Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

Proposed high-risk screening protocol for Fabry disease in patients with renal and vascular disease.

Fabry disease is a complex, multisystemic and clinically heterogeneous disease with prominent urinary excretion of globotriaosylceramide (Gb(3)), the principal substrate of the deficient enzyme, alpha-galactosidase A. Some measure of specific treatment is possible with enzyme replacement therapy, which can be applied safely and effectively to Fabry patients. Incidence estimations of Fabry disease vary widely from 1:55 000 to 1:3000 male births. The true incidence is likely to be higher than originally thought, owing to the existence of milder variants of the disease. The main complications of Fabry disease are a 100-fold increased risk of ischaemic stroke, cardiac disease, a wide variety of arrhythmias, valvular dysfunction and cardiac vascular disease, as well as progressive renal failure usually associated with significant proteinuria. These clinical manifestations are non-specific and are often mistaken for symptoms of other disorders, thus complicating the confirmation of diagnosis. Other clinical features of the disease are often absent (angiokeratoma), subtle (corneal opacities and hypohidrosis), or unaccompanied by specific physical findings (acroparaesthesias) indicating the true nature of the underlying disease. We propose the hypothesis that alpha-galactosidase A deficiency is a modifiable cardiovascular risk factor in the general population. This hypothesis may be tested by a non-invasive high-risk screening protocol for Fabry patients with ischaemic strokes and a variety of cardiac, and renal complications. These patients would benefit from diagnosis, appropriate treatment, follow-up and surveillance. Early detection of Fabry patients would also benefit affected relatives, many of whom do not have a clear diagnosis of their clinical condition.

Identification of 3-methylglutarylcarnitine. A new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.

Deficiency of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) lyase affects the metabolism of leucine as well as ketogenesis. This disorder is one of an increasing list of inborn errors of metabolism that presents clinically like Reye's Syndrome or nonketotic hypoglycemia. Four patients with proven 3-hydroxy-3-methylglutaryl-CoA lyase deficiency were shown to excrete a new diagnostically specific metabolite. The technique of fast atom bombardment and tandem mass spectrometry revealed that only 3-methylglutaryl-CoA is a substrate for acylcarnitine formation. Neither 3-methylglutaconyl-CoA nor 3-hydroxy-3-methylglutaryl-CoA are excreted as acylcarnitines. The excretion of 3-methylglutarylcarnitine may explain, in part, the apparent secondary carnitine deficiency in this disorder. Carnitine supplementation with moderate dietary restrictions may be a useful treatment strategy for this disorder.

L-carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in propionic acidemia.

Treatment with L-carnitine greatly enhanced the formation and excretion of short-chain acylcarnitines in three patients with propionic acidemia and in three normal controls. The use of fast atom bombardment mass spectrometry and linked scanning at constant magnetic (B) to electric (E) field ratio identified the acylcarnitine as propionylcarnitine in patients with propionic acidemia. The normal children excreted mostly acetylcarnitine. Propionic acidemia and other organic acidurias are characterized by the intramitochondrial accumulation of short-chain acyl-Coenzyme A (CoA) compounds. The substrate specificity of the carnitine acetyltransferase enzyme and its steady state nature appears to facilitate elimination of propionyl groups while restoring the acyl-CoA:free CoA ratio in the mitochondrion. We suggest that L-carnitine may be a useful therapeutic approach for elimination of toxic acyl CoA compounds in several of these disorders.

L-carnitine therapy in isovaleric acidemia.

Isovaleric acidemia, resulting from isovaleryl-coenzyme A dehydrogenase deficiency, is associated with marked reduction of free carnitine in both plasma and urine. Fast atom bombardment-mass spectrometry, hydrolysis, and gas chromatography/mass spectrometry have unequivocally identified the existence of isovalerylcarnitine, a new metabolite specific for this disorder. Administration of equimolar amounts of glycine or L-carnitine separately with leucine demonstrated that isovaleryl-coenzyme A is removed by supplemental L-carnitine in the form of isovalerylcarnitine as effectively as it is by glycine, in the form of isovalerylglycine. When L-carnitine is given alone, excretion of isovalerylglycine decreases in preference to enhanced excretion of isovalerylcarnitine and hippurate. Treatment with L-carnitine alone has proven effective in preventing further hospitalizations in a patient with this genetic disorder.

