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Background: The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) was designed to assess new immuno-oncology (IO) combinations in patients with advanced renal cell carcinoma (aRCC). We present results in IO-naive patients treated with nivolumab (NIVO) + relatlimab (RELA) or NIVO + ipilimumab (IPI) in track 1.

Methods: The open-label, randomised, phase II FRACTION-RCC trial enrolled patients with aRCC from 32 hospitals and cancer centres across six countries. Patients were enrolled in track 1 (IO-naive) or track 2 (IO-experienced). IO-naive patients were stratified by previous tyrosine kinase inhibitor therapy and randomised to NIVO (240 mg) + RELA (80 mg) intravenously once every 2 weeks or NIVO (3 mg/kg) + IPI (1 mg/kg) intravenously once every 3 weeks for four doses, followed by NIVO (480 mg) once every 4 weeks, each up to ∼2 years. The primary endpoints were objective response by investigator (RECIST version 1.1), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Safety was a secondary endpoint; biomarker analyses were exploratory.

Results: FRACTION-RCC enrolled patients between 2 February 2017 and 23 January 2020. In track 1, 30 patients each were treated with NIVO + RELA or NIVO + IPI (clinical database lock, 1 November 2021). With NIVO + RELA [median follow-up, 48.6 months; interquartile range (IQR) 46.9-51.7 months], objective response was 30% [95% confidence interval (CI) 15% to 49%], with 33 weeks (95% CI 16-53 weeks) median DOR. The PFS rate at 24 weeks was 43% (95% CI 25% to 60%). With NIVO + IPI (median follow-up, 48.7 months; IQR 47.1-52.0 months), the objective response was 20% (95% CI 8% to 39%), with the median DOR not reached (95% CI 33 weeks-not estimable). The PFS rate at 24 weeks was 49% (95% CI 29% to 66%). Higher baseline lymphocyte activation gene 3 (LAG-3) and programmed death-ligand 1 (PD-L1) expression levels were detected among track 1 NIVO + RELA responders. Grade 3-4 treatment-related adverse events were reported in 4/30 (13%) patients treated with NIVO + RELA and 10/30 (33%) patients treated with NIVO + IPI. No deaths were attributed to study treatments.

Conclusions: Results showed antitumour activity and manageable safety with NIVO + RELA. Findings also support NIVO + IPI as an effective combination regimen in IO-naive patients with aRCC.

Background: Drug regulators assess and describe uncertainties regarding treatment outcomes and the benefit-risk balance of newly authorised medicines. We aimed to evaluate the type and number of uncertainties described in the benefit-risk assessment for initial marketing authorisations of oncology medicines assessed by the European Medicines Agency (EMA). We also aimed to develop a systematic classification of uncertainties to contribute to improved communication about uncertainties.

Materials and methods: We included all medicines containing a new active substance assessed by the EMA and granted an initial marketing authorisation by the European Commission in 2011-2022 for an oncology indication. We extracted characteristics of these oncology medicines and uncertainties described under the benefit-risk balance section of European public assessment reports. Uncertainties were categorised and their frequencies stratified according to time of marketing authorisation, and medicine and regulatory characteristics.

Results: In total, 121 oncology medicines were included for which 800 (median 6, range 0-23) uncertainties were identified. Uncertainties were classified into five categories: safety (n = 404, 51%), efficacy (n = 322, 40%), pharmacology (n = 58, 7%), use in clinical practice (n = 10, 1%), and quality (n = 6, 1%). Among 27 subcategories, most uncertainties were related to specific adverse events (n = 156, 20%), effect size (n = 155, 20%), safety in subpopulations (n = 124, 16%), or efficacy in subpopulations (n = 88, 11%). The type of medicine (P = 0.012), type of marketing authorisation (P = 0.001), and year of marketing authorisation (P = 0.007) were associated with the number of uncertainties per medicine, with the highest number observed for cell and gene therapies [8 (3-23)], medicines granted conditional marketing authorisation [7 (3-23)], and medicines authorised in 2019-2022 [7 (2-23)].

