Pembrolizumab-Induced Anti-GBM Glomerulonephritis: A Case Report.

Immune checkpoint inhibitors are known to have a wide range of autoimmune toxicities, such as acute interstitial nephritis. Immunotherapy induced glomerulonephritis has been described, but anti-glomerular basement membrane disease (anti-GBM) is rarely reported. We present a case report of a 60-year-old woman with squamous cell carcinoma of the cervix who was treated with pembrolizumab, an anti-programmed cell death protein 1, and who developed severe acute kidney injury 4 months after therapy initiation. The immune workup showed a positive serum anti-GBM antibody (24 U/mL). The kidney biopsy showed crescentic glomerulonephritis with linear immunoglobulin G2 glomerular basement membrane staining, compatible with anti-GBM glomerulonephritis. The patient was treated with plasmapheresis, IV steroids, and cyclophosphamide, but she developed kidney failure, necessitating dialysis. Few case reports, such as the present case, provide a possible link between anti-GBM glomerulonephritis and immune checkpoint inhibitors, warranting early clinical suspicion and investigation in patients who are treated with these agents and subsequently develop acute kidney injury.

The ever wider clinical spectrum of RMND1-related disorders and limitedness of phenotype-based classifications.

RMND1 has been identified as a mitochondriopathy-associated gene less than 12 years ago. The most common phenotype related to this gene is an early onset, severe form of encephalomyopathy that leads to death in a medium time of three years after birth. However, milder and later onset presentations have been reported in some individuals, including two in whom the mitochondriopathy was identified at ~ 40 years of age, and the early onset presentations have been the object of no reports in those who survived beyond age 10. It is thus unclear how lethal RMND1-related conditions really are. We herein describe the oldest case to have been identified hitherto with this condition, i.e., that of a white female who was 61 at the time of diagnosis but was still active in her everyday life. The gene defect identified was nonetheless associated with many manifestations including ovarian insufficiency and sensorineural hearing loss (two features of what is currently designated as Perrault syndrome) as well as chronic renal failure, asymptomatic myopathy, leukopenia, and a few others. In our opinion, this case is of great translational interest for at least three reasons. First, it hints towards the possibility of near-normal life expectancies in some if not many individuals with RMND1 insufficiency. Second, it underlines the wide clinical spectrum associated with this gene. Third, it brings us to question the use of eponyms and syndromic features to identify the true etiology of multisystemic phenotypes. KEY MESSAGES: RMND1-related conditions typically manifest at an early age with a progressive and lethal form of encephalomyopathy. More benign presentations have been described with some being categorized as Perrault syndrome but none have been diagnosed after the age of 45. The clinical spectrum and presenting age of RMND1-related mitochondriopathies are probably much more varied than implied in the current literature. The case reported in this manuscript illustrates the limitedness of phenotype-based classifications of genetic disorders to identify the defect at cause.

Real-world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study.

OBJECTIVES: We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra-skeletal mesenchymal CS (ESMC). METHODS: After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12-76); median starting dose was 60 mg for CABO (n = 37, range 40-60) and 120 mg for REGO (n = 29, range 40-160). Twenty-eight (42.4%) patients required dose reduction: hand-foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7-13.1); 13.4 months (n = 18, 95% CI 3.4-27.2), 8.1 (n = 4, 95% CI 4.1-9.3) and 18.2 (n = 5, 95% CI (10.4-na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8-5), 3.9 (n = 18, 95% CI 2.1-5.9), 5.53 (n = 4. 95% CI 2.13-NA) and 11.4 (n = 5, 95% CI 1.83-14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis. CONCLUSION: Our real-world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research.

Durvalumab therapy following chemoradiation compared with a historical cohort treated with chemoradiation alone in patients with stage III non-small cell lung cancer: A real-world multicentre study.

BACKGROUND: The PACIFIC trial demonstrated that durvalumab therapy following chemoradiation (CRT) was associated with improved overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC). It is unclear whether the results obtained as part of randomised controlled trials are a reflection of real-world (RW) data. Several questions remain unanswered with regard to RW durvalumab use, such as optimal time to durvalumab initiation, incidence of pneumonitis and response in PD-L1 subgroups. METHODS: In this multicentre retrospective analysis, 147 patients with stage III NSCLC treated with CRT followed by durvalumab were compared with a historical cohort of 121 patients treated with CRT alone. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test in univariate analysis. Multivariate analysis was performed to evaluate the effect of standard prognostic factors for durvalumab use. RESULTS: Median OS was not reached in the durvalumab group, compared with 26.9 months in the historical group (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.37-0.85, p = 0.001). In the durvalumab group, our data suggest improved 12-month OS in patients with PD-L1 expression ≥50% (100% vs 86%, HR: 0.25, 95% CI: 0.11-0.58, p = 0.007). There was no difference in OS between patients with a PD-L1 expression of 1-49% and patients with PD-L1 expression <1%. Delay in durvalumab initiation beyond 42 days did not impact OS. Incidence of pneumonitis was similar in the durvalumab and historical groups. In the durvalumab group, patients who experienced any-grade pneumonitis had a lower 12-month OS than patients without pneumonitis (85% vs 95%, respectively; HR: 3.3, 95% CI: 1.2-9.0, p = 0.006). CONCLUSIONS: This multicentre analysis suggests that PD-L1 expression ≥50% was associated with favourable OS in patients with stage III NSCLC treated with durvalumab after CRT, whereas the presence of pneumonitis represented a negative prognostic factor.

EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes.

PURPOSE: Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized. METHODS: We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed. RESULTS: We included 67 patients-38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation. CONCLUSION: There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.

Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion.

We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired CCDC6-RET fusion. Although RET fusions have been identified in resistant EGFR-mutant non-small cell lung cancer (NSCLC), their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of RET fusions in an EGFR-mutant cancer, we expressed CCDC6-RET in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR tyrosine kinase inhibitors (TKI). The selective RET inhibitors BLU-667 and cabozantinib resensitized CCDC6-RET-expressing cells to EGFR inhibition. Finally, we treated 2 patients with EGFR-mutant NSCLC and RET-mediated resistance with osimertinib and BLU-667. The combination was well tolerated and led to rapid radiographic response in both patients. This study provides proof of concept that RET fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients. SIGNIFICANCE: The role of RET fusions in resistant EGFR-mutant cancers is unknown. We report that RET fusions mediate resistance to EGFR inhibitors and demonstrate that this bypass track can be effectively targeted with a selective RET inhibitor (BLU-667) in the clinic.This article is highlighted in the In This Issue feature, p. 1494.