Clinical Activity Research Articles

Differences in cancer clinical trial activity and trial characteristics at metropolitan and rural trial sites in Victoria, Australia

AbstractObjectiveCancer clinical trials (CCTs) provide access to emerging therapies and extra clinical care. We aimed to describe the volume and characteristics of CCTs available across Victoria, Australia, and identify factors associated with rural trial location.MethodsQuantitative analysis of secondary data from Cancer Council Victoria's Clinical Trials Management Scheme dataset.DesignA cross‐sectional study design was used.SettingCCTs were available Victoria‐wide in 2018.ParticipantsThere were 1669 CCTs and 5909 CCT participants.Main Outcome MeasuresRural CCT location was assessed as a binary variable with categories of ‘yes’ (modified Monash [MM] categories 2–7) and ‘no’ (MM category 1). MM categories were determined from postcodes. The highest (‘least rural’) MM category was used for postcodes with multiple MM categories.ResultsOf 1669 CCTs, 168 (10.1%) were conducted in rural areas. Of 5909 CCT participants, 315 (5.3%) participated in rural CCTs. There were 526 CCTs (31.5%) with 1907 (32.3%) newly enrolled participants. Of 1892 newly enrolled participants with postcode data, 488 (25.8%) were rural residents. Of them, 368 (75.4%) participated in metropolitan CCTs. In a multivariable logistic regression analysis for all 1669 CCTs, odds of a rural rather than metropolitan CCT location were significantly (p‐value <0.05) lower for early‐phase than late‐phase trials and non‐solid than solid tumour trials but significantly (p‐value <0.05) higher for non‐industry than industry‐sponsored trials.ConclusionsIn Victoria, 10% of CCTs are at rural sites. Most rural‐residing CCT participants travel to metropolitan sites, where there are more late‐phase, non‐solid‐tumour and industry‐sponsored trials. Approaches to increase the volume and variety of rural CCTs should be considered.

Safety and efficacy of belantamab mafodotin with pembrolizumab in patients with relapsed or refractory multiple myeloma.

Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell-mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM. DREAMM-4 (NCT03848845) was an open-label, single-arm, phase 1/2 study divided into dose-escalation (part 1) and dose-expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles. Of 41 enrolled patients, 34 (n=6 part 1, n=28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti-B-cell maturation antigen therapy achieved partial response or better, including two who had B-cell maturation antigen-refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf-related ocular events, quality-of-life measures remained stable over time. No new safety signals were observed. The results of DREAMM-4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www. gov as NCT03848845.

Central and peripheral contrast sensitivity in thyroid eye disease.

Assessment of central and peripheral contrast sensitivity (CS) in thyroid eye disease (TED) with and without dysthyroid optic neuropathy (DON). This cross-sectional study enrolled 33 eyes of 18 treatment-naïve TED patients and 18 age- and sex-matched healthy controls for comparative analysis. A detailed ophthalmic examination included visual acuity (VA), intraocular pressure measurement, slit-lamp biomicroscopy, and CS testing (central and four peripheral regions) using Spaeth-Richman Contrast Sensitivity test was done. The average age of TED patients was 47.17 ± 13.99 years and a female preponderance was noted (66.66%, n = 12). Twenty-five eyes (75.8%) were diagnosed as TED without DON, while eight eyes (24.2%) had DON. Nine eyes (27.2%) were in the active stage of disease and 29 eyes (87.8%) had proptosis. The difference in mean logMAR visual acuities between TED patients and controls was statistically insignificant (P = 0.189), but a significant difference was noted in central and total CS score (P < 0.001, Wilcoxon-Mann-Whitney test). On CS comparison between DON and non-DON eyes, a significant difference in average scores was noted in central and all peripheral areas (P < 0.05, Wilcoxon-Mann-Whitney test). With increasing clinical activity score, a statistically significant reduction was noted in CS in three out of four peripheral regions (Spearman correlation, P < 0.05). Visual function compromise can be detected in TED in the presence of intact VA, by testing CS. Peripheral CS deteriorates with increasing inflammation and in DON. Serial monitoring of both central and peripheral CS may help in diagnosing DON early.

Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant thyroid eye disease: a prospective study.