Conclusion: At the time of initial marketing authorisation of oncology medicines, uncertainties about their benefit-risk balance most often concerned safety aspects, followed by efficacy. The number of uncertainties was highest for cell and gene therapies, conditionally authorised medicines, and medicines authorised in recent years.

Background: RECIST may not be optimal for assessing treatment response with current systemic regimens. We evaluated RECIST, morphologic, and pathologically documented response (pathological response) in patients with initially unresectable colorectal cancer liver-only metastases (CRLM).

Patients and methods: Four hundred and eighty-nine patients from the phase III CAIRO5 trial were included who were treated with FOLFOX/FOLFIRI/FOLFOXIRI and bevacizumab or panitumumab. The association of the different response tools with overall survival (OS) was evaluated for all patients, and with early recurrence (<6 months) for patients after complete local treatment.

Results: In the overall population, suboptimal [hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.83-1.47] and optimal (HR 0.95, 95% CI 0.74-1.22) morphologic response were not associated with OS compared with no response. RECIST partial response (HR 0.61, 95% CI 0.49-0.76) and progressive disease (HR 5.77, 95% CI 3.97-8.39) were associated with OS compared with stable disease. In 242 patients who underwent local treatment, suboptimal (HR 1.22, 95% CI 0.76-1.96) and optimal (HR 1.28, 95% CI 0.89-1.86) morphologic response were not associated with OS compared with no response. RECIST partial response was not significantly associated with OS (HR 0.73, 95% CI 0.52-1.01), whereas progressive disease was (HR 19.74, 95% CI 5.75-67.78), compared with stable disease. While major pathological response (HR 0.66, 95% CI 0.44-0.99) was associated with OS, partial pathological response (HR 0.82, 95% CI 0.57-1.19) was not, compared with no pathological response. Pathological response, but not morphologic response and RECIST, was significantly associated with early recurrence (P < 0.001) which occurred in 13/58 (22%) patients with major response, 29/61 (48%) patients with partial response, and 51/88 (58%) patients with no response.

Conclusions: Our results show that RECIST but not morphologic response was prognostic for OS. In patients eligible for local treatment, neither RECIST nor morphologic response were associated with early recurrence. Pathological response was associated with early recurrence but is only available post-operatively. Hence, novel preoperative parameters are warranted to predict early recurrence and prevent potentially futile liver surgery.

Background: The IMvigor210 trial demonstrated clinical benefit and manageable toxicity with atezolizumab monotherapy [anti-programmed death-ligand 1 (PD-L1)] in patients with metastatic urothelial carcinoma (UC) in primary analyses. Final efficacy and safety results after long-term follow-up are reported.

Patients and methods: This phase II single-arm trial of atezolizumab monotherapy in patients with advanced UC included two cohorts: untreated patients ineligible for cisplatin-based chemotherapy (cohort 1; n = 119) and those previously treated with platinum-based chemotherapy (cohort 2; n = 310). Atezolizumab was administered i.v. (1200 mg every 21 days) until progression or unacceptable toxicity. Primary endpoints were independent review facility-assessed confirmed objective response rate (ORR) per RECIST 1.1 in cohort 1 and independent review facility-assessed ORR per RECIST 1.1 and investigator-assessed modified (m)RECIST in cohort 2. Overall survival (OS), efficacy by PD-L1 status, and safety were also assessed.

Results: At data cut-off (1 June 2023), the median survival follow-up was 96.4 months (range, 0.2-103.4 months) in cohort 1 and 46.2 months [0.2 (censored)-54.9 months] in cohort 2. In cohort 1, the ORR [95% confidence interval (CI)] was 23.5% (16.2% to 32.2%) in all patients and 28.1% (13.8% to 46.8%) in the PD-L1 tumor-infiltrating immune cell (IC)2/3 subgroup. Median OS (95% CI) was 16.3 months (10.4-24.5 months) overall and 12.3 months (6.0-49.8 months) in the PD-L1 IC2/3 subgroup. In cohort 2, the ORR (95% CI) was 16.5% (12.5% to 21.1%) per RECIST 1.1 and 19.7% (95% CI 15.4% to 24.6%) per mRECIST in all patients and 27.0% (18.6% to 36.8%) and 28.0% (19.5% to 37.9%), respectively, in the PD-L1 IC2/3 subgroup. Median OS (95% CI) was 7.9 months (6.7-9.3 months) in all patients and 11.9 months (9.0-22.8 months) in the IC2/3 subgroup. Treatment-related grade 3/4 adverse events occurred in 21.8% (cohort 1) and 18.7% (cohort 2); one treatment-related death occurred in cohort 1.

