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.

Automatic sensor adjustment in a rate modulated pacemaker. North American Trilogy DR+ Phase I Clinical Investigators.

A new feature (AutoSlope) has been introduced that can automatically adjust the sensor slope based on the chronic activity level of the patient. The algorithm adjusts the slope once per week so that 99% of the sensor response is maintained between the base rate and 23% of the difference between the programmed Base Rate and the Max Sensor Rate. Offsets are available for fine titration of sensor response in individual patients. The AutoSlope feature was evaluated in 93 patients with DDDR pacemakers (Trilogy DR+, Pacesetter). Patients were seen at 1, 3, and 6 months for a total of 178 evaluations. At each evaluation, the AutoSlope value was recorded. Patients then performed a brisk walk at sensor values equivalent to the AutoSlope value. Desired sensor rate was compared to the rate achieved by AutoSlope for the exercise period. Longterm sensor performance was evaluated by analyzing the sensor histogram. AutoSlope provided the desired sensor rate in most patients. Use of AutoSlope offsets allows fine titration of rate modulation in individual patients. Ongoing changes in sensor performance provided by AutoSlope allow patients to achieve a desired sensor rate from one evaluation to another without changes in permanent programmed settings. Programming a low maximum sensor rate may limit sensor response in some patients.

Coronary atherectomy. An alternative to balloon angioplasty.

To date, physicians at our hospital have performed coronary atherectomy on 15 patients. Of these patients, four needed open heart surgery. One patient needed surgery because a vessel was dissected during the procedure, and the three other patients had unsuccessful procedures. One patient died due to a cerebrovascular bleed related to the anticoagulation therapy required for the procedure. Of the remaining patients, three had no reocclusion and four had reocclusion at their six-month follow-up examinations. The remaining patients have not had a six-month follow-up examination. The restenosis rate at our institution is 25%. It is hoped that catheter-mediated atherectomy will be an effective, predictable transluminal treatment of single or multiple focal stenosis. Because of the small patient sampling and short duration follow-up, no trends have been established. A six-month follow-up with angiography will establish patency and restenosis rates.

Characterization of left ventricular chamber distortion: alterations in cavity shape and orientation in mitral stenosis.

Distortion of the left ventricular (LV) chamber silhouette was identified in 28 patients with mitral stenosis (MS) by disparity between normally identical chamber volumes calculated independently from the frontal (AP) and lateral (LAT) views of biplane cineangiograms (AP end diastolic volume 157.8 +/- 10.0 ml, LAT end diastolic volume 115.6 +/- 7.2 ml, p less than .001). Similar systematic disparity was observed in estimates of end systolic volume in these views. While no directional difference in ejection fraction was found, identical (+/- 10%) AP and LAT measurements were obtained in only 36% of patients, indicating poor reproducibility of the estimate of LV function between single radiographic views. A technique was also devised for determining the spatial orientation of the LV long axis (mid mitral valve to apex) from biplane cineangiograms; this axis was shown to intercept the frontal plane at an angle of 50.9 +/- 2.4 degrees in 12 subjects with normal LV anatomy and 36.1 +/- 4.5 degrees in seven patients with MS, indicating that the long axis was rotated posteriorly toward alignment with the frontal plane in the latter group. The presence and magnitude of LV chamber distortion was clearly related to the degree of angiographically estimated right ventricular dilatation. Implications of these observations, particularly with reference to the estimation of single plane LV volume characteristics in patients with MS, are discussed.

Coronary thrombolysis by intravenous streptokinase in acute myocardial infarction: acute and follow-up studies.

Coronary arteriography was performed before, immediately after, and 9 to 14 days after administering i.v. streptokinase (850,000 to 1,500,000 IU) to 43 patients within 6 hours of myocardial infarction. Ventricular function was determined by contrast ventriculography before and 9 to 14 days later and by radionuclide studies at clinical follow-up 8 months later. Early reperfusion occurred in 49% of patients, but in only 35% was it sustained. In patients with sustained reperfusion, early ventricular dysfunction was significantly reduced 9 to 14 days and 10 months later, and frequency of infarction, sudden death, and angina pectoris was not increased at follow-up. No serious bleeding occurred.

High-dose, brief intravenous streptokinase early in acute myocardial infarction.

An acute thrombus at the proximal border of a high-grade atherosclerotic obstruction is the usual cause of myocardial infarction. Although intracoronary thrombolysis is potentially an exciting new therapy for reducing the extent of myocardial infarction by lysing coronary clot, a number of major difficulties limit its widespread application. It is a complex procedure requiring intracoronary visualization and infