Intolerable Side Effects Research Articles

Beyond epithelial damage: vascular and endothelial contributions to idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment remains limited. Currently, two drugs can slow the scarring process but often at the expense of intolerable side effects, and without substantially changing overall survival. A better understanding of mechanisms underlying IPF is likely to lead to improved therapies. The current paradigm proposes that repetitive alveolar epithelial injury from noxious stimuli in a genetically primed individual is followed by abnormal wound healing, including aberrant activity of extracellular matrix-secreting cells, with resultant tissue fibrosis and parenchymal damage. However, this may underplay the importance of the vascular contribution to fibrogenesis. The lungs receive 100% of the cardiac output, and vascular abnormalities in IPF include (a) heterogeneous vessel formation throughout fibrotic lung, including the development of abnormal dilated vessels and anastomoses; (b) abnormal spatially distributed populations of endothelial cells (ECs); (c) dysregulation of endothelial protective pathways such as prostacyclin signaling; and (d) an increased frequency of common vascular and metabolic comorbidities. Here, we propose that vascular and EC abnormalities are both causal and consequential in the pathobiology of IPF and that fuller evaluation of dysregulated pathways may lead to effective therapies and a cure for this devastating disease.

Transition from Intravenous Epoprostenol to Treprostinil Due to Intolerable Side Effects in Patients With Pulmonary Arterial Hypertension

Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension (PAH); however, it has side effects. Reviewing the side effects associated with epoprostenol and treprostinil is essential for improving the long-term treatment strategies for PAH. This retrospective review included patients with PAH who transitioned from intravenous epoprostenol to intravenous treprostinil owing to intolerable side effects, including high cardiac output symptoms, ascites, and thrombocytopenia. Of the 85 patients who received epoprostenol at our hospital between 2013 and 2021, 16 (11 women), with a median age of 33 (range 26 to 40) years (including 12 with idiopathic PAH, 3 with hereditary PAH, and 1 with connective tissue disease pulmonary hypertension), had to switch from intravenous epoprostenol to treprostinil owing to the side effects. After transitioning, epoprostenol-associated intolerable side effects, such as high cardiac output symptoms, ascites, and thrombocytopenia, were ameliorated. In conclusion, for patients with PAHwho have intolerable side effects fromepoprostenol and have difficulty in continuing treatment, switching from epoprostenol to treprostinil may be an option. Switching treatment leads to better adherence and improved long-term prostacyclin therapy.

Considerations When Using Gabapentinoids to Treat Trigeminal Neuralgia: A Review.

Despite the exemplary efficacy of voltage-gated sodium channel blockers as a first-line treatment of trigeminal neuralgia, the pharmacological management of this excruciating facial pain condition remains a major issue, as these first-line drugs produce intolerable side effects in a significant portion of patients. In addition, in patients with concomitant continuous pain, the efficacy of these drugs may drop, thus suggesting the opportunity to test the efficacy of different drug categories. The aim of this review is to provide current, evidence-based, knowledge about the use of gabapentin and other α2δ ligands in patients with trigeminal neuralgia. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials database (ClinicalTrials.gov), considering publications up to April 2023. Two authors independently selected studies for inclusion and data extraction. The efficacy of α2δ ligands, gabapentin and pregabalin, has been assessed in seven controlled or open-label studies. Despite the low quality of evidence, the favorable tolerability profile and the possible action on concomitant continuous pain make this drug category of interest for future trials in trigeminal neuralgia.

Combination of adipose-derived stem cell conditioned media and minoxidil for hair regrowth in male androgenetic alopecia: a randomized, double-blind clinical trial

IntroductionTreatments for AGA have yet to produce satisfactory outcomes and may cause intolerable side effects. Recent studies have reported that adipose tissue-derived stem cell conditioned media (ADSC-CM) could induce hair growth and regeneration.ObjectiveTo investigate the efficacy of ADSC-CM combined with minoxidil for hair regeneration therapy in male AGA.MethodsThis study lasted for 6 weeks. Subjects were divided into two groups: concentrated and non-concentrated ADSC-CM. Scalp was divided vertically in half before intradermal injection was administered from the frontal region of the scalp toward the vertex with a 30G needle, spaced about 1 cm apart. Treatment side received 2 ml of ADSC-CM; the other side was given 2 ml of NaCl 0.9% as placebo. Patients applied 5% minoxidil twice daily post-injection. Improvements were assessed using photographs and trichoscan every 2 weeks.ResultsHair count, hair density, and mean thickness increased significantly on both sides after 6 weeks, while vellus rate decreased proportionally with the increase of terminal rate. No statistically significant differences between treatment groups were found. Minimum side effects were reported, and subjects were satisfied with the results.ConclusionCombination of ADSC-CM and minoxidil could be a potential agent for hair regrowth. Follow-up research with extensive populations, longer duration, and different study design may be required to confirm the exact mechanisms of ADSC-CM on hair growth.Trial registration: Clinicaltrials.gov, NCT05296863. Registered 25 March 2022—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05296863.