To evaluate the clinical outcomes of intravenous tocilizumab (TCZ) injection in patients with moderate-to-severe active thyroid eye disease (TED). Patients with active and moderate-to-severe TED who did not respond to conventional therapies were treated with TCZ from June 2019 to January 2021. The medical records of the patients were evaluated before the treatment. We analyzed patient demographics, including the duration of Graves' disease and TED, and assessed subjective symptoms, such as diplopia and ocular movement, clinical activity score (CAS), modified NOSPECS score, and exophthalmos before treatment and at 4, 8, 12, and 16weeks after the first drug injection. Blood tests, including TSH Rc Ab and TS Ab, were performed before treatment and 24weeks after the first injection. And orbital computed tomography (CT) was performed and Barrett's Index was calculated at baseline and after completion of all injections. Nineteen completed the scheduled treatment. There were no significant side effects, other than herpes zoster in one case and headache and dermatitis in another. Clinical symptoms before and 16 weeks after the treatment showed mean CAS decreased by 2.4 points, mean modified NOSPECS score decreased by 3.7 points, and mean exophthalmos decreased by 0.4 mm. Diplopia and extraocular muscle limitation improved in ten and remained stationary in five of the 15 patients, who presented with extraocular motility abnormalities. Six of 11 patients who underwent orbit CT showed improvement in muscle size. The mean TSH Rc Ab decreased by 7.5 IU/L and TS-Ab decreased by 162.9%. TCZ can treat active moderate-to-severe TED, showing high drug compliance and reasonable response to inflammation and extraocular motility abnormality.

Preclinical evaluation and first-in-dog clinical trials of PBMC-expanded natural killer cells for adoptive immunotherapy in dogs with cancer

BackgroundNatural killer (NK) cells are cytotoxic cells capable of recognizing heterogeneous cancer targets without prior sensitization, making them promising prospects for use in cellular immunotherapy. Companion dogs develop spontaneous cancers...

Upadacitinib in Rheumatoid Arthritis and Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs: Efficacy and Safety Through 5 Years (SELECT-NEXT).

To report 5-year efficacy and safety of upadacitinib (UPA) in rheumatoid arthritis (RA) from the phase III long-term extension (LTE) of SELECT-NEXT. Patients on stable conventional synthetic disease-modifying antirheumatic drugs were randomized to UPA 15 mg once daily (QD), UPA 30 mg QD, or placebo for 12 weeks. Following this, placebo-randomized patients were switched to UPA 15 mg QD or UPA 30 mg QD in the LTE; UPA-randomized patients continued their original dose. Blinding remained until dose switching from UPA 30 mg QD to UPA 15 mg QD because of approval of UPA 15 mg QD; the earliest switch occurred at week 168. Efficacy (as observed) and treatment-emergent adverse events (TEAEs) are reported through 5 years. Overall, 611 (92%) randomized patients entered the LTE; 271 (44%) discontinued the study drug by 5 years, primarily because of adverse events (16%). Clinical outcomes improved or were maintained at 5 years; 51% and 43% of patients achieved Clinical Disease Activity Index remission and 75% and 66% achieved Disease Activity Score in 28 joints based on C-reactive protein < 2.6 among those initially randomized to UPA 15 mg QD and UPA 30 mg QD, respectively. Proportions of patients achieving ≥ 20%/50%/70% improvement in American College of Rheumatology criteria responses increased from week 60 through 5 years. Results were similar regardless of initial randomization to UPA or placebo. TEAEs, including TEAEs of special interest, were consistent with earlier analyses and other SELECT studies. Malignancies (excluding nonmelanoma skin cancer), major adverse cardiovascular events, and venous thromboembolic events were reported infrequently. No new safety signals were observed. The 5-year benefit-risk profile for UPA in RA remains favorable. (SELECT-NEXT; ClinicalTrials.gov: NCT02675426).

Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study

BackgroundIn patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti–PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4).MethodsIn phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations.ResultsIn phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs.ConclusionsThe RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC.Trial registrationNCT03271047 (09/01/2017).

Assessing Hospital Pharmacists' Scope of Clinical Practice in Ontario.

