Background
In the phase 3 KEYNOTE-061 study (cutoff: 10/26/2017), pembrolizumab did not significantly prolong OS vs paclitaxel as second-line (2L) therapy in PD-L1 combined positive score (CPS) ≥ 1 ...gastric/GEJ cancer. We present results in CPS ≥ 1, ≥ 5, and ≥ 10 populations after two additional years of follow-up (cutoff: 10/07/2019).
Methods
Patients were randomly allocated 1:1 to pembrolizumab 200 mg Q3W for ≤ 35 cycles or standard-dose paclitaxel. Primary endpoints: OS and PFS (CPS ≥ 1 population). HRs were calculated using stratified Cox proportional hazards models.
Results
366/395 patients (92.7%) with CPS ≥ 1 died. Pembrolizumab demonstrated a trend toward improved OS vs paclitaxel in the CPS ≥ 1 population (HR, 0.81); 24-month OS rates: 19.9% vs 8.5%. Pembrolizumab incrementally increased the OS benefit with PD-L1 enrichment (CPS ≥ 5: HR, 0.72, 24-month rate, 24.2% vs 8.8%; CPS ≥ 10: 0.69, 24-month rate, 32.1% vs 10.9%). There was no difference in median PFS among treatment groups (CPS ≥ 1: HR, 1.25; CPS ≥ 5: 0.98; CPS ≥ 10: 0.79). ORR (pembrolizumab vs paclitaxel) was 16.3% vs 13.6% (CPS ≥ 1), 20.0% vs 14.3% (CPS ≥ 5), and 24.5% vs 9.1% (CPS ≥ 10); median DOR was 19.1 months vs 5.2, 32.7 vs 4.8, and NR vs 6.9, respectively. Fewer treatment-related AEs (TRAEs) occurred with pembrolizumab than paclitaxel (53% vs 84%).
Conclusion
In this long-term analysis, 2L pembrolizumab did not significantly improve OS but was associated with higher 24-month OS rates than paclitaxel. Pembrolizumab also increased OS benefit with PD-L1 enrichment among patients with PD-L1-positive gastric/GEJ cancer and led to fewer TRAEs than paclitaxel.
Trial registration
ClinicalTrials.gov, NCT02370498
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors.
To evaluate the antitumor activity of ...pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received.
This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively.
Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062.
Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing.
At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months 95% CI, 2.0-9.8 months for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy.
Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received.
ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.
ObjectivesLarge disparities in colorectal cancer (CRC) management and survival have been observed across Europe. Despite recent increases, the survival deficit of Estonian patients with CRC persists, ...particularly for rectal cancer. The aim of this study was to examine diagnostic, staging and treatment patterns of CRC in Estonia, comparing clinical data from 1997 and 2011.DesignNationwide population-based retrospective study.SettingEstonia.ParticipantsAll incident cases of colon and rectal cancer diagnosed in 1997 and 2011 identified from the Estonian Cancer Registry. Clinical data gathered from medical records.Outcome measuresDifferences in diagnostic, staging and treatment patterns; 5-year relative survival ratios.ResultsThe number of colon cancer cases was 337 in 1997 and 498 in 2011; for rectal cancer, the respective numbers were 209 and 349. From 1997 to 2011, large increases were seen in the use of colonoscopy and lung and liver imaging. Radical resection rate increased from 48% to 59%, but emergency surgeries showed a rise from 18% to 26% in colon and from 7% to 14% in rectal cancer. The proportion of radically operated patients with ≥12 lymph nodes examined pathologically increased from 2% to 58% in colon cancer and from 2% to 50% in rectal cancer. The use of neoadjuvant radiotherapy increased from 6% to 39% among stage II and from 20% to 50% among patients with stage III rectal cancer. The use of adjuvant chemotherapy in stage III colon cancer increased from 42% to 63%. The 5-year RSR increased from 50% to 58% in colon cancer and from 37% to 64% in patients with rectal cancer.ConclusionsMajor improvements were seen in the diagnostics, staging and treatment of CRC in Estonia contributing to better outcomes. Increase in emergency surgeries highlights possible shortcomings in timely diagnosis and treatment.
