LIBRETTO-431: Confirming the Superiority of Selpercatinib to Chemotherapy and the Lack of Efficacy of Immune Checkpoint Inhibitors in Advanced RET Fusion-Positive (RET+) NSCLC, Another Unique Never-Smoker Predominant Molecular Subtype of NSCLC.

Selpercatinib, a potent and highly selective RET kinase inhibitor with significant CNS activity, has recently gained US approval for the treatment of NSCLC harboring RET fusions (RET+) based on a large-scale single-arm study. The LIBRETTO-431 trial was the global pivotal registration phase 3 trial comparing selpercatinib to platinum-based chemotherapy with or without pembrolizumab as the first-line treatment of patients with advanced RET+ NSCLC. Never-smokers constituted 67.4% of the RET+ NSCLC patients enrolled. KIF5B-RET made up the vast majority (77%) of the RET+ fusion variant with known fusion partner. The results of this study demonstrated significant improvement in progression-free survival (PFS) benefit as well as impressive intracranial disease response in participants treated with selpercatinib as compared to those treated with chemotherapy, with a HR [hazard ratio] of 0.46 (95% CI 0.33-0.70; P < 0.001) for the intention-to-treat (ITT)-pembrolizumab group and HR of 0.46 (95% CI 0.31-0.70, P < 0.001) for the overall ITT-group of patients. The addition of pembrolizumab to platinum/pemetrexed chemotherapy resulted in numerically identical PFS (11.2 months). These results point to selpercatinib's superiority to traditional chemotherapy regimens in the treatment of NSCLC harboring RET fusions and add to literature on the salience of targeted precision oncology and lack of efficacy of immune checkpoint inhibitor in NSCLC patients with never-smoker predominant actionable driver mutations. RET+ NSCLC should be added to the list of molecular subtypes (EGFR+, ALK+, ROS1+) of NSCLC to be excluded in chemoimmunotherapy trial.

Overcoming Central ß-Sheet #6 (Cß6) ALK Mutation (L1256F), TP53 Mutations and Short Forms of EML4-ALK v3/b and v5a/b Splice Variants are the Unmet Need That a Re-Imagined 5th-Generation (5G) ALK TKI Must Deliver.

Despite the development and approval of seven anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) spanning over three "generations" since the discovery of ALK fusion positive (ALK+) non-small cell lung cancer (NSCLC), there remains intrinsic and acquired resistances to these approved TKIs. Currently, a fourth-generation (4G) ALK TKI, NVL-655, is being developed to attack some of the unmet needs such as compound resistance mutations in cis. However, EML4-ALK variant 3 and TP53 mutations are intrinsic genomic alterations that negatively modulate efficacy of ALK TKIs. Potentially, in the shifting landscape where lorlatinib should be the first-line ALK TKI of choice based on the CROWN trial, the central ß-sheet #6 (Cß6) mutation ALK L1256F will be the potential acquired resistance mutation to lorlatinib which may be resistant to current ALK TKIs. Here we opine on what additional capacities a putative fifth-generation (5G) ALK TKI will need to possess if it can be achieved in one single molecule. We propose randomized trial schemas targeting some of the intrinsic resistance mechanisms that will lead to approval of a prototypic fifth-generation (5G) ALK TKI and actually be beneficial to ALK+ NSCLC patients rather than just design a positive pivotal superiority trial for the sole purpose of drug approval.

MARIPOSA-2: Is the treatment worse than the disease?

Passaro et al.1 demonstrated in EGFR+ NSCLC post-1L osimertinib both "quad" (lazertinib [L] + amivantamab [A] + chemotherapy [CP]) and "triplet" (ACP) regimens achieved improved median progression-free survival over CP. Nonetheless, a high incidence of adverse events requiring dose modifications may limit adaptation of the triplet and quad MARIPOSA-2 regimens.

ALESIA 5-Year Update: Alectinib at 600 mg Twice Daily Gives Lorlatinib a Run for Its Money in Asia.