Expansion of the scope of pharmacists' activities in hospital is associated with reductions in adverse events and drug-related readmissions. However, the breadth of hospital pharmacists' clinical activities varies widely across Ontario due to provisions in the provincial Public Hospitals Act. Few data exist defining expanded scope in institutions across Ontario. The primary objective was to describe the scope of practice of hospital pharmacists in Ontario who were undertaking expanded clinical activities based on policies or medical directives. The secondary objectives included determining benefits, limitations, facilitators, and barriers associated with implementing these activities. A survey was sent to the pharmacy leadership of Groups A and B public hospitals across Ontario. The survey contained quantitative and qualitative questions focused on 3 domains of expanded-scope activities: adaptation, discontinuation, and renewal of medication orders; prescriptive authority; and drug monitoring. Of 56 hospitals invited, 46 (82%) submitted a survey response, with 1 exclusion (due to no response on some mandatory questions). The most common expanded-scope activity was independent performance of therapeutic drug monitoring (71%, 32/45). Pharmacists had the authority to independently adapt, discontinue, or renew inpatient medication orders in 60% (27/45) of hospitals, and could independently initiate medication orders in 20% (9/45). Barriers to implementing expanded-scope activities included limited time and staffing. Facilitators included proactive leadership, demonstrated clinical value, and strong rapport with other health care providers. Many institutions in Ontario have established polices to expand pharmacists' clinical activities, but there is a great deal of variability in scope of practice. Advocacy at the provincial level to unify scope of practice will help to optimize patient outcomes.

Clinical significance of anti-mutated citrullinated vimentin antibodies in rheumatoid arthritis patients.

Anti-mutated citrullinated vimentin (MCV) antibodies have recently been recommended as a better arthritis diagnostic marker. To investigate the association between anti-MCV antibodies and the clinical, functional, and radiographic characteristics of rheumatoid arthritis (RA) patients. This case-control study was conducted on 40RApatients and 40healthy subjects. All patients were subjected to an assessment of disease using the 28-joint DAS (DAS28) and Clinical Disease Activity Index (CDAI), function by HAQ-DI, physical activity by International Physical Activity Questionnaire (IPAQ), fatigue by Functional Assessment of Chronic Illness Therapy (FACIT), serological tests as well as anti-MCV Abs measurement. A plain X-ray of both hands and wrists was done. The anti-MCV Abs level was significantly higher in RA patients than in healthy controls (P< 0.001). The anti-MCV Abs had a significant positive correlation with DAS, CDAI, HAQ, RF, Anti-CCP, and CRP (P= 0.006, 0.013, 0.005, < 0.001, < 0.001and 0.041respectively) and a significant negative correlation with FACIT (p= 0.007). Positive anti-MCV RA patients had significantly higher erosions, JSN, and a total sharp score. Anti-MCV Abs may contribute to poor physical activity and more fatigue in RA patients beyond their established role in disease activity and erosion.

Physical Activity Levels and Social Cognitive Theory Correlates among Adults with Crohn's Disease: Preliminary Results from a Cross-Sectional Analysis.

There is increasing research and clinical interest in physical activity (PA) as an adjuvant therapy for improving health outcomes among persons with Crohn's disease. To date, little is known regarding PA behavior and its cognitive and behavioral correlates in Crohn's disease. Thus, we assessed self-reported PA and its social cognitive theory (SCT) correlates in a sample of persons with Crohn's disease. Data on demographic and clinical characteristics, disease activity, leisure-time PA, and SCT variables were collected from 30 participants with Crohn's disease (90% White, 60% female) through an online survey. SCT variables assessed included exercise self-efficacy, social support, outcome expectations, goal setting, and planning. Analyses involved comparing PA levels and SCT survey scores using independent sample t-tests and non-parametric bivariate correlations. The majority of participants were in clinical remission (60%) and over half (57%) were classified as physically active, yet the mean PA level was lower than normative values for adults. Females (n = 18) and participants who reported previous surgery for Crohn's disease (n = 18) were almost twice as physically active as male participants and those without a history of Crohn's disease-related surgery, respectively (p's < 0.05). Overall, participants who reported greater exercise goal setting behaviors had higher levels of PA (rs = 0.34; p < 0.05). These findings highlight lower overall levels of PA in persons with Crohn's disease, and exercise goal setting represents a potential target of behavior change interventions for increasing PA in this population.

Changes Over Time in the Lémann Index and the Inflammatory Bowel Disease Disability Index in a Prospective Cohort of Patients With Crohn's Disease.

