the inclusion of 27 patients, the protocol was amended for safety reasons, reducing the dose of capecitabine to 1,000 mg/m² every 12 hours. Thirty-nine additional patients were treated with the reduced dose of capecitabine.

Results.

The overall response rate was 31.8%. KRAS status was determined in 58 patients (88%). Fourteen of 29 patients with wild-type KRAS tumors responded (48.3%; 95% confidence interval [CI], 29.4%–67.5%), compared with six of 29 patients with mutant KRAS tumors (20.7%; 95% CI, 8.0%–39.7%). The median progression-free survival (PFS) interval was 7.1 months. The median PFS interval for patients whose tumors were wild-type KRAS was significantly longer than for those with mutant KRAS tumors (8.4 months versus 6.0 months; p = .024). The high incidence of severe paronychia (29.6%) declined (7.7%) after capecitabine dose adjustment.

Conclusions.

Cetuximab plus capecitabine at a dose of 1,000 mg/m² every 12 hours may be an alternative to more aggressive regimens in elderly patients with advanced wild-type KRAS CRC.     

Docetaxel (Taxotere), cisplatin, UFT, and leucovorin combination chemotherapy in advanced gastric cancer

We conducted this study to ascertain the efficacy and toxicity of docetaxel and cisplatin combined with oral UFT and leucovorin as a first-line treatment for patients with advanced gastric cancer. In all, 52 patients received courses of docetaxel 60 mg m(-2) intravenously (i.v.) for 1 h and then cisplatin 75 mg m(-2) i.v. for 2 h on day 1. Oral UFT at 400-600 mg day(-1), as determined by body surface area, and leucovorin at 75 mg day(-1) were administered for 21 consecutive days from day 1, and this was followed by a 7-day drug-free interval. A total of 225 courses were administered, and the median number of courses per patient was four. Four complete responses (7.7%) and 22 partial responses (42.3%) were achieved, giving an overall response rate of 50% (95% Confidence Interval: 36.4-63.6%). The major toxicity was neutropenia, which reached grade 3/4 in 36 patients (69.3%). Grade 3/4 nausea and vomiting was observed in 12 patients (23.1%). Median time to progression was 22 weeks (4 to 156+ weeks), median survival duration was 48 weeks (4 to 156+ weeks), and median response duration was 24 weeks (6-152 weeks). We conclude that docetaxel, cisplatin, oral UFT, and leucovorin combination chemotherapy is effective and tolerable for the treatment of advanced gastric cancer.