Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who ...discontinue combination therapy due to irAEs is not known.
We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs.
Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1–2, seven grade 3–4, and one grade 5 Steven–Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1–2 and 6 grade 3–4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03).
Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.
Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one ...has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients.
Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified.
One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N=52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N=6) or neurological disorders (N=5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N=67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3–4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.
In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.
Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune ...checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma.
IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population.
Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months interquartile range (IQR) 4.8-9.9 for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months 95% confidence interval (CI) 3.8-7.2 with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab.
Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.
•Cobimetinib plus atezolizumab did not improve PFS versus pembrolizumab monotherapy in BRAFV600 wild-type advanced melanoma.•Results were consistent across prespecified subgroups according to known prognostic factors.•Higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms.•As expected, the combination was associated with a higher incidence of AEs than pembrolizumab monotherapy.
Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell ...death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636).
In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability.
Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 interquartile range (IQR) 57.0-73.0 years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% 95% confidence interval (CI) 12% to 36%, with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached 95% CI 10 months–not evaluable (NE). The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue 23 (43%) and diarrhoea 20 (37%). There were no treatment-related deaths.
Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.
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•There is no standard second-line treatment for patients with mBCC who progress on or are intolerant to HHIs.•In this phase II study (NCT03132636), cemiplimab showed an ORR of 22% and acceptable safety in patients with mBCC.•This is the first study to show activity of a systemic therapy in mBCC after HHI use.•The results support the use of cemiplimab in patients with mBCC who progress on or are intolerant to HHIs.•Cemiplimab addresses an unmet need by providing a treatment option for patients with mBCC following first-line HHI therapy.
Brain metastases are common in advanced melanoma and cause death in >50% of patients. Until recently, median survival was only ∼4 months. Improved systemic treatment including immune checkpoint ...inhibitors and combinations of BRAF/MEK inhibitors, however, has significantly improved intracranial tumor response and survival. In addition, advances in radiation therapy have also improved the intracranial outcomes for advanced melanoma patients with brain metastases (MBM). There has long been concern that systemic treatment of the central nervous metastases would be ineffective due to inability of active agents to cross an intact blood–brain barrier. Recent studies have shown, however, that highly active systemic therapy can have significant benefit in these patients. When determining a patient’s treatment, the important factors in predicting the likelihood of benefit including the presence of neurologic symptoms, the number and size of brain metastases, performance status/status of extracranial disease, and BRAF mutation status should all be considered. In this review, we will discuss the challenges and treatment options for patients with advanced melanoma and brain metastases.
•For asymptomatic MBM, intracranial response and survival high with ipilimumab/nivolumab and may be possible to omit radiation in select patients.•For symptomatic MBM, outcomes far worse with immunotherapy and localized treatment such as stereotactic radiosurgery usually needed for control.•Multidisciplinary approach with team of med-oncs, rad-oncs. neurosurgery, and enrollment into MBM trials crucial for optimal treatments.
First PCSK-9 mutant patient in Turkey Kaya Kocabas, E; Kayikcioglu, M; Tetik Vardarli, A ...
Atherosclerosis,
September 2016, Letnik:
252
Journal Article
The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance ...develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.
Seventy-one adults with advanced STS who received ⩽ 2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).
There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N = 11) over single agent (N = 10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P = 0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).
While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.
The Chinese Communist Party (CCP) granted Sinophone Muslims minzu 民族 (ethnicity/nationality) status, finally settling a debate on the nature of Chinese Muslim identity. This article argues that the ...CCP’s decision should be contextualized within Nationalist-era politics. Sinophone Muslim intellectuals strategically employed their historical, cultural, and political resources to negotiate with the Nationalist Party (GMD) to secure autonomous rights for all Muslims of China. The secular state, however, denied autonomy to religious groups. As such, a cohort of influential Sinophone Muslim intellectuals wrapped their demands in the minzu discourse. Negotiations with the GMD finally reached a compromise, which granted a representative quota in the National Assembly exclusively to Sinophone Muslims, recognizing their distinct status on the grounds of their “special ways of living and habits.” When the CCP confirmed Sinophone Muslims’ minzu identity, it also legalized their de facto status already recognized by the GMD.
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