Crohn's disease (CD) is a progressive, destructive, and disabling disorder. Our study aimed to assess changes over time in the Lémann index (LI) and the Inflammatory Bowel Disease Disability Index (IBD-DI) in a cohort of CD patients. This was a single-center prospective cohort study of 130 consecutive CD patients with a follow-up of at least 4 years. The LI 1 and the IBD-DI 1 questionnaires were assessed in 2016 and again between September 2020 and October 2021 (LI 2 and IBD-DI 2). Of the 130 patients with assessment of both LI 1 and IBD-DI 1, 61 had calculation of the LI 2 and 98 patients answered the IBD-DI 2 questionnaire, with a median time between the 2 evaluations of 4.2 years. The LI increased for 16 (26%), decreased for 26 (43%), and remained unchanged for 19 (31%) patients. The median LI did not change over time (9.6 vs 9.3; P = .14). Clinical disease activity was significantly associated with bowel damage progression. A high initial LI (>7.9) was not associated with CD progression (surgery, drug dose escalation, or change of biologic). The IBD-DI decreased for 59 (60.2%), increased for 37 (37.8%), and remained unchanged for 2 (2%) patients. The median IBD-DI decreased significantly over time (23.2 vs 21.4; P = .006). There was no correlation between the 2 indexes. This is the first prospective cohort study assessing changes over time in both the LI and the IBD-DI in CD patients. After 4 years, the LI appeared to be stable and the IBD-DI decreased, with no correlation between the 2 indexes.

One Incremental Stride for Doxycycline, One Substantial Advancement for Thyroid Eye Disease.

The aim of this study is to assess the effectiveness of a 12-week doxycycline treatment for thyroid eye disease (TED), an autoimmune condition associated with thyroid dysfunction. In this randomized controlled clinical trial, 82 patients were randomly assigned at a 1:1 ratio to receive doxycycline (50 mg) or to undergo no treatment. Various metrics, including margin reflex distance (MRD1 and MRD2), eyelid aperture, levator muscle function, lagophthalmos, proptosis, ocular motility, diplopia, and Graves' ophthalmopathy-specific quality-of-life (GO-QOL) scale scoring were assessed. Exclusion criteria were uncontrolled systemic diseases, tetracycline allergies, pregnancy, lactation, or age below 18. The mean age was 51.6 years (SD), 87.8% of participants were female, and all were Caucasians. By week 12, the doxycycline group exhibited a significant improvement rate based on MRD2 (from 4 to 15 participants with physiological findings), clinical activity score (from 7 to 35 participants with non-active disease), and GO-QOL (from 51.22% to 70.73% of participants with a good life quality). Doxycycline showcased anti-inflammatory and immunomodulatory effects in treating TED, suggesting its potential efficacy for TED and other orbit inflammatory conditions. However, these results warrant further validation through future research involving extended follow-up periods and larger cohorts.

Assessing the Impact of Immune Checkpoint Inhibitor Therapy on Clinical and MRI Activity in Patients with Multiple Sclerosis (P9-6.003)

Assessing the Impact of Immune Checkpoint Inhibitor Therapy on Clinical and MRI Activity in Patients with Multiple Sclerosis (P9-6.003)

Ofatumumab Reduces Clinical and Radiological Activity in People with Recently Diagnosed Treatment-naive Relapsing Multiple Sclerosis Irrespective of Baseline Serum Neurofilament Light Chain Levels (P9-6.008)

Ofatumumab Reduces Clinical and Radiological Activity in People with Recently Diagnosed Treatment-naive Relapsing Multiple Sclerosis Irrespective of Baseline Serum Neurofilament Light Chain Levels (P9-6.008)

Management of sotorasib-related adverse events and hepatotoxicities following anti-PD-(L)1 therapy: Experience with sotorasib in two French anti-cancer centers and practical guidance proposal