2,4-Dienoyl-coenzyme A reductase deficiency: a possible new disorder of fatty acid oxidation.

Several inherited disorders of fatty acid beta-oxidation have been described that relate mainly to saturated precursors. This study is the first report of an enzyme defect related only to unsaturated fatty acid oxidation and provides the first in vivo evidence that fat oxidation in humans proceeds by the reductase-dependent pathway. The patient was a black female, presenting in the neonatal period with persistent hypotonia. Biochemical studies revealed hyperlysinemia, hypocarnitinemia, normal organic acid profile, and an unusual acylcarnitine species in both urine and blood. The new metabolite was positively identified by mass spectrometry as 2-trans,4-cis-decadienoylcarnitine, derived from incomplete oxidation of linoleic acid. In spite of dietary therapy, the patient died of respiratory acidosis at four months of age. Samples of liver and muscle from the autopsy were assayed for 2,4-dienoyl-coenzyme A reductase activity. Using the substrate 2-trans,4-cis-decadienoylcoenzyme A, the reductase activity was 40% of the control value in liver and only 17% of that found in normal muscle. It is suggested that unsaturated substrates should be used for in vitro testing to cover the full range of potential beta-oxidation defects and that acylcarnitine species identification be used for in vivo detection of this disorder.

Effects of intranigral application of clinically-effective anticonvulsants on electroshock-induced seizures.

The authors sought to determine whether focal application of clinically-effective anticonvulsants to the substantia nigra produced anticonvulsant effects. To this end, the effects of phenobarbital, carbamazepine and phenytoin were examined on the electroshock seizure model in rats. Anticonvulsant efficacy was assessed by measuring the duration of tonic hindlimb extension before and after injection. It was found that application of phenobarbital into the nigra produced behavioral stereotypy and suppressed tonic hindlimb extension in a dose-dependent manner. These effects were spatially specific to the substantia nigra. By contrast, application of phenytoin or carbamazepine to the nigra produced neither anticonvulsant effects nor behavioral changes. Direct measurement of phenobarbital and carbamazepine in the substantia nigra showed that differences in concentration in the substantia nigra did not account for the lack of efficacy of carbamazepine. Moreover, concentrations of phenobarbital in the nigra after effective injection into the nigra exceeded concentrations in the nigra after effective systemic injections, by tenfold. Taken together, these data provide no compelling evidence that an action of the substantia nigra alone is sufficient to explain the therapeutic action of clinically-useful anticonvulsants.

Reaction products of aquatic humic substances with chlorine.

A major concern of the chlorination of aquatic humic materials is the ubiquitous production of trihalomethanes. A large number of other chlorinated organic compounds, however, have been shown to be formed by chlorine's reaction with humic substances. In this study, humic material was concentrated from a coastal North Carolina lake and chlorinated at a chlorine to carbon mole ratio of 1.5 at pH 12. A high pH was necessary for complete dissolution of the humic material and for production of adequate quantities of oxidation and chlorination products for extraction, separation and mass spectrometric identification. After concentration in ether, samples were methylated, separated with a 50-m OV-17 glass capillary column or a 25 m SP-2100 fused-silica column and identified. A Hewlett-Packard 5710A gas chromatograph interfaced to a VG Micromass 7070F double-focusing mass spectrometer was used. Low resolution, accurate mass measurements were made with a combined EI-Cl source. The ability to do low resolution, accurate mass measurements made possible a rapid scan function necessary for capillary column gas chromatography. Accurate mass measurements allowed increased confidence in the identification of compounds, most of which are not available as standards. The products identified in these studies were chlorinated aliphatic straight-chain acids dominated by di- and trichloroacetic acid and the chlorinated dicarboxylic acids: succinic, fumaric and maleic acids. Chlorinated and unchlorinated aliphatic mono- and dicarboxylic acids and unchlorinated polycarboxylic aromatic acids comprise the remaining bulk of the compounds identified.

Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate.