Alectinib, a next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has demonstrated superior progression-free survival over crizotinib with both 300 mg twice daily (J-ALEX) or 600 mg twice daily (ALEX, ALESIA) dosing in three pivotal clinical trials. Given the similar median PFS achieved in the J-ALEX trial and the Asian subgroup of the ALEX trial, there remains debate about the optimal alectinib dose for Asians. The third pivotal alectinib trial, ALESIA, which was conducted exclusively in Asia to support the registration of alectinib in China, utilized 600 mg alectinib twice daily. The mature PFS was not reached at the initial publication of ALESIA. At ESMO Asia 2022, the 5-year update of ALESIA was presented with an impressive mature investigator-assessed PFS of 41.6 months (95% CI 33.1-58.9), which is numerically longer than the mature PFS of 34.1 months achieved by alectinib at 300 mg twice daily in the J-ALEX trial. Based on these results, as well as retrospective pharmacokinetic and responses and PFS data, Alectinib at 600 mg twice daily is the optimal dose for Asians. This has been based on the ALESIA trial and on the retrospective pharmacokinetic and responses and PFS data and has set the benchmark for ALK TKI as the first-line treatment for advanced ALK+ NSCLC in Asia. Importantly, lorlatinib, another next generation ALK TKI, also achieved an impressive hazard ratio with a still immature PFS in all patients, including Asian patients, in a recent subgroup analysis after a median follow-up time of 36.7 months. We await the final mature PFS of lorlatinib overall and for Asian patients in the CROWN trial to see if lorlatinib will set a new standard.

From ASCEND-5 to ALUR to ALTA-3, an Anti-Climactic End to the Era of Randomized Phase 3 Trials of Next-Generation ALK TKIs in the Crizotinib-Refractory Setting.

The competing roles of various next-generation ALK TKIs in the first and second line treatment setting of advanced ALK+ NSCLC were based on many phase 3 clinical trials in both the first-line and crizotinib-refractory settings. The approval of all next-generation ALK TKIs was first in the crizotinib-refractory setting, based on a large-scale Phase 2 trial, and was then followed by at least one global randomized phase 3 trial comparing to platinum-based chemotherapy (ASCEND-4) or to crizotinib (ALEX, ALTA-1L, eXalt3, CROWN). In addition, three randomized phase 3 trials in the crizotinib-refractory setting were also conducted by next-generation ALK TKIs that were developed earlier before the superiority of next-generation ALK TKIs was demonstrated in order to secure the approval of these ALK TKIs in the crizotinib-refractory setting. These three crizotinib-refractory randomized trials were: ASCEND-5 (ceritinib), ALUR (alectinib), and ALTA-3 (brigatinib). The outcome of the ATLA-3 trial was recently presented closing out the chapter where next-generation ALK TKIs were investigated in the crizotinib-refractory setting as they have replaced crizotinib as the standard of care first-line treatment of advanced ALK+ NSCLC. This editorial summarizes the results of next-generation ALK TKIs in randomized crizotinib-refractory trials and provides a perspective on how natural history of ALK+ NSCLC may potentially be altered with sequential treatment. ALTA-3 compared brigatinib to alectinib, showing that both achieved near identical blinded independent review committee (BIRC)-assessed progression-free survival (PFS) (19.2-19.3 months). Importantly, 4.8% of brigatinib-treated patients developed interstitial lung disease (ILD) while no alectinib-treated patients developed ILD. Dose reduction and discontinuation due to treatment-related adverse events were 21% and 5%, respectively, for brigatinib-treated patients compared to 11% and 2%, respectively, for alectinib-treated patients. Upon analysis of these findings, we speculate that brigatinib may have a diminishing role in the treatment of advanced ALK+ NSCLC.

From preclinical efficacy to 2022 (36.7 months median follow -up) updated CROWN trial, lorlatinib is the preferred 1st-line treatment of advanced ALK+ NSCLC.

Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various countries. In Ba/F3 cells, lorlatinib achieved lowest IC50 among these 6 ALK TKIs against EML4-ALK variant 1 or 3. In 2022, 7 abstracts reported updated efficacy and safety data from CROWN. With a median follow-up time of 36.7 months, the 3-year progression-free survival (PFS) rate was 63.5% for lorlatinib-treated patients and the median PFS of lorlatinib still has not been reached. Importantly, post-lorlatinib treatment median PFS2 was 74.0% at 3-years. Lorlatinib-treated Asian patients achieved similar 3-year PFS rate as overall lorlatinib-treated patients. Median PFS was 33.3 months among lorlatinib-treated EML4-ALK v3 patients. CNS AE occurred fewer than 1 event per patient over the median follow-up time of 36.7 months and most resolved without intervention. Altogether these data affirm our belief that lorlatinib should be the treatment of choice of advanced ALK+ NSCLC.

CheckMate-722: The Rise and Fall of Nivolumab with Chemotherapy in TKI-Refractory EGFR-Mutant NSCLC.

The treatment of non-small cell lung cancer (NSCLC) has increasingly been driven by the presence of targetable driver mutations, including epidermal growth factor receptor (EGFR) mutations. Tyrosine receptor inhibitors (TKIs) have subsequently emerged as the standard-of-care treatment for EGFR-mutant NSCLC. However, there are currently limited treatment options for TKI-refractory EGFR-mutant NSCLC. It is in this context that immunotherapy has arisen as a particularly promising player, especially in the context of favorable results from the ORIENT-31 and IMpower150 trials. Thus, the results of the CheckMate-722 trial were highly anticipated, as it was the first global trial to evaluate the efficacy of immunotherapy in addition to standard platinum-based chemotherapy, specifically in the treatment of EGFR-mutant NSCLC post-progression on TKIs.

CodeBreak 200: Sotorasib Has Not Broken the KRASG12C Enigma Code.

Thirteen percent of non-small cell lung cancer (NSCLC) patients are estimated to have the KRAS G12C mutation. Sotorasib is a novel KRAS G12C inhibitor that has shown promising results in preclinical and clinical studies, granting its conditional approval by the FDA in May 2021. The phase I clinical trial resulted in a confirmed response of 32% and progression free survival (PFS) of 6.3 months while the phase II trial resulted in a confirmed response of 37.1% and a PFS of 6.8 months. It was also shown to be tolerable with most subjects experiencing grade one or two adverse events, most commonly diarrhea and nausea. The CodeBreaK 200 phase III trial data have recently resulted and showed an improved PFS with the use of sotorasib at 5.6 months compared to that of standard docetaxel of 4.5 months in locally advanced or unresectable metastatic KRAS G12C NSCLC previously treated with at least one platinum-based chemotherapy and checkpoint inhibitor. The lower than expected PFS of sotorasib from the phase III trial opens up opportunities for other G12C inhibitors to join the field. Indeed, adagrasib, another G12C inhibitor just recently gained FDA accelerated approval in NSCLC patients based on the KRYSTAL-1 study where the response rate was 43% with a median duration of response of 8.5 months. With novel agents and combinations, the field of KRAS G12C is quickly evolving. While sotorasib was an exciting start, there is more to do to break the KRAS G12C Enigma code.

Association of preconception mixtures of phenol and phthalate metabolites with birthweight among subfertile couples.

Although parental preconception exposure to some phenols and phthalates have been associated with reduced birthweight, few studies have examined these chemicals as complex mixtures. Methods: We included 384 mothers and 211 fathers (203 couples) who gave birth to 384 singletons from a prospective cohort of couples seeking fertility evaluation. Urinary concentrations of bisphenol A (BPA), parabens, and 11 phthalate metabolites including those of di(2-ethylhexyl) phthalate (DEHP) were examined. Birthweight was abstracted from delivery records. We used principal component analysis and Bayesian Kernel Machine Regression (BKMR) to examine maternal and paternal preconception mixtures in relation to singleton birthweight. We also fit couple-based BKMR with hierarchical variable selection to assess couples' joint mixtures in relation to birthweight. Results: PC scores of maternal and paternal preconception low molecular weight phthalates factor, and paternal preconception DEHP-BPA factor were associated with reduced birthweight. In BKMR models, we found that maternal preconception monoethyl phthalate and BPA concentrations, and paternal preconception mono-n-butyl phthalate concentrations were inversely associated with birthweight when the remaining mixture components were held at their median concentrations. In couple-based BKMR models, paternal preconception biomarkers contributed more to couples' joint effect on birthweight compared with maternal preconception biomarkers. A decreasing trend of birthweight was observed across quantiles of maternal, paternal, and couples' total preconception mixture concentrations, respectively. Conclusions: Results from this preconception cohort of subfertile couples suggest a complex interplay between paternal and maternal preconception exposure to mixtures of nonpersistent chemicals, with both parental windows of exposure jointly contributing to reduced birthweight.