IntroductionSotorasib is a first-in-class KRASG12C inhibitor that showed significant clinical activity in KRASG12C-mutated non-small cell lung cancer (NSCLC). The most frequent grade 3 or 4 sotorasib-related adverse events (AEs) were diarrhea (4–12 %) and hepatotoxicity (10.1–15.1 %). Data is lacking about the management of these AEs, especially in patients receiving sequential anti-PD-(L)1 and sotorasib therapy. Our aim was to report the management of grade ≥ 2 sotorasib-related AEs in real-world setting and to propose practical guidance for the management of grade ≥ 2 sotorasib-related AEs and more generally KRASG12C inhibitors-related AEs. Materials and methodsRecords from all consecutive patients who initiated sotorasib through expanded access program in two French anti-cancer centers from January 1st 2021 to April 1st 2023 were reviewed to identify and grade sotorasib-related AEs, according to NCI-CTCAE v5.0., and to collect AEs management data. Patients were included in the analysis if they presented a grade ≥ 2 sotorasib-related AE. ResultsFrom 57 patients identified, 21 met inclusion criteria including eighteen (86 %) who received sequential anti-PD-(L)1 and sotorasib therapy. Hepatotoxicity (76 %) and diarrhea (24 %) were the most common grade ≥ 2 sotorasib-related AEs. Among the 16 patients with a grade ≥ 2 hepatotoxicity, 12 (75 %) definitely discontinued sotorasib, among which 9 (56 %) after dose reductions and rechallenge, and five (32 %) received corticosteroids, allowing only one patient to resume sotorasib. Diarrhea and nausea were usually manageable and not associated with sotorasib discontinuation. We propose a step-by-step management practical guidance for sotorasib-related hepatotoxicity based on dose-reduction and careful monitoring. Liver biopsy is strongly encouraged for grade 3 and 4 hepatotoxicity to assess candidates for corticosteroids. DiscussionThe experience with sotorasib might help better prevent, screen and manage sotorasib-related and other KRASG12C inhibitors-related AEs, particularly hepatotoxicity.

Safety and efficacy of parsaclisib in combination with rituximab, bendamustine + rituximab, or ibrutinib in patients with previously treated B-cell lymphoma: analysis of a phase 1 dose-finding study (CITADEL‑112)

Parsaclisib, a potent and highly selective phosphoinositide 3-kinase δ inhibitor, has shown clinical activity in relapsed/refractory (R/R) B-cell lymphoma. The phase 1 CITADEL-112 (NCT03424122) study assessed safety and efficacy of parsaclisib in combination with investigator choice standard of care (SOC; rituximab [Treatment A], rituximab plus bendamustine [Treatment B], or ibrutinib [Treatment C]) in 50 patients with R/R B-cell lymphoma. The most common treatment-emergent adverse events included neutropenia (62.5%, 50.0%, and 50.0% of patients in Treatments A, B, and C, respectively); diarrhea (37.5%) and anemia (31.3%) in Treatment A; abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Treatment B; and increased alanine and aspartate aminotransferase (each 37.5%) in Treatment C. Objective responses were observed in 13 patients (81.3%) in Treatment A, 10 (55.6%) in Treatment B, and 8 (50.0%) in Treatment C. Parsaclisib combined with SOC therapies had an expected safety profile and promising efficacy in patients with R/R B-cell lymphomas.

Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1–2, open-label, multicohort trial