The silent world of assisted reproduction: A qualitative account of communication between doctors and patients undergoing in vitro fertilisation in Australia.

In vitro fertilisation (IVF) is now a common assisted reproductive technology (ART) procedure globally, with 8 million children alive today having been conceived utilising IVF. For many patients, IVF is a difficult experience with many discontinuing treatment because of emotional, relationship and financial stress,or intolerable physical side effects of hormone treatments. A qualitative study, in which 31professionals and 25patients from the ART sector in Australia were interviewed. The interviews were analysed using codebook thematic analysis. Our data indicates there are 'silences' within the therapeutic relationship of IVF, which may limit the capacity for patients to prepare emotionally, financially,or medically for the procedure, and may contribute to psychological distress and dissatisfaction with care. These 'silences' include what the patient 'is not told' by their clinician or 'does not hear' and what the patient feels they 'cannot say'. Drawing upon the work of Jay Katz, Charis Thompson,and Miles Little on 'silences' and performance in clinical practice, we argue that although IVF is a complex and multifaceted procedure that is often conducted in a commercial setting, the clinical and therapeutic relationship between doctor and patient remains pivotal to the experiences of patients. The 'silences' within this relationship may impact negatively on decision-making, and on the delivery and experience of care. Careful attention to the realities of IVF treatment in the clinic room (and awareness of the performances that hide them) should allow for more present and compassionate care. Such care may leave patients more satisfied with their experience and their choices, regardless of treatment outcomes. This article draws on interviews with patients who had undergone or were currently undergoing IVF, as well as a range of representatives from the ART community (including reproductive medicine specialists, general practitioners, fertility nurses, counsellors, administrators in ART businessesand embryologists).

Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches.

Mitochondria serve as a vital energy source for nerve cells. The mitochondrial network also acts as a defense mechanism against external stressors that can threaten the stability of the nervous system. However, excessive accumulation of damaged mitochondria can lead to neuronal death. Mitophagy is an essential pathway in the mitochondrial quality control system and can protect neurons by selectively removing damaged mitochondria. In most neurological disorders, dysfunctional mitochondria are a common feature, and drugs that target mitophagy can improve symptoms. Here, we reviewed the role of mitophagy in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, stroke, and traumatic brain injuries. We also summarized drug and non-drug approaches to promote mitophagy and described their therapeutic role in neurological disorders in order to provide valuable insight into the potential therapeutic agents available for neurological disease treatment. However, most studies on mitophagy regulation are based on preclinical research using cell and animal models, which may not accurately reflect the effects in humans. This poses a challenge to the clinical application of drugs targeting mitophagy. Additionally, these drugs may carry the risk of intolerable side effects and toxicity. Future research should focus on the development of safer and more targeted drugs for mitophagy.

Treatment with Antiobesity Drugs in Weight Regain After Bariatric Surgery: a Retrospective Cohort Study.

Bariatric surgery is the most efficient treatment for obesity. However, in some cases, weight regain can occur. Currently, it is unknown the best antiobesity medication (AOM) for such clinical situation. This study aims to evaluate the effect of AOM in patients with weight regain after bariatric surgery. A retrospective cohort study from December 2010 to July 2019 with patients submitted to bariatric surgery that had weight regain and received AOM for at least 2 years. Of 96 patients that had weight regain in the analyzed period and received AOM, 16 were excluded from the analysis due to non-compliance (n = 7), treatment failure (n = 5), intolerable side effects with all available AOM (n = 2), or interaction with other medications (n = 2). Eighty patients were included in the analysis. The mean age was 59.0 ± 10.1 years, 88.8% were female, 91.2% white, and most of them were submitted to gastric bypass (87.6%). The mean preoperative and nadir weight after surgery were 127.9 ± 25.5 kg and 84.7 ± 22.8 kg, respectively. At the initiation of AOM, the mean baseline weight was 99.4 ± 23.1 kg. After 2 years of follow-up, there was significant weight loss in the groups treated with topiramate-alone (- 3.2 kg), topiramate plus sibutramine (- 6.1kg), and orlistat-alone or in combination (- 3.9kg). No statistical difference was observed in the sibutramine-alone group. Topiramate (alone or associated with sibutramine) and orlistat (alone or in combination) promoted significant weight loss after 2 years of use in patients submitted to bariatric surgery with weight regain.