There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly ...selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer.
We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine–tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1–21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine–tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting.
Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3–6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7–8·2) in the fruquintinib group versus 4·8 months (4·0–5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55–0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 14%), asthenia (n=35 8%), and hand-foot syndrome (n=29 6%). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group).
Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population.
HUTCHMED.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To observe changes in symptoms and health-related quality of life (HRQoL) over 7 years among cancer patients at different stages of the disease.
This prospective cross-sectional study at the Helsinki ...University Hospital Cancer Center, was carried out in 2006 and repeated in 2013. All participants filled in the EORTC-QLQ-C30 questionnaire.
Altogether, 581 patients responded (49% in 2006 and 54% in 2013). The disease was local in 51% and advanced in 49% of patients. The HRQoL was significantly lower, except for emotional and cognitive functions, and the symptom burden more severe in advanced cancer. The most prevalent symptoms were fatigue (93% and 85%; moderate/severe 22% and 9%), pain (65% and 47%; moderate/severe 16% and 5%), and insomnia (64% and 60%; moderate/severe 20 and 21%), respectively. No changes in HRQoL or symptoms were found at 7 years.
There is a need for early integrated palliative care to improve HRQoL during cancer treatments.
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Background: 10-20% of GC are HER-2 positive. The role of perioperative anti-HER2-directed treatment is yet undefined. Methods: This randomized, open-label phase II-trial investigates the benefit ...of combining T alone or with P and perioperative CT for GC and EGJC. Between 2015 and 2021,172 of a planned 215 patients (pts) with centrally confirmed, positive HER-2 status and resectable GC or EGJC (UICC TNM stages Ib-III) were included. Recruitment was prematurely terminated due to slow accrual. Pts were randomized in a 1:2:2 ratio to: Arm A (CT alone) (35 pts); Arm B (CT+ T 8mg/kg, followed by 6mg every 3 weeks) (67 pts); Arm C (CT + T+ P 840mg every 3 weeks) (70 pts). CT was initially cisplatin (80 mg/m
2
d1) and capecitabine (2 x 1000 mg/m
2
/d d1) for 3 cycles before and after surgery. After publication of the FLOT-4 study, the protocol was amended. CT changed to four cycles FLOT (Al-Batran Lancet 2019) with FOLFOX or CAPOX as alternative for pts ineligible for FLOT. In the experimental arms, T and P were continued beyond CT at the same dose for a total of 17 cycles. Major pathological response rate (mpRR) determined by central pathology review was the primary endpoint. The study was designed to have 80% power to detect an increase in mpRR from 25% with CT to 45% with CT+T+P or CT+T with a one-sided alpha of 10%. CT+T+P was first tested versus CT and if positive, CT+T would be tested versus CT. Results: Out of 172 pts randomized, 161 fulfilled all important eligibility criteria and started their allocated treatment (per protocol population). 62.1% of pts had EGJC and 72.0% an intestinal subtype. Main CT regimens were cisplatin+capecitabine (42.2%) and FLOT (46.6%). In Arm A:B:C, 90.9%, 92.2% and 81.3% completed neoadjuvant treatment. Major reason for treatment discontinuation was toxicity (70%). Surgery was performed in 84.8%, 98.4%, 92.2% pts in Arm A:B:C. R0 resection rates were 83.9%, 90.3% and 85.9%. At present, results of central pathology review of mpRR are available for 126 out of 150 operated pts (84.0%). Pts not operated (n=11) were considered as failures for mpRR. MpRR was 23.3%, 37.0%, 26.4% in Arm A:B:C. The increase of 3.1% (80% CI: -9.5%, 15.7%, one-sided p=0.378) in Arm C vs. A was not statistically significant. The increase in Arm B vs. A was 13.7% (80% CI: 0.7%,26.7%, one-sided p=0.099). MpRR was 33.3%, 53.3% and 37.9% in Arm A:B:C after amending the protocol while, in contrast, it was 8.3%, 16.7% and 12.5% before. Conclusions: The primary endpoint analysis did not meet the pre-specified criteria of efficacy for the combination of CT+T+P. However, CT+T showed interesting response rates, especially with FLOT as CT backbone. Follow-up data including survival is necessary to define the clinical value of this regimen. Clinical trial information: NCT02205047 .