In preliminary findings from the recurrent or metastatic cervical cancer cohort of CheckMate 358, nivolumab showed durable anti-tumour responses, and the combination of nivolumab plus ipilimumab showed promising clinical activity. Here, we report long-term outcomes from this cohort. CheckMate 358 was a phase 1-2, open-label, multicohort trial. The metastatic cervical cancer cohort enrolled patients from 30 hospitals and cancer centres across ten countries. Female patients aged 18 years or older with a histologically confirmed diagnosis of squamous cell carcinoma of the cervix with recurrent or metastatic disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and up to two previous systemic therapies were enrolled into the nivolumab 240 mg every 2 weeks group, the randomised groups (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks [NIVO3 plus IPI1] or nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for four cycles then nivolumab 240 mg every 2 weeks [NIVO1 plus IPI3]), or the NIVO1 plus IPI3 expansion group. All doses were given intravenously. Patients were randomly assigned (1:1) to NIVO3 plus IPI1 or NIVO1 plus IPI3 via an interactive voice response system. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, or for up to 24 months. The primary endpoint was investigator-assessed objective response rate. Anti-tumour activity and safety were analysed in all treated patients. This study is registered with ClinicalTrials.gov (NCT02488759) and is now completed. Between October, 2015, and March, 2020, 193 patients were recruited in the recurrent or metastatic cervical cancer cohort of CheckMate 358, of whom 176 were treated. 19 patients received nivolumab monotherapy, 45 received NIVO3 plus IPI1, and 112 received NIVO1 plus IPI3 (45 in the randomised group and 67 in the expansion group). Median follow-up times were 19·9 months (IQR 8·2-44·8) with nivolumab, 12·6 months (7·8-37·1) with NIVO3 plus IPI1, and 16·7 months (7·2-27·5) with pooled NIVO1 plus IPI3. Objective response rates were 26% (95% CI 9-51; five of 19 patients) with nivolumab, 31% (18-47; 14 of 45 patients) with NIVO3 plus IPI1, 40% (26-56; 18 of 45 patients) with randomised NIVO1 plus IPI3, and 38% (29-48; 43 of 112 patients) with pooled NIVO1 plus IPI3. The most common grade 3-4 treatment-related adverse events were diarrhoea, hepatic cytolysis, hyponatraemia, pneumonitis, and syncope (one [5%] patient each; nivolumab group), diarrhoea, increased gamma-glutamyl transferase, increased lipase, and vomiting (two [4%] patients each; NIVO3 plus IPI1 group), and increased lipase (nine [8%] patients) and anaemia (seven [6%] patients; pooled NIVO1 plus IPI3 group). Serious treatment-related adverse events were reported in three (16%) patients in the nivolumab group, 12 (27%) patients in the NIVO3 plus IPI1 group, and 47 (42%) patients in the pooled NIVO1 plus IPI3 group. There was one treatment-related death due to immune-mediated colitis in the NIVO1 plus IPI3 group. Nivolumab monotherapy and nivolumab plus ipilimumab combination therapy showed promise in the CheckMate 358 study as potential treatment options for recurrent or metastatic cervical cancer. Future randomised controlled trials of nivolumab plus ipilimumab or other dual immunotherapy regimens are warranted to confirm treatment benefit in this patient population. Bristol Myers Squibb and Ono Pharmaceutical.

Don't wait for the perfect moment: The national training program in family medicine in Angola.

Like many Sub-Saharan countries, Angola struggles with a shortage of trained health professionals, especially for primary care. In 2021, the Angolan Ministry of Health in collaboration with the Angolan Medical Council launched the National Program for the Expansion of Family Medicine as a long-term strategy for the provision, fixation and training of family physicians in community health centres. Of the 425 residents 411 (96.7%) who entered the programme in 2021 will get their diplomas in the following months and will be certified as family physicians. Three main aspects make this National Programme unique in the Angolan context: (1) the common effort and engagement of the Ministry of Health with the Angolan Medical Council and local health authorities in designing and implementing this programme; (2) decentralisation of the training sites, with residents in all 18 provinces, including in rural areas and (3) using community health centres as the main site of practice and training. Despite this undeniable success, many educational improvements must be made, such as expanding the use of new educational resources, methodologies and assessment tools, so that aspects related to knowledge, practical skills and professional attitudes can be better assessed. Moreover, the programme must invest in faculty development courses aiming to create the next generation of preceptors, so that all residents can have in every rotation one preceptor or tutor responsible for the supervision of their clinical activities, case discussions and sharing their clinical duties, both at community health centres and municipal hospitals.

Nucleic acid-based drugs for patients with solid tumours.

The treatment of patients with advanced-stage solid tumours typically involves a multimodality approach (including surgery, chemotherapy, radiotherapy, targeted therapy and/or immunotherapy), which is often ultimately ineffective. Nucleic acid-based drugs, either as monotherapies or in combination with standard-of-care therapies, are rapidly emerging as novel treatments capable of generating responses in otherwise refractory tumours. These therapies include those using viral vectors (also referred to as gene therapies), several of which have now been approved by regulatory agencies, and nanoparticles containing mRNAs and a range of other nucleotides. In this Review, we describe the development and clinical activity of viral and non-viral nucleic acid-based treatments, including their mechanisms of action, tolerability and available efficacy data from patients with solid tumours. We also describe the effects of the tumour microenvironment on drug delivery for both systemically administered and locally administered agents. Finally, we discuss important trends resulting from ongoing clinical trials and preclinical testing, and manufacturing and/or stability considerations that are expected to underpin the next generation of nucleic acid agents for patients with solid tumours.

Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer.

Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897.