A patient with severe pyruvate carboxylase deficiency presented at age 11 weeks with metabolic decompensation after routine immunization. She was comatose, had severe lactic acidemia (22 mM) and ketosis, low aspartate and glutamate, elevated citrulline and proline, and mild hyperammonemia. Head magnetic resonance imaging showed subdural hematomas and mild generalized brain atrophy. Biotin-unresponsive pyruvate carboxylase deficiency was diagnosed. To provide oxaloacetate, she was treated with high-dose citrate (7.5 mol/kg(-1)/day(-1)), aspartate (10 mmol/kg(-1)/day(-1)), and continuous drip feeding. Lactate and ketones diminished dramatically, and plasma amino acids normalized, except for arginine, which required supplementation. In the cerebrospinal fluid (CSF), glutamine remained low and lysine elevated, showing the treatment had not normalized brain chemistry. Metabolic decompensations, triggered by infections or fasting, diminished after the first year. They were characterized by severe lactic and ketoacidosis, hypernatremia, and a tendency to hypoglycemia. At age 3(1/2) years she has profound mental retardation, spasticity, and grand mal and myoclonic seizures only partially controlled by anticonvulsants. The new treatment regimen has helped maintain metabolic control, but the neurological outcome is still poor.

Benzoate therapy and carnitine deficiency in non-ketotic hyperglycinemia.

Five patients presenting with non-ketotic hyperglycinemia in the neonatal period were treated with sodium benzoate to normalize plasma glycine levels. This therapy resulted in seizure reduction and a marked increase in wakefulness. Plasma carnitine deficiency was noted in three of four patients tested, and benzoylcarnitine was identified in plasma, urine, and CSF. Treatment with L-carnitine normalized plasma free carnitine. L-carnitine showed a tendency to increase the glycine conjugation of benzoate. An episode of coma and increased seizures in one patient was associated with a toxic level of benzoate, probably due to insufficient mobilization of glycine for conjugation. High dose benzoate therapy improved the quality of life of surviving patients. Close monitoring of glycine, benzoate and carnitine levels is advised.

Acetyl-L-carnitine deficiency as a cause of altered nerve myo-inositol content, Na,K-ATPase activity, and motor conduction velocity in the streptozotocin-diabetic rat.

Defective metabolism of long-chain fatty acids and/or their accumulation in nerve may impair nerve function in diabetes by altering plasma or mitochondrial membrane integrity and perturbing intracellular metabolism and energy production. Carnitine and its acetylated derivatives such as acetyl-L-carnitine (ALC) promote fatty acid beta-oxidation in liver and prevent motor nerve conduction velocity (MNCV) slowing in diabetic rats. Neither the presence nor the possible implications of putative ALC deficiency have been definitively established in diabetic nerve. This study explored sciatic nerve ALC levels and the dose-dependent effects of ALC replacement on sciatic nerve metabolites, Na,K-ATPase, and MNCV after 2 and 4 weeks of streptozotocin-induced diabetes (STZ-D) in the rat. ALC treatment that increased nerve ALC levels delayed (to 4 weeks) but did not prevent nerve myo-inositol (MI) depletion, but prevented MNCV slowing and decreased ouabain-sensitive (but not -insensitive) ATPase activity in a dose-dependent fashion. However, ouabain-sensitive ATPase activity was also corrected by subtherapeutic doses of ALC that did not increase nerve ALC or affect MNCV. These data implicate nerve ALC depletion in diabetes as a factor contributing to alterations in nerve intermediary and energy metabolism and impulse conduction in diabetes, but suggest that these alterations may be differentially affected by various degrees of ALC depletion.

Quantitative assay of free and total carnitine using tandem mass spectrometry.

A new, specific method for isotope dilution assay of total and free carnitine in urine has been developed. The method utilizes fast atom bombardment ionization with tandem mass spectrometry and requires minimal sample preparation. It compared well with radioenzymatic assay in terms of specificity, precision and accuracy, but was much more convenient in terms of analysis time and sample throughput. The new method is also applicable to the determination of free and short-chain total carnitine in plasma.

Valproylcarnitine: a novel drug metabolite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry.

Urine samples from three children at different stages of chronic valproate therapy were partially purified using a cation exchange column. A signal consistent with either valproylcarnitine or octanoylcarnitine was observed in one of these extracts by direct fast atom bombardment-mass spectrometry analysis. These isomeric acylcarnitines were synthesized, separated and characterized by thermospray high performance liquid chromatography-mass spectrometry. This new technique was then employed to positively identify intact valproyl-carnitine in the patients' urine samples. The implications of this finding with regard to a mechanism to account for carnitine deficiency in patients receiving valproate are discussed.