Prescribing for depression in primary care

The term ‘depression’ covers a variety of mental health problems characterised by a loss of interest and enjoyment, low mood and other emotional, cognitive, physical, and behavioural symptoms. Most people experiencing depression are treated in primary care. These treatments include various talking therapies and support to aid physical, psychological and social wellbeing. For people with moderate-to-severe depression, treatment with medication is recommended. This may be prescribed in addition to therapy and support. It is important that the person diagnosed with depression is monitored to assess how they respond to the antidepressants. A different type may need to be offered if response is poor or they have intolerable side effects. Antidepressants need to be prescribed for a given period, the length of which is dependent on whether this is the first or a further episode.

Persistence to extended adjuvant endocrine therapy following Breast Cancer Index (BCI) testing in women with early-stage hormone receptor-positive (HR +) breast cancer

PurposeExtending adjuvant endocrine therapy (ET) beyond the standard 5 years offers added protection against late breast cancer recurrences in women with early-stage hormone receptor-positive (HR +) breast cancer. Little is known about treatment persistence to extended ET (EET) and the role that genomic assays may play. In this study, we evaluated persistence to EET in women who had Breast Cancer Index (BCI) testing.MethodsWomen with stage I-III HR + breast cancer who had BCI testing after at least 3.5 years of adjuvant ET and ≥ 7 years of follow-up after diagnosis were included (n = 240). Data on medication persistence was based on prescriptions in the electronic health record.ResultsBCI predicted 146 (61%) patients to have low – BCI (H/I)-low – and 94 (39%) patients to have high likelihood of benefit from EET (BCI (H/I)-high). Continuation of ET after BCI occurred in 76 (81%) (H/I)-high and 39 (27%) (H/I)-low patients. Non-persistence rates were 19% in the (H/I)-high and 38% in the (H/I)-low group. The most common reason for non-persistence was intolerable side effects. Patients on EET underwent more DXA bone density scans than those who stopped ET at 5 years (mean 2.09 versus 1.27; p < 0.001). At a median follow-up of 10 years from diagnosis, there were 6 metastatic recurrences.ConclusionsIn patients who continued ET after BCI testing, the rates of persistence to EET were high, particularly in patients with predicted high likelihood of benefit from EET. Use of EET is associated with increased use of DXA scans.

CPC05 A case of extensive hypertrophic lupus erythematosus responsive to topical steroids

Abstract Hypertrophic lupus erythematosus (HLE) is a rare variant of lupus erythematosus, occurring in 2% of cases of chronic cutaneous lupus erythematosus (CCLE). It is an exaggerated proliferative epithelial response manifesting as verrucous-appearing hypertrophic indurated lesions occurring on sun-exposed sites. We present a case of the development of extensive HLE in a patient with subacute cutaneous lupus erythematosus (SCLE) with underlying pulmonary malignancy. A 74-year-old woman with Sjögren syndrome presented to dermatology with a 2-month history of a rash affecting her face and décolletage. Laboratory studies illustrated elevated antinuclear and anti-Ro antibodies. Biopsy from her chest confirmed SCLE. Malignancy screening revealed T1aN0 pulmonary lepidic adenocarcinoma, which was successfully managed with a lower lobectomy. Hydroxychloroquine was initially trialled but required discontinuation following intolerable side-effects. Mepacrine was then initiated, which allowed clearance of the rash, alongside yellow discoloration of the skin. Six months later, she developed a raised pruritic rash on her arms, legs and buttocks, resistant to current management alongside a trial of mycophenolate mofetil. Examination revealed violaceous hypertrophic plaques affecting 40% of her body-­surface area. The differential included hypertrophic lichen planus, nodular prurigo and HLE. Repeat lesional biopsies highlighted a lichenoid inflammatory infiltrate with overlying scale, favouring HLE. Owing to patient choice, topical mometasone furoate 0.1% was used to manage cutaneous disease, with a reduction in lesion size. HLE is a distinct subset of CCLE, regarded as a separate entity to SCLE. Twenty per cent of patients with SCLE also exhibit other types of cutaneous lupus erythematosus (CLE) lesions. No cases in the literature describe progression from SCLE to CCLE, or HLE, in particular. Hallmarks of HLE include verrucous lesions, chronicity and treatment resistance. Early recognition and follow-up are essential as malignancy may arise in long-standing lesions. Lung adenocarcinomas and hypertrophic lupus are both associated with p53 mutations and decreased granzyme B expression. Mutated p53 results in constitutive cell proliferation and DNA damage can accumulate in cells. Granzyme B is a protease in cytotoxic T cells involved in immune-mediated cell lysis. Both processes result in the potential to produce exaggerated hyperproliferative lesions, such as those observed in HLE and the lepidic adenocarcinomas. HLE is a rare clinical entity that can be easily misdiagnosed clinically and histopathologically. Increased awareness of this condition is essential to highlight the variety of clinical presentations of uncommon variants of CLE, to ensure they are considered while approaching clinical diagnosis.

Model-Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy.