We assessed the treatment effect of panitumumab plus best supportive care (BSC) vs BSC on overall survival (OS) in patients with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer ...(mCRC) and report the first prospective extended RAS analysis in a phase 3 trial.
Patients with wild-type KRAS exon 2 mCRC were randomised 1 : 1 to panitumumab (6 mg kg
Q2W) plus BSC or BSC. On-study crossover was prohibited. RAS mutation status was determined by central laboratory testing. The primary endpoint was OS in wild-type KRAS exon 2 mCRC; OS in wild-type RAS mCRC (KRAS and NRAS exons 2, 3, and 4) was a secondary endpoint.
Three hundred seventy seven patients with wild-type KRAS exon 2 mCRC were randomised. Median OS was 10.0 months with panitumumab plus BSC vs 7.4 months with BSC (HR=0.73; 95% CI=0.57-0.93; P=0.0096). RAS ascertainment was 86%. In wild-type RAS mCRC, median OS for panitumumab plus BSC was 10.0 vs 6.9 months for BSC (HR=0.70; 95% CI=0.53-0.93; P=0.0135). Patients with RAS mutations did not benefit from panitumumab (OS HR=0.99; 95% CI=0.49-2.00). No new safety signals were observed.
Panitumumab significantly improved OS in wild-type KRAS exon 2 mCRC. The effect was more pronounced in wild-type RAS mCRC, validating previous retrospective analyses.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD).
...Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD.
Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended.
These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.
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•Multidisciplinary European clinical practice guidelines were developed.•One organ with ≤ 3 metastases is considered OMD.•One extra-regional lymph node station is considered OMD.•Patients with OMD undergo systemic therapy followed by restaging.•Patients without progression at 18F-FDG PET/CT restaging undergo local treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Smoking cessation after a cancer diagnosis is associated with improved overall survival. Few studies have reported oncologists' cessation practice patterns, but differences between the curative and ...palliative settings have not been described. We aimed to study the oncologist's perceptions on patients' tobacco use, current practices and barriers to providing smoking cessation support, while distinguishing between treatment with curative (C) and palliative (P) intent.
In 2019, an online 34-item survey was sent to approximately 6235 oncologists from 16 European countries. Responses were descriptively reported and compared by treatment setting.
Responses from 544 oncologists were included. Oncologists appeared to favour addressing tobacco in the curative setting more than in the palliative setting. Oncologists believe that continued smoking impacts treatment outcomes (C: 94%, P: 74%) and that cessation support should be standard cancer care (C: 95%, P: 63%). Most routinely assess tobacco use (C: 93%, P: 78%) and advise patients to stop using tobacco (C: 88%, P: 54%), but only 24% (P)–39% (C) routinely discuss medication options, and only 18% (P)–31% (C) provide cessation support. Hesitation to remove a pleasurable habit (C: 13%, P: 43%) and disbelieve on smoking affecting outcomes (C: 3%, P: 14%) were disparate barriers between the curative and palliative settings (p < 0.001), but dominant barriers of time, resources, education and patient resistance were similar between settings.
Oncologists appear to favour addressing tobacco use more in the curative setting; however, they discuss medication options and/or provide cessation support in a minority of cases. All patients who report current smoking should have access to evidence-based smoking cessation support, also patients treated with palliative intent given their increasing survival.
•Most oncologists ask about tobacco use and advise patients to quit, but few provide assistance to help patients quit smoking.•Oncologists address tobacco use more frequently in the curative setting than in the palliative setting.•Inability, resistance, lack of time, education and resources were barriers comparable in curative and palliative setting.•Smoking cessation programs should be available to all patients who report smoking.•Given the increasing survival of stage IV patients, smoking cessation should be focused on in the palliative setting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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