A novel Vascular Leak Index identifies sepsis patients with a higher risk for in-hospital death and fluid accumulation.

PURPOSE: Sepsis is a leading cause of morbidity and mortality worldwide and is characterized by vascular leak. Treatment for sepsis, specifically intravenous fluids, may worsen deterioration in the context of vascular leak. We therefore sought to quantify vascular leak in sepsis patients to guide fluid resuscitation. METHODS: We performed a retrospective cohort study of sepsis patients in four ICU databases in North America, Europe, and Asia. We developed an intuitive vascular leak index (VLI) and explored the relationship between VLI and in-hospital death and fluid balance using generalized additive models (GAM). RESULTS: Using a GAM, we found that increased VLI is associated with an increased risk of in-hospital death. Patients with a VLI in the highest quartile (Q4), across the four datasets, had a 1.61-2.31 times increased odds of dying in the hospital compared to patients with a VLI in the lowest quartile (Q1). VLI Q2 and Q3 were also associated with increased odds of dying. The relationship between VLI, treated as a continuous variable, and in-hospital death and fluid balance was statistically significant in the three datasets with large sample sizes. Specifically, we observed that as VLI increased, there was increase in the risk for in-hospital death and 36-84 h fluid balance. CONCLUSIONS: Our VLI identifies groups of patients who may be at higher risk for in-hospital death or for fluid accumulation. This relationship persisted in models developed to control for severity of illness and chronic comorbidities.

Parental preconception exposure to phenol and phthalate mixtures and the risk of preterm birth.

BACKGROUND: Parental preconception exposure to select phenols and phthalates was previously associated with increased risk of preterm birth in single chemical analyses. However, the joint effect of phenol and phthalate mixtures on preterm birth is unknown. METHODS: We included 384 female and 211 male (203 couples) participants seeking infertility treatment in the Environment and Reproductive Health (EARTH) Study who gave birth to 384 singleton infants between 2005 and 2018. Mean preconception urinary concentrations of bisphenol A (BPA), parabens, and eleven phthalate biomarkers, including di(2-ethylhexyl) phthalate (DEHP) metabolites, were examined. We used principal component analysis (PCA) with log-Poisson regression and Probit Bayesian Kernel Machine Regression (BKMR) with hierarchical variable selection to examine maternal and paternal phenol and phthalate mixtures in relation to preterm birth. Couple-based BKMR model was fit to assess couples' joint mixtures in relation to preterm birth. RESULTS: PCA identified the same four factors for maternal and paternal preconception mixtures. Each unit increase in PCA scores of maternal (adjusted Risk Ratio (aRR): 1.36, 95%CI: 1.00, 1.84) and paternal (aRR: 1.47, 95%CI: 0.90, 2.42) preconception DEHP-BPA factor was positively associated with preterm birth. Maternal and paternal BKMR models consistently presented the DEHP-BPA factor with the highest group Posterior Inclusion Probability (PIP). BKMR models further showed that maternal preconception BPA and mono(2-ethyl-5-hydroxyhexyl) phthalate, and paternal preconception mono(2-ethylhexyl) phthalate were positively associated with preterm birth when the remaining mixture components were held at their median concentrations. Couple-based BKMR models showed a similar relative contribution of paternal (PIP: 61%) and maternal (PIP: 77%) preconception mixtures on preterm birth. We found a positive joint effect on preterm birth across increasing quantiles of couples' total mixture concentrations. CONCLUSION: In this prospective cohort of subfertile couples, maternal BPA and DEHP, and paternal DEHP exposure before conception were positively associated with preterm birth. Both parental windows jointly contributed to the outcome. These results suggest that preterm birth may be a couple-based pregnancy outcome.