Ethosuximide was identified as the optimal option for new-onset childhood absence epilepsy (CAE) in a randomized, two-phase dose escalation comparative effectiveness trial of ethosuximide, lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short-term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure-response relationship and to propose model-informed precision dosing guidance. Dose titration occurred over a 16-20-week period until patients experienced seizure freedom or intolerable side effects. Subjects with initial monotherapy failure were randomized to one of the other two medications and dose escalation was repeated. A population pharmacokinetic model was created using plasma concentration data (n = 1,320), collected at 4-week intervals from 211 unique participants during both the initial and second monotherapy phases. A logistic regression analysis was performed on the initial monotherapy cohort (n = 103) with complete exposure-response data. Eighty-four participants achieved seizure freedom with a wide range of ethosuximide area under the curves (AUC) ranging from 420 to 2,420 μg·h/mL. AUC exposure estimates for achieving a 50% and 75% probability of seizure freedom were 1,027 and 1,489 μg·h/mL, respectively, whereas the corresponding cumulative frequency of intolerable adverse events was 11% and 16%. Monte Carlo Simulation indicated a daily dose of 40 and 55 mg/kg to achieve 50% and 75% probability of seizure freedom in the overall population, respectively. We identified the need for adjusted mg/kg dosing in different body weight cohorts. This ethosuximide proposed model-informed precision dosing guidance to achieve seizure freedom carries promise to optimize initial monotherapy success for patients with CAE.

Phase 3 randomized study for evaluation of physician choice Rx and triple metronomic as second-line therapy in head and neck cancer (CRSF 2021-HN-001).

LBA6004 Background: There are multiple options of treatment in second-line therapy in locally advanced head and neck squamous cell carcinoma (LAHNSCC) with recurrent or metastatic disease. However triple metronomic chemotherapy is oral, affordable, and requires minimal resources. Hence in this study, we compared NCCN-recommended physician choice of standard systemic therapy versus triple metronomic therapy in the second-line treatment of head and neck cancer. Methods: This was a phase 3, multicentric (16 sites), randomized study with a superiority design that was approved by the institutional ethics committees and registered with CTRI (CTRI/2021/08/036002) conducted in India under the aegis of Cancer Research Statistics Foundation. The study recruited LAHNSCC with a recurrent and metastatic disease that either was platinum-refractory or was planned for second-line chemotherapy. The key inclusion criteria were: Age ≥18 years, ECOG PS 0-2, and the presence of normal hematological and biochemical parameters. These patients underwent 1:1 central stratified randomization (Stratification - site of disease &amp; ECOG PS) to either triple metronomic chemotherapy (methotrexate 9 mg/m2 PO weekly, celecoxib 200 mg PO twice daily and erlotinib 150 mg PO once daily) or physician choice therapy ( nivolumab or pembrolizumab or cetuximab or taxane or afatinib or 5-FU or capecitabine). The study drugs were administered either till disease progression or the development of intolerable side effects. The primary endpoint of the study is overall survival (OS). The secondary endpoints are adverse events (CTCAE version 5.0), progression-free survival (PFS), and quality of life (EORTC). The sample size required was 114. The OS and PFS were estimated using Kaplan-Meier method and were compared using the log-rank test. Cox proportional hazard model was constructed for the calculation of the hazard ratio. The adverse events were compared using Fisher's test. A p-value of 0.05 was considered significant. Results: At a median follow-up of 258 (95% CI 209-306) days.The median overall survival of the triple metronomic chemotherapy was 181 days (95%CI 142.7-219.2) versus 123 days (95%CI 94-152) in the physician choice therapy arm (P=.0.002). The corresponding hazard ratio of death was 0.58 (95%CI 0.33-0.79, P=0.003). The 6-month OS was 52.9% (95%CI 36.9-65.1) versus 14.8% (95%CI 6.4-26.4). The median progression-free survival was 120 days (95%CI 89.2-150.8) versus 70 days (95% CI 58.2-81.8) in metronomic chemotherapy and in the physician choice therapy arms respectively (P=0.000). The corresponding hazard ratio of progression was 0.5 (95%CI 0.33-0.74, P=0.001). Conclusions: In this phase 3 multicentric study, triple metronomic chemotherapy as second-line therapy had an overall survival and progression-free survival advantage over NCCN-recommended physician choice therapy. Clinical trial information: CTRI/2021/08/036002 .

Next-Generation Adjuvants: Applying Engineering Methods to Create and Evaluate Novel Immunological Responses.

