The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost. Evidence for clinical benefit from new treatment options is ...derived from clinical research, in particular phase III randomised trials, which generate unbiased data regarding the efficacy, benefit and safety of new therapeutic approaches. To date, there is no standard tool for grading the magnitude of clinical benefit of cancer therapies, which may range from trivial (median progression-free survival advantage of only a few weeks) to substantial (improved long-term survival). Indeed, in the absence of a standardised approach for grading the magnitude of clinical benefit, conclusions and recommendations derived from studies are often hotly disputed and very modest incremental advances have often been presented, discussed and promoted as major advances or ‘breakthroughs’. Recognising the importance of presenting clear and unbiased statements regarding the magnitude of the clinical benefit from new therapeutic approaches derived from high-quality clinical trials, the European Society for Medical Oncology (ESMO) has developed a validated and reproducible tool to assess the magnitude of clinical benefit for cancer medicines, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). This tool uses a rational, structured and consistent approach to derive a relative ranking of the magnitude of clinically meaningful benefit that can be expected from a new anti-cancer treatment. The ESMO-MCBS is an important first step to the critical public policy issue of value in cancer care, helping to frame the appropriate use of limited public and personal resources to deliver cost-effective and affordable cancer care. The ESMO-MCBS will be a dynamic tool and its criteria will be revised on a regular basis.
The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.0 (v1.0) was published in May 2015 and was the first version of a validated and reproducible tool to assess the magnitude of ...clinical benefit from new cancer therapies. The ESMO-MCBS was designed to be a dynamic tool with planned revisions and updates based upon recognition of expanding needs and shortcomings identified since the last review.
The revision process for the ESMO-MCBS incorporates a nine-step process: Careful review of critiques and suggestions, and identification of problems in the application of v1.0; Identification of shortcomings for revision in the upcoming version; Proposal and evaluation of solutions to address identified shortcomings; Field testing of solutions; Preparation of a near-final revised version for peer review for reasonableness by members of the ESMO Faculty and Guidelines Committee; Amendments based on peer review for reasonableness; Near-final review by members of the ESMO-MCBS Working Group and the ESMO Executive Board; Final amendments; Final review and approval by members of the ESMO-MCBS Working Group and the ESMO Executive Board.
Twelve issues for revision or amendment were proposed for consideration; proposed amendments were formulated for eight identified shortcomings. The proposed amendments are classified as either structural, technical, immunotherapy triggered or nuanced. All amendments were field tested in a wide range of studies comparing scores generated with ESMO-MCBS v1.0 and version 1.1 (v1.1).
ESMO-MCBS v1.1 incorporates 10 revisions and will allow for scoring of single-arm studies. Scoring remains very stable; revisions in v1.1 alter the scores of only 12 out of 118 comparative studies and facilitate scoring for single-arm studies.
Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterised by limited treatment options and a poor prognosis. At relapse after platinum-based chemotherapy, single-agent ...chemotherapy is commonly used and single-arm trials of immune-checkpoint inhibitors have demonstrated encouraging activity.
PROMISE-meso is an open-label 1:1 randomised phase III trial investigating the efficacy of pembrolizumab (200 mg/Q3W) versus institutional choice single-agent chemotherapy (gemcitabine or vinorelbine) in relapsed MPM patients with progression after/on previous platinum-based chemotherapy. Patients were performance status 0–1 and unselected for programmed cell death ligand 1 (PD-L1) status. At progression, patients randomly assigned to receive chemotherapy were allowed to crossover to pembrolizumab. The primary end point was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary end points were overall survival (OS), investigator-assessed PFS, objective response rate (ORR), and safety. Efficacy by PD-L1 status was investigated in exploratory analyses.
Between September 2017 and August 2018, 144 patients were randomly allocated (pembrolizumab: 73; chemotherapy: 71). At data cut-off 20 February 2019, median follow-up of 11.8 months (interquartile range: 9.9–14.5), 118 BICR-PFS events were observed. No difference in BICR-PFS was detected hazard ratio = 1.06, 95% confidence interval (CI): 0.73–1.53; P = 0.76, and median BICR-PFS (95% CI) for pembrolizumab was 2.5 (2.1–4.2), compared with 3.4 (2.2–4.3) months for chemotherapy. A difference in ORR for pembrolizumab was identified (22%, 95% CI: 13% to 33%), over chemotherapy (6%, 95% CI: 2% to 14%; P = 0.004). Forty-five patients (63%) assigned to chemotherapy received pembrolizumab at progression. With follow-up to 21 August 2019 17.5 months: (14.8–19.7), no difference in OS was detected between groups (HR = 1.12, 95% CI: 0.74–1.69; P = 0.59), even after adjusting for crossover. Pembrolizumab safety was consistent with previous observations. Exploratory efficacy analyses by PD-L1 status demonstrated no improvements in ORR/PFS/OS.