Ethylmalonic aciduria: an organic acidemia with CNS involvement and vasculopathy.

Five infants from 3 families, one Egyptian, two Yemeni, are described with a progressive encephalopathy, four of whom have been studied in detail. All patients showed vascular lesions of the skin, characterized by waxing and waning petechiae and ecchymoses. Acrocyanosis was present in three patients. All patients showed retinal lesions characterized by tortuous veins. Protracted diarrhea was not a consistent finding, although they had metabolic crisis in association with diarrhea. They did not show failure to thrive. The neurologic symptoms were indicative of a progressive pyramidal tract disease. Three patients died following sudden emergence of severe basal ganglia, putaminal and head of caudate lesions. In one patient the CT changes in brain were suggestive of infarction. The patients who died manifested pulmonary congestion, or wet lung, and respiratory difficulties during the terminal stage of the disease. In all patients before and during the terminal event, mild-to-moderate hematuria, and in two RBC in CSF, was observed. In one patient there was mild hemoperitoneum at the terminal event. The urine organic acids indicated increased excretion of ethylmalonic, methylsuccinic, glutaric, and adipic acids. The patients invariably showed lactic acidosis, but no ketosis, during and in between the acidotic attacks of the disease. The acylcarnitine profile in blood of two patients showed a pronounced increase in C4 and C5 carnitine esters. In three patients, biopsies from petechiae indicated absence of an immune event, showing only fresh hemorrhage. An immunologic study in one patient was normal for the suppressor:cytotoxic lymphocyte ratio and concentration of interleukin-2 receptor during and in between hemorrhagic attacks. The cytochrome c oxidase activity in fibroblasts was normal. The rate of oxidation of glucose, leucine, isoleucine, valine, propionate and butyrate by fibroblasts was normal. The disease is not responsive to treatment with riboflavin, ascorbic acid, vitamin E, glycine, or carnitine. One patient remained stable on prolonged large doses of methylprednisolone. The biochemical defect leading to ethylmalonic aciduria in this disease remains unknown.

Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)?

The purpose of this study was to further identify and quantify the fatty acid oxidation abnormalities in spinal muscular atrophy, correlate these with disease severity, and identify specific underlying defect(s). Fifteen children with spinal muscular atrophy (3 type I, 8 type II, 4 type III) were studied. Serum carnitine total/free ratios demonstrated a tendency toward an increased esterified fraction ranging 35-58% of total carnitine (normal: 25-30% of total) in younger children with types I and II. The remaining type II and III patients, older than 23 months of age at sampling, had normal esterified carnitine levels. Urinary organic acid analysis demonstrated mild to moderate medium-chain dicarboxylic aciduria in type I patients and normal, mild, or moderate increases in short-chain and medium-chain organic acids in type II patients. In the type III group, the organic acids were normal except for one patient with mild medium-chain dicarboxylic aciduria. Muscle intramitochondrial beta-oxidation was measured in 5 children (2 type I, 2 type II, and 1 type III) and a significant reduction in the activities of short-chain L-3-hydroxyacyl-CoA dehydrogenase, long-chain L-3-hydroxyacyl-CoA dehydrogenase, acetoacetyl-CoA thiolase, and 3-ketoacyl-CoA thiolase were found; however, normal crotonase activity was documented. Most strikingly, there was a marked increase (3- to 5-fold) in the activity ratios of crotonase to L-3-hydroxyacyl-CoA dehydrogenase and thiolase activities with both short- and long-chain substrates. The combined abnormalities suggest a defect in a mitochondrial multifunctional enzyme complex, distinct from the trifunctional enzyme. These abnormalities may be either primary or secondary and may respond to dietary measures to reduce the dependence on fatty acid oxidation.

Performance of the serum cobalamin assay for diagnosis of cobalamin deficiency.