Adjuvants are a critical component of vaccines. Adjuvants typically target receptors that activate innate immune signaling pathways. Historically, adjuvant development has been laborious and slow, but has begun to accelerate over the past decade. Current adjuvant development consists of screening for an activating molecule, formulating lead molecules with an antigen, and testing this combination in an animal model. There are very few adjuvants approved for use in vaccines, however, as new candidates often fail due to poor clinical efficacy, intolerable side effects, or formulation limitations. Here, we consider new approaches using tools from engineering to improve next-generation adjuvant discovery and development. These approaches will create new immunological outcomes that will be evaluated with novel diagnostic tools. Potential improved immunological outcomes include reduced vaccine reactogenicity, tunable adaptive responses, and enhanced adjuvant delivery. Evaluations of these outcomes can leverage computational approaches to interpret "big data" obtained from experimentation. Applying engineering concepts and solutions will provide alternative perspectives, further accelerating the field of adjuvant discovery.

Updated safety and efficacy results of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC) from a phase II trial.

8580 Background: CAPSTONE-1 study showed that SHR-1316 (PD-L1 antibody) combined with first-line chemotherapy could prolong overall survival in patients (pts) with ES-SCLC. Previous studies have shown that radiotherapy could potentially promote tumor antigen presentation and reverse immunosuppressive microenvironment in tumor. The purpose of this study was to explore the efficacy and safety of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Pts included in this study received 4~6 cycles of SHR-1316 (20mg/kg, D1, q3w) combined with EP/EC (cisplatin, 75mg/m², D1-3, q3w or carboplatin, AUC = 5, D1, q3w and etoposide, 100mg/m2, D1-5, q3w), sequentially SHR-1316 combined with chest radiotherapy (≥3Gy*10f or ≥2Gy*25f, involved-field irradiation), and then entered the maintenance treatment stage until disease progression or intolerable side effects. The main endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: From October 2020 to January 2023, 63 pts with ES-SCLC were enrolled and received at least one dose of SHR-1316, 33 of them have received chest radiotherapy. The median age was 63 (range: 38-75), and most pts were male (53, 84.1%), former smokers (42, 66.7%) with an ECOG performance status 1 (60, 95.2%). At baseline, 24 (38.1%) pts were diagnosed with brain metastasis and 19 (30.2%) pts had liver metastasis. At the data cutoff date, the average number of treatment cycles was 6.9, 17 pts remained on treatment. 55 pts had at least one post-treatment tumor assessment. 41 pts achieved a confirmed partial response, and 12 pts had stable disease. The confirmed ORR and DCR were 74.5% and 96.4%, respectively. The median PFS was 7(CI: 4.3~9.7) months. Adverse events (AEs) occurred in 47 (74.6%) pts. Grade 3 or 4 AEs occurred in 35 (55.6%) pts. The most common grade 3 or 4 AEs included neutropenia (27, 42.9%), leukopenia (13, 20.6%), lymphocytopenia (5, 7.9%), pneumonia (4, 6.3%), anemia (3, 4.8%), and thrombocytopenia (2, 3.2%). Conclusions: SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. It is worthy of further clinical exploration. Clinical trial information: NCT04562337 .

Preliminary efficacy and safety of camrelizumab plus metronomic oral vinorelbine as first-line therapy for people aged 70 and above with advanced non-small cell lung cancer (NSCLC) from a phase II trial.

e14677 Background: Traditional platinum-based combination chemotherapy used as the standard first‐line treatment for advanced NSCLC poses potential safety risk for patients (pts) aged 70 years and above. Moreover, data on immune checkpoint inhibitors treating older pts with lung cancer in the current pivotal trials is limited. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time. Compared with traditional chemotherapy, MCT shows better safety profile and antitumor angiogenesis and immunomodulatory effects. Camrelizumab, an anti-PD-1 inhibitor, demonstrated encouraging efficacy in NSCLC (CameL study and CameL-sq study). Here, we designed a phase II trial to evaluate the efficacy and safety of camrelizumab plus metronomic oral vinorelbine (mOV) as first-line therapy for Chinese older pts with advanced NSCLC. Methods: Key inclusion factors were pts aged 70 years and above, histologically or cytologically confirmed unresectable stage III and IV NSCLC without positive EGFR mutation, ALK fusions or ROS1 fusions, ECOG performance status 0-2, no previous systematic treatment. Pts received camrelizumab (200mg, D1, q3w) combined with mOV (30mg, tiw1, day 1-3-5 per week) for 6 cycles, followed by camrelizumab monotherapy maintenance until disease progression or intolerable side effects. The primary endpoint was progression free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: From March 2021 to November 2022, 12 pts were evaluable for inclusion in the study. The median age was 77 (range: 70-85) with 8 (67%) males. Median follow-up was 7.2 months (range 2.8 months-22.1 months). The median PFS was 9.3 months (95%CI: 3.9 months-14.7 months). The one-year OS rate was 66.3%. The ORR and DCR were 50% (95%CI: 25.4%-74.6%) and 83.3% (95%CI: 50.9%-90.1%), respectively. Pts with positive or negative PD-L1 responded similarly to the treatment (respectively at 5/8 and 1/2 on ORR). The median OS and DoR have not been reached. Adverse events (AEs) with any grade were observed in 10 (83.3%) pts, of which grade III-IV AEs were observed in 2 (16.7%) pts with neutropenia and interstitial pneumonia, respectively. Immune-related adverse events (irAEs) occurred in 3 (25%) pts, of which grade III-IV irAEs occurred in one (8.3%) patient with interstitial pneumonia. No grade 5 adverse event happened. Conclusions: The regimen of camrelizumab plus mOV for the first-line therapy for older NSCLC pts showed initial promising efficacy and safety profile, which suggests it is worth further exploration. Clinical trial information: ChiCTR2100049487 .