Conclusions: With long-term follow-up, atezolizumab monotherapy demonstrated clinically meaningful efficacy with durable responses in a subset of patients with metastatic UC; there were no new safety signals.

Background: In addition to the effect of body weight, a patient's sex can influence the pharmacokinetics (PK) of anticancer agents, and thereby their activity and safety. The magnitude and relevance of sex differences, however, are currently unclear.

Methods: We carried out a systematic review of published studies (clinical, n ≥ 10) on Food and Drug Administration (FDA)-approved (on 31 January 2022) anticancer drugs (excluding hormonal agents), aiming to identify significant PK differences between male and female patients. A difference of ≥20% on PK parameters (clearance or trough concentration) was considered significant. The methodological quality was assessed using the National Institutes of Health study quality assessment tool. This systematic review was conducted according to the PRISMA2020 guidelines and a previously published protocol, which was registered in the PROSPERO database (number 291008).

Results: Data on 99 anticancer agents (for a total of 1643 abstracts and European Medicines Agency/FDA documents) were screened. The final dataset included 112 articles and 8 European Medicines Agency/FDA documents. The median size of a study cohort was 445 patients (range: 12-6468 patients). Significant PK differences (>+20% in clearance or apparent clearance in women) were identified for 14 drugs, and potentially significant PK differences (due to conflicting reports) for another 8 drugs. None of the studies included sex-based summaries to assess whether the observed differences in PK may impact the efficacy or safety profile.

Conclusions: Significant sex differences in PK have been identified including commonly used drugs of different classes, such as 5-fluorouracil, doxorubicin, paclitaxel, regorafenib, atezolizumab, and temozolomide. The risk-benefit ratio for such anticancer drugs is likely to be improved by the development of sex-specific dosing strategies. Additional sex-based PK-pharmacodynamic analyses are recommended during dose optimisation and are to be conducted in line with the FDA Project Optimus guidance. They should be reported even if no association between the patients' sex and the activity and/or toxicity of an anticancer drug has been identified.

Background: Adjuvant radiotherapy (RT) plays an essential role in the management of early breast cancer (BC), but can lead to cardiovascular and lung toxicities. RT in deep inspiration breath hold (DIBH) often allows better protection of organs at risk. This prospective study compares surface-guided DIBH with free breathing (FB) in patients with left-sided BC, by evaluating individual cardiovascular risks and treatment plan dosimetry.

Patients and methods: The study enrolled 585 patients from October 2016 to January 2021 with left-sided invasive breast carcinoma with indicated adjuvant RT of the breast/thoracic wall with or without regional lymph nodes. The ability to hold breath for 20 s was a prerequisite. The treatments were either hypofractionated (HF; 40.05 Gy/15Fx) or normofractionated (NF; 50.00 Gy/25Fx). DIBH was applied using the automatically triggered surface guidance system Catalyst with audio-video feedback. Computed tomography and surface data were acquired during both DIBH and FB. The primary endpoint of the study was the comparative evaluation of heart dose reduction using DIBH.

Results: Plan dosimetry was significantly improved by DIBH. The mean and maximum doses to the heart and the left coronary artery were significantly reduced by 36%-42% in HF and NF plans (P < 0.001), while the mean ipsilateral lung dose was reduced by 12%-14% (P < 0.001). Furthermore, DIBH resulted in a 5% reduction in the cumulative 10-year cardiovascular disease risk (10-year cardiovascular disease risk) compared with FB (3.59% to 3.41%; P < 0.001).

Conclusion: To the best of our knowledge, this is the largest prospective study showing better sparing for cardiac and ipsilateral lung doses with surface-guided DIBH compared with FB in patients with left-sided BC.