This is the first randomised trial evaluating the efficacy of pembrolizumab in MPM patients progressing after/on previous platinum-based chemotherapy. In biologically unselected patients, although associated with an improved ORR, pembrolizumab improves neither PFS nor OS over single-agent chemotherapy.
•First randomised, controlled trial evaluating efficacy of an anti-PD1 agent versus chemotherapy in relapsed MPM, with immunotherapy crossover allowed.•Objective response rate was significantly improved for pembrolizumab (22% versus 6%, P = 0.004).•No improvement for independently reviewed PFS for pembrolizumab over chemotherapy (HR = 1.06, 95% CI: 0.73–1.53, P = 0.76).•No overall survival improvement for pembrolizumab over chemotherapy (HR = 1.04, 95% CI: 0.66–1.67, P = 0.85).
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a systematic review and meta-analysis ...to assess its efficacy on previously treated advanced metastatic cutaneous melanoma. The PubMed electronic database was searched from inception to 17 December 2018 to identify studies administering TIL-ACT and recombinant interleukin-2 (IL-2) following non-myeloablative chemotherapy in previously treated metastatic melanoma patients. Objective response rate (ORR) was the primary end point. Secondary end points were complete response rate (CRR), overall survival (OS), duration of response (DOR) and toxicity. Pooled estimates were derived from fixed or random effect models, depending on the amount of heterogeneity detected. Analysis was carried out separately for high dose (HD) and low dose (LD) IL-2. Sensitivity analyses were carried out. Among 1211 records screened, 13 studies (published 1988 − 2016) were eligible for meta-analysis. Among 410 heavily pretreated patients (some with brain metastasis), 332 received HD-IL-2 and 78 LD-IL-2. The pooled overall ORR estimate was 41% 95% confidence interval (CI) 35% to 48%, and the overall CRR was 12% (95% CI 7% to 16%). For the HD-IL-2 group, the ORR was 43% (95% CI 36% to 50%), while for the LD-IL-2 it was 35% (95% CI 25% to 45%). Corresponding pooled estimates for CRR were 14% (95% CI 7% to 20%) and 7% (95% CI 1% to 12%). The majority of HD-IL-2 complete responders (27/28) remained in remission during the extent of follow-up after CR (median 40 months). Sensitivity analyses yielded similar results. Higher number of infused cells was associated with a favorable response. The ORR for HD-IL-2 compared favorably with the nivolumab/ipilimumab combination following anti-PD-1 failure. TIL-ACT therapy, especially when combined with HD-IL-2, achieves durable clinical benefit and warrants further investigation. We discuss the current position of TIL-ACT in the therapy of advanced melanoma, particularly in the era of immune checkpoint blockade therapy, and review future opportunities for improvement of this approach.
Anti-programmed cell death protein (death-ligand) 1 PD-(L)1 therapy alone cancer immunotherapy (CIT)-mono or combined with platinum-based chemotherapy (CIT-chemo) is used as the first-line treatment ...for patients with metastatic non-small-cell lung cancer (NSCLC). Our study compared clinical outcomes with CIT-mono versus CIT-chemo in the specific clinical scenario of non-squamous (Nsq)-NSCLC with a high PD-L1 expression of ≥50% tumor proportion score (TPS) or tumor cells (TC).
This was a retrospective cohort study using a real-world de-identified database. Patients with metastatic Nsq-NSCLC with high PD-L1 expression initiating first-line CIT-mono or CIT-chemo between 24 October 2016 and 28 February 2019 were followed up until 28 February 2020. We compared overall survival (OS) and real-world progression-free survival (rwPFS) using the Kaplan–Meier methodology. Hazard ratios (HRs) were adjusted (aHR) for differences in baseline key prognostic characteristics using the inverse probability of treatment weighting methodology.