The PRIME-CUT study: A single-arm phase 2 study of ADT with PD-1 blockade and docetaxel in men with metastatic hormone-sensitive prostate cancer.

e17089 Background: Overall survival of patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) is improved with androgen deprivation therapy (ADT) and treatment intensification. Initially, ADT induces a robust and functional immune infiltrate into the tumor microenvironment (TME), with upregulation of immune checkpoint molecules. These effects diminish as castration-resistant prostate cancer (CRPC) invariably develops. We report the first results of the phase 2 PRIME-CUT study (modulating the PRostate cancer Immune MicroEnvironment with ChemoimmUnoTherapy for metastatic prostate cancer). Methods: Eligible pts had newly diagnosed mHSPC, ECOG performance status (PS) 0 or 1, serum testosterone levels &gt; 150 ng/dL, agreed to undergo serial metastatic tumor biopsies, and had not received ADT in the prior 6 months. Treatment consisted of ADT (degarelix 240 mg subcutaneously (SC) for one dose, followed by leuprolide 22.5 mg SC every 12 weeks) followed by anti-PD-1 antibody (cemiplimab 350 mg IV every 3 weeks) beginning four weeks after ADT initiation. With the intent of immune priming, a two-cycle lead-in of anti-PD-1 therapy was administered prior to standard of care docetaxel (75 mg/m2 every 3 weeks for six cycles). Participants received ADT and cemiplimab until study completion (52 weeks) or until a lack of clinical benefit or intolerable side effects. The primary endpoint was the rate of undetectable PSA at 6 months after chemotherapy initiation (week 37) and compared to the historical rate from the phase III CHAARTED trial (32%). Subjects were monitored for toxicity using a Bayesian adaptive study design with an early stopping rule for toxicity. Results: The study completed accrual of 20 pts (median age 62 years) from Columbia University Irving Medical Center in Aug 17, 2022. Among them, 7 self-identified race as Black and 12 self-identified their ethnicity as Hispanic. Baseline PSA ranged from 8.15 to &gt; 5000 ng/dL (median 2513.1 ng/dL). Site of metastatic disease included: 17/20 bone, 12/20 lymph nodes, 11/20 visceral organs. Overall, 14 of 20 patients received at least 4 cycles of docetaxel. Of the 12 patients that were still on-study at 37 weeks, 2 had an undetectable PSA, and 4 additional pts had PSA &lt; 1.0 ng/dL. Twelve pts experienced ≥ Grade 3 adverse events (AEs), 6 AEs were attributed to study intervention including cytopenias (3), hypotension (1), pneumonitis (1), and stenosis of gastrointestinal stoma (1). Unfortunately, two patients deceased on-study (myocardial infarction after 13 weeks, severe SARS-CoV-2 infection after 19 weeks). Conclusions: The Prime-Cut study did not meet its primary endpoint. However, PSA kinetics and results from the pre-planned correlative science demonstrate ongoing role for immunotherapeutic approaches in mHSPC. No new safety signals were observed. Clinical trial information: NCT03951831 .

Phase IIa study of αDC1 vaccines targeting HER2/HER3 combined with pembrolizumab in patients with asymptomatic brain metastasis from triple negative breast cancer or HER2+ breast cancer.