The authors' objective, with this study, was to determine the use in routine clinical practice of the cobalamin serum assay in evaluating patients suspected of having cobalamin deficiency. The design was a prospective observational study of a diagnostic test compared with a criterion gold standard. The setting was the Veterans Affairs hospital inpatient wards and outpatient clinics. The authors prospectively identified all patients who had serum cobalamin measured and enrolled all those with cobalamin < 133 pmol/L (180 pg/mL) and a random sample of patients with cobalamin greater than or equal to 133 pmol/L (N = 168). There were no interventions. To identify cobalamin deficiency, subjects underwent blinded clinical and laboratory examinations, Schilling test, and urinary methylmalonic acid assay, with a trial of cobalamin replacement, if needed. Of 1,599 patients assayed, 84 (5.2%) had low cobalamin levels. After evaluation, 16 of those with low cobalamin levels, but none of those with normal cobalamin levels, were confirmed as deficient. Positive predictive value of a low cobalamin level in this population was 22.2% (95% confidence interval, 12.6-31.8%). After correcting for sampling procedure, the calculated sensitivity rate was 100% (95% confidence interval, 20.6-100%), and specificity rate was 95.8% (95% confidence interval, 95.2-100%). The authors conclude that in routine use, the positive predictive value of the cobalamin assay is low. Low cobalamin levels should not be used alone to justify a lifetime of parenteral therapy or to rule out other conditions that mimic cobalamin deficiency.

Valproate-associated carnitine deficiency and malignant cerebral edema in the absence of hepatic failure.

We describe a 27-year-old woman who developed encephalopathy and cerebral edema during treatment of refractory complex partial seizures that included acute administration of valproate (VPA) at a dosage of 35 mg/kg per day. Multiple random VPA levels were within therapeutic range, and results of liver function studies did not show evidence of hepatic failure. Cerebral computerized tomography (CT) showed evidence of massive cerebral edema with central herniation. Just prior to death, plasma levels of free and acyl carnitines were markedly decreased. Analysis of urinary organic acids showed increased excretion of lactate, but a normal distribution of VPA metabolites. Carnitine deficiency may predispose patients to the development of coma and life-threatening cerebral edema associated with acute administration of VPA, even in the absence of concomitant hepatic failure. We suggest specific guidelines for the evaluation and management of altered consciousness in patients with seizures receiving VPA.

The clinical and metabolic effects of rapid weight loss in obese pet cats and the influence of supplemental oral L-carnitine.

The efficacy, safety, and metabolic consequences of rapid weight loss in privately owned obese cats by means of a canned weight-reduction diet and the influence of orally administered L-carnitine on rate of weight loss, routine clinical evaluations, hepatic ultrasonography, plasma amino acid profiles, and carnitine analytes were evaluated. A double-blinded placebo-controlled design was used with cats randomly divided into 2 groups: Group 1 (n = 14) received L-carnitine (250 mg PO q24h) in aqueous solution and group 2 (n = 10) received an identical-appearing water placebo. Median obesity (body condition scores and percentage ideal body weight) in each group was 25%. Caloric intake was restricted to 60% of maintenance energy requirements (60 kcal/kg) for targeted ideal weight. The reducing formula was readily accepted by all cats. Significant weight loss was achieved by week 18 in each group without adverse effects (group 1 = 23.7%, group 2 = 19.6%). Cats receiving carnitine lost weight at a significantly faster rate (P < .05). Significant increases in carnitine values developed in each group (P < .02). However, significantly higher concentrations of all carnitine moieties and a greater percentage of acetylcarnitine developed in cats of group 1 (P < .01). The dietary formula and described reducing strategy can safely achieve a 20% weight reduction within 18 weeks in obese cats. An aqueous solution of L-carnitine (250 mg PO q12h) was at least partially absorbed, was nontoxic, and significantly increased plasma carnitine analyte concentrations as well as rate of weight loss.

3-hydroxy-3-methylglutaric aciduria presenting with Reye like syndrome: report of one case.

We report the case of a patient with 3-hydroxy-3-methylglutaric aciduria who presented with a repeat attack of Reye like syndrome clinically. Vomiting and somnolence, generalized tonic and clonic convulsions with hepatomegaly, hyperammonemia, liver function impairment, and mild metabolic acidosis were the presenting signs. 3-hydroxyisovaleric, 3-methylglutaric, 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids were detected in the urine by gas chromatography-mass spectrometry. 3-methylglutarylcarnitine was also identified in the urine by fast atom bombardment and tandem mass spectrometry. Therefore, the possibility of metabolic disease should be considered in neonates and infants with repeat attacks of Reye like syndrome and a history of similarly affected siblings.