Patients with PD-L1−high Nsq-NSCLC treated with CIT-mono (n = 351) were older and less often presented with de novo stage IV disease than patients treated with CIT-chemo (n = 169). With a median follow-up of 19.9 months for CIT-chemo versus 23.5 months for CIT-mono, median OS and rwPFS did not differ between the two groups median OS: CIT-chemo, 21.0 months versus CIT-mono, 22.1 months, aHR = 1.03, 95% confidence interval (CI) 0.77-1.39, P = 0.83; median rwPFS: CIT-chemo, 10.8 months versus CIT-mono, 11.5 months, aHR = 1.04, 95% CI 0.78-1.37, P = 0.81. CIT-chemo showed significant and meaningful improvement in OS and rwPFS versus CIT-mono only in the never-smoker subgroup, albeit among a small sample of patients (n = 50; OS HR = 0.25, 95% CI 0.07-0.83, interaction P = 0.02; rwPFS HR = 0.40, 95% CI 0.17-0.95, interaction P = 0.04).
Except in the subgroup of never-smoker patients, sparing the chemotherapy in first-line CIT treatment does not appear to impact survival outcomes in Nsq-NSCLC patients with high PD-L1 expression.
•PD-L1−high Nsq-NSCLC patients treated with CIT-mono versus CIT-chemo had older age and higher frequency of recurrent disease.•No difference was found in median OS between PD-L1-high Nsq-NSCLC patients treated with CIT-mono as compared to CIT-chemo.•No difference was found in median rwPFS between PD-L1-high Nsq-NSCLC patients treated with CIT-mono as compared to CIT-chemo.•In exploratory analysis, superior OS and rwPFS were found for the small never-smoker subgroup treated with CIT-chemo.
The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in ...oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018.
Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here.
Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man’s and 65% of the woman’s body mass, and is not taken into account in body-surface area based dosing of chemotherapy.
Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.
Summary Background Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of ...adjuvant bisphosphonate treatment in breast cancer. Methods We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal combining natural and artificial or not), and bisphosphonate class (aminobisphosphonate eg, zoledronic acid, ibandronate, pamidronate or other ie, clodronate). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). Findings We received data on 18 766 women (18 206 97% in trials of 2–5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002), distant recurrence (0·82, 0·74–0·92; 2p=0·0003), bone recurrence (0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75–0·97; 2p=0·02). Interpretation Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Funding Cancer Research UK, Medical Research Council.
•Immune- plus chemo-radiotherapy as promising strategy in curative setting of NSCLC.•Concurrent PD-1/L1-inhibition and radiotherapy not yet assessed in clinical trials.•Safety results of prospective ...trial of concurrent nivolumab and chemo-radiotherapy.•No unexpected adverse events or increased risk for severe pneumonitis observed.
Chemo-radiotherapy (CRT) and concurrent PD-1 inhibition has shown promising results in pre-clinical models. So far, the feasibility of delivering concurrent CRT and PD-1/PD-L1 inhibition has never been assessed in a clinical trial.
NICOLAS is a phase-II trial evaluating the safety and efficacy of nivolumab combined with CRT in stage III NSCLC. Patients received 3 cycles of platinum-based chemotherapy and concurrent RT (66 Gy/33fractions). Nivolumab started concurrently with RT. The primary endpoint was 6-month post-RT rate of grade-≥3-pneumonitis. A formal interim safety analysis (IA) was scheduled when the first 21 patients reached 3 months follow-up post-RT. An early positive safety conclusion would be reached at IA if there were no grade ≥3-pneumonitis in those patients. Efficacy evaluation was planned provided the safety conclusion was reached.
As of 13 December 2018, 82 patients were recruited with median follow-up of 13.4 months. The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed. For the first 21 patients, no grade-≥3-pneumonitis was observed by the end of the 3-month post-RT follow-up period.
The early safety IA provides evidence that the addition of nivolumab to concurrent CRT is safe and tolerable regarding the 6-month rate of pneumonitis grade ≥3 at the one-sided significance level of 5%. Following that, the 1-year progression-free survival will be evaluated in an expanded patient cohort. NICOLAS trial creates the opportunity for assessing the activity of the combination of checkpoint with concurrent CRT in larger prospective trials for locally advanced NSCLC.
Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL-ACT) has consistently shown efficacy in advanced melanoma. New results in the field provide now the opportunity to assess overall ...survival (OS) after TIL-ACT and to examine the effect of prior anti-PD-(L)1 therapy on its efficacy.
A comprehensive search was conducted in PubMed up to 29 February 2024. Ιn this meta-analysis we focused on studies including high-dose interleukin-2 (HD IL-2), doubling the patient numbers from our previous meta-analysis conducted up to December 20181 and using OS as the primary endpoint. Objective response rate (ORR), complete response rate (CRR) and duration of response (DOR) were secondary endpoints. Findings are synthesized using tables, Kaplan-Meier plots and forest plots. Pooled estimates for ORR and CRR were derived from fixed or random effect models.
A total of 13 HD IL-2 studies were included in this updated meta-analysis, with OS information available for 617 patients. No difference was found in median OS between studies with prior anti-PD-(L)1 treatment n=238; 17.5 months (95% confidence interval (CI):13.8-20.5) and without n=379; 16.3 months (95%CI:14.2-20.6) (log-rank p=0.53). ORR was estimated to be 34% (95%CI:16%-52%) and 44% (95%CI:37%-51%), for the studies with and without prior anti-PD-(L)1, respectively. The pooled estimate for CRR was 10% for both groups. No statistically significant difference was observed between the two groups, either for ORR (p=0.15) or CRR (p=0.45).
Prior anti-PD-(L)1 treatment has no effect on the clinical response or survival benefit from TIL-ACT in advanced cutaneous melanoma. The benefit of TIL therapy in the second-line setting is also present post anti-PD-(L)1 treatment. Our data reinforce the evidence that TIL-ACT should be considered as a treatment of choice in second-line for metastatic melanoma patients failing anti-PD-(L)1 therapy.
•This updated meta-analysis examines the efficacy of TIL-ACT therapy in advanced melanoma patients post anti-PD-(L)1 or not.•No significant survival or clinical response effect of prior anti-PD-(L)1 therapy was found when treated with TIL-ACT.•Further studies are needed to evaluate whether TIL-ACT should be proposed as front-line therapy in melanoma patients.
Therapeutic cancer vaccination is an area of interest, even though promising efficacy has not been demonstrated so far.
A systematic review and meta-analysis was conducted to evaluate vaccines’ ...efficacy on breast cancer (BC) and ovarian cancer (OC) patients. Our search was based on the PubMed electronic database, from 1st January 2000 to 4th February 2020.
response rate (ORR) was the primary end-point of interest, while progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Analysis was performed separately for BC and OC patients. Pooled ORRs were estimated by fixed or random effects models, depending on the detected degree of heterogeneity, for all studies with more than five patients. Subgroup analyses by vaccine type and treatment schema as well as sensitivity analyses, were implemented.
Among 315 articles initially identified, 67 were eligible for our meta-analysis (BC: 46, 1698 patients; OC: 32, 426 patients; where both BC/OC in 11). Dendritic-cell and peptide vaccines were found in more studies, 6/10 BC and 10/13 OC studies, respectively.
In our primary BC analysis (21 studies; 428 patients), the pooled ORR estimate was 9% (95%CI5%,13%). The primary OC analysis (12 studies; 182 patients), yielded pooled ORR estimate of 4% (95%CI1%,7%). Similar were the results derived in sensitivity analyses. No statistically significant differences were detected by vaccine type or treatment schema.
Median PFS was 2.6 months (95% confidence interval (CI)1.9,2.9) and 13.0 months (95%CI8.5,16.3) for BC and OC respectively, while corresponding median OS was 24.8 months (95%CI15.0,46.0) and 39.0 months (95%CI31.0,49.0). In almost all cases, the observed toxicity was only moderate.
Despite their modest results in terms of ORR, therapeutic vaccines in the last 20 years display relatively long survival rates and low toxicity. Since a plethora of different approaches have been tested, a better understanding of the underlying mechanisms is needed in order to further improve vaccine efficacy.
•First meta-analysis in therapeutic vaccines for breast/ovarian cancer.•Many alternative approaches have been tested in heterogeneous cohorts.•Most patients included in these studies were advanced and heavily pre-treated ones.•Response results are only modest, but survival rates are long and toxicity low.•More studies are needed to evaluate basic mechanisms and improve vaccines' efficacy.
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