Reproductive and metabolic determinants of granulosa cell dysfunction in normal-weight women with polycystic ovary syndrome.

OBJECTIVE: To determine the degree to which E2 hyperresponsiveness to FSH and antimüllerian hormone (AMH) overproduction in normal-weight women with polycystic ovary syndrome (PCOS) correlate with increased antral follicle number (AFN), hyperandrogenism, and/or metabolic dysfunction. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): Seven normal-weight women with PCOS (1990 National Institutes of Health criteria) ages 20-34 years and 13 age- and body mass index- (BMI-; 18.5-25 kg/m2) matched normoandrogenic ovulatory women were studied. INTERVENTION(S): All women underwent basal serum hormone and metabolic measurements, FSH stimulation testing with transvaginal ovarian sonography, frequently sampled IV glucose tolerance testing, and whole-body dual-energy x-ray absorptiometry. MAIN OUTCOME MEASURE(S): Serum hormone/metabolite levels, 24-hour serum E2 response to 150 IU recombinant human (rh) FSH infusion, AFN, insulin sensitivity, and body mass measurements. RESULT(S): Serum E2 responsiveness to rhFSH and AMH levels were greater in women with PCOS than in BMI- and age-matched control women, as were serum androgen levels, AFN, and abdominal fat mass. In all women combined, serum E2 responsiveness to rhFSH was associated with AFN. Serum AMH levels, however, positively correlated with AFN but remained positively correlated with serum LH and free T levels and negatively correlated with total body fat and percent body fat, adjusting for AFN. CONCLUSION(S): In normal-weight women with PCOS, serum E2 hyperresponsiveness to rhFSH represents increased AFN, while elevated serum AMH levels reflect opposing effects of stimulatory reproductive (hyperandrogenism and increased AFN) versus inhibitory metabolic (body fat) factors. Given the small number of subjects reported, additional follow-up studies are required to confirm these data.

Gastric Spindle Cell Neuroendocrine Tumor Mimicking Gastrointestinal Stromal Tumor: Unique Morphology and Diagnostic Pitfall.

Gastric neuroendocrine tumors (GNETs) with spindle cell morphology are extremely rare. We present a case of a 49-year-old female patient with a history of systemic lupus erythematosus, Sjogren's syndrome, and gastroesophageal reflux disease. She was initially thought to have a spindle cell gastrointestinal stromal tumor per histological studies of the fundic polypectomy samples. Immunohistochemically, the tumor cells were negative for CD117, and CD34, but positive for chromogranin, synaptophysin, and CD56 with a 6% Ki-67 index, consistent with a spindle cell-type well differentiated neuroendocrine tumor, World Health Organization (WHO) Grade 2. To the best of our knowledge, this is the first case report of a gastric spindle cell neuroendocrine tumor in the English literature.

Voicing Ageism in Nursing Home Dementia Care.

Elderspeak (i.e., infantilizing communication) is a common form of ageism that has been linked to resistiveness to care in nursing home residents with dementia. Nursing home staff use elderspeak by modifying speech with older residents based on negative stereotypes, which results in patronizing communication that provides a message of incompetence. The purpose of the current secondary analysis was to describe communication practices used by nursing home staff that reflect ageism. Transcripts of 80 video recordings of staff-resident communication collected during nursing home care activities were re-analyzed to identify specific elderspeak patterns, including diminutives, collective pronouns, tag questions, and reflectives. Elderspeak was used in 84% of transcripts, and specifically during bathing, dressing, oral care, and other activities. Collective pronoun substitution occurred most frequently-in 69% of recorded conversations. Subgroup analysis of the inappropriate terms of endearment found that "honey"/"hon" and "sweetheart"/"sweetie" were most commonly used. [Journal of Gerontological Nursing, 43(9), 16-20.].