TPS1112 Background: Brain metastases develop in up to 50% patients (pts) with metastatic triple negative breast cancer (TNBC) and HER2+ BC, constituting an increasing source of morbidity and mortality. HER3, overexpressed in triple negative and HER2+ brain metastatic breast cancer (BMBC), is a resistance factor to HER2-targeted therapies and a driver of CNS metastasis. Disease progression is associated with loss of anti-HER2 and anti-HER3 immunity. Previously, we have demonstrated that glioma-specific peptide-loaded αDC1 which produce CXCL9, CXCL10, CXCL11, CCL5, the chemokines which attract CXCR3- and CCR5- expressing cytotoxic T-lymphocytes (CTLs) and T-helper 1 (Th1) cells, induce clinical responses and long-term disease stabilization in pts with aggressive recurrent primary brain tumors (Okada et al. JCO 2011. PMID: 21149657). We hypothesized that anti-HER2/3-loaded αDC1 in combination with PD1 blockade will result in strong Th1/CTL response against HER2/3 epitopes (Basu A et al. Cancer Immunol Res. 2022 PMID: 34785506), being effective against brain lesions and systemic disease. Methods: This is a phase II single-arm, non-randomized multicenter study (NCT04348747). Eligibility includes pts with triple negative and HER2+ BMBC ≥18 years, ECOG PS ≤1, normal marrow and organ function with asymptomatic untreated brain metastases ≥ 5 mm who will receive αDC1 q3 weeks x 3 along with pembrolizumab every 3 weeks. Thereafter, αDC1 booster doses (if available) would be administered every 3 months until disease progression, intolerable side effects or withdrawal from study, up to 24 months. Baseline and 9-week post-αDC1 peripheral biopsies (non-CNS) are required for six pts. 1 of the planned 21 pts have been enrolled and is undergoing treatment. Primary endpoint is CNS response rate (RR) by RANO-BM criteria. If no CNS response is observed after 12 pts, study will be terminated. If ≥ 1 response observed, then 9 more pts will be enrolled, for a total of 21 pts. If ≥ 3 CR are observed, the proposed therapy will be considered as promising for further evaluation. Secondary endpoints include non-CNS RR per RECIST v1.1, median CNS, non-CNS and overall progression-free survival, overall survival and safety. Exploratory endpoints include changes in intratumoral biomarkers (CTLs, PDL1, chemokines) in pre- and post-treatment peripheral tumor biopsies and immune changes in the blood. Clinical trial information: NCT04348747 .

Utility of pharmacogenomic testing in predicting intolerance to BTK inhibitors.

7541 Background: Oral inhibitors of Bruton’s tyrosine kinase (BTKi) are used for a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL). Real-world data has demonstrated that BTKi discontinuation is commonly due to intolerance, but contributing factors are not fully understood. Prior work suggests that cytochrome P450 (CYP) polymorphisms may increase the risk of targeted therapy discontinuation in CLL. We utilized pharmacogenomic (PGx) testing in Veterans treated with BTKi to evaluate the potential contribution of CYP polymorphisms to intolerance and responses to BTKi. Methods: We identified Veterans receiving care through the Veterans Administration (VA) who were prescribed a BTKi and underwent testing through the Pharmacogenomic Testing for Veterans (PHASER) program, currently offered at 22 VA facilities. We analyzed factors including time on BTKi therapy, reasons for discontinuation, and use of concomitant medications known to strongly inhibit CYP. Event-free survival (EFS) was defined as time from BTKi initiation to discontinuation. Results: Eighty-nine Veterans treated with BTKi who had PGx testing were identified, of which 97% (86) were male and 85% (76) were diagnosed with CLL. Other diagnoses included LPL (4), MCL (3), and MZL (3). Seventy-seven patients (pts) were treated with ibrutinib, nine with acalabrutinib and three with zanubrutinib. Three pts had poor metabolizer genotype (PMG) for CYP2C19 and 25 pts received strong CYP2C19 inhibitors (inh). Thirty-two pts had PMG for CYP2D6, and 12 pts received strong CYP2D6 inh. With a median follow up time of 38.9 months, 25 pts (28%) permanently discontinued due to intolerance and 10 pts (11%) progressed on BTKi therapy. Another 25 pts temporarily discontinued therapy. Median duration of BTKi therapy was 11.0 months for pts discontinuing for intolerance, 23.2 months for pts discontinuing for progression, and 38.5 months for pts not discontinuing therapy. Reasons for intolerance included arrhythmia, bleeding, and infections. EFS due to intolerance or progression was not statistically different between pts who were either CYP2C19 PMG or who received strong CYP2C19 inh, compared to all other pts. Interestingly, EFS due to intolerance alone was statistically different comparing these groups (p = 0.014, median 49.4m vs NR), but EFS due to progression was not (p = 0.76, median 79.6m vs NR). EFS was not significantly different comparing pts who were either receiving strong CYP2D6 inh or were PM to those who were not. Conclusions: We found that Veterans who were treated with BTKi and who either took concomitant strong CYP2C19 inh or had a CYP2C19 PMG were more likely to have intolerable side effects of BTKi therapy leading to discontinuation. Our results suggest that evaluating polypharmacy and PGx factors should be considered when prescribing BTKi.

Investigating the patterns of treatment failure in patients with advanced stage III and IV melanoma receiving adjuvant therapy.

e21532 Background: The landscape of treatment of patients with resectable stage III melanoma has evolved considerably given studies demonstrating survival benefit of anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy in the adjuvant setting, as well as surgical changes relating to the Multicenter Selective Lymphadenectomy Trial (MSLT)-II trial. Currently, the decision to treat with anti-PD-1 or BRAF/MEKi therapy in the adjuvant setting is dependent upon patient, provider, and institutional preferences, but no comparative analysis has been done between adjuvant therapy options. Methods: Clinical data from 141 surgically-resected staged III and oligometastatic stage IV patients receiving adjuvant anti-PD-1 (n = 66), BRAF/MEKi (n = 36), or surgery only (n = 39) between 2017 and 2021 was analyzed retrospectively. Primary endpoints were overall survival (OS) and progression free survival (PFS) between the three treatment groups. Secondary endpoints include the duration of adjuvant treatment and reasons for termination of therapy. Results: During a mean follow-up period of 17 months, 33.3% of anti-PD-1 patients and 16.7% of BRAF/MEKi patients experienced recurrence, while 41.0% of the surgery only patients experienced recurrence. In univariate Cox regression analyses of the survival data, patients who received anti-PD-1 (HR = 0.46, 95% CI: 0.25-0.87, p = 0.016) or BRAF/MEKi (HR = 0.44, 95% CI:0.21-0.90, p = 0.024) had significantly improved PFS compared to patients treated with surgery only, but the OS was not significantly different with treatment. A multivariate Cox regression model was performed, adjusting for age, sex, and melanoma disease stage. In this model, anti-PD-1 was still associated with improved PFS (HR = 0.33, p &lt; 0.001), while BRAF/MEKi also trended towards improved PFS, but was not statistically significant (HR = 0.54, p = 0.13). Other associations include males having a significantly worse PFS (HR = 2.32, p = 0.009) and OS (HR = 5.86, p = 0.02), and patients with stage IIIC or worse disease having worse PFS (HR = 4.56, p &lt; 0.001), but not significantly worse OS (HR = 4.84, p = 0.05). The average duration of adjuvant therapy was similar between both groups (250-260 days) with approximately half of the patients completing the treatment course. A larger proportion of BRAF/MEKi patients stopped treatment due to intolerable side effects compared to anti-PD-1 patients (83.3% vs. 64.0%). Conclusions: Adjuvant treatment decreases the chance of recurrence compared to surgery alone, but the benefit on overall survival is still inconclusive. Male and more advanced stage III melanoma prior to initiating adjuvant therapy are factors associated with an increased likelihood of recurrence. Although it appears that more patients terminated BRAF/MEKi therapy early due to side effects compared to anti-PD-1, additional follow-up will be needed to confirm this finding.

Surgery as first-line treatment for prolactinoma? Discussion of the literature and results of a consecutive series of surgically treated patients

Initial treatment for prolactinoma is usually conservative with dopamine agonists. However, the duration of treatment is often lifelong and can be associated with significant side effects. Surgical outcomes are usually favorable and treatment complications low, raising the question whether surgical therapy should be included earlier in the treatment of prolactinoma. The aim of this study was to analyze the outcome of surgical resection of prolactinomas at our institution, to compare it with other published surgical and conservative series and to discuss the role of surgery in modern prolactinoma therapy. The authors reviewed a database of single-center consecutively operated prolactinoma cases and analyzed the extent of resection (EOR), endocrinological and neurological outcomes, and complications. Thirty patients were analyzed. Mean patient age was 37.2 ± 15.5 years (range 16–76) and consisted of 17 (56.7%) females and 13 (43.3%) males. Twenty-one patients (70%) failed medical therapy, the main reasons being intolerable side effects in 11 cases (52.4%) and insufficient response in 10 cases (47.6%). Nine patients (30%) received no medical treatment prior to surgery, of which five (55.6%) were operated because of pituitary apoplexy, two (22.2%) because of acute visual deterioration and two (22.2%) refused medical treatment and opted for surgery as first-line treatment. Of the 30 operated tumors, 56.7% (n = 17) were microadenomas, 30% (n = 9) were macroadenomas (≥ 10 mm), and 13.3% (n = 4) were giant adenomas (≥ 40 mm). GTR was achieved in 75% (n = 21) of cases. The overall remission rate was 63.3%. MRI showed a residual tumor in seven patients (25%), typically with invasive growth. Postoperative CSF leaks did not occur. Mean follow-up was 34.9 ± 60.3 months (range 0–246 months). Endocrine remission was defined as a morning fasting basal PRL level of 22.3 < ng/mL and measured at the last available follow-up. Postoperative Prolactine levels were missing in three patients. Our analysis describes a highly selected sample with a disproportionate number of larger, invasive tumors and emergency cases. Nevertheless, the results are satisfactory and comparable with other published series. The consistently good results of transphenoidal surgery, especially for microprolactinomas, have led to a greater acceptance of surgery in the treatment of prolactinomas in recent years. The timing of surgery in each individual case must be determined by a multidisciplinary team to ensure the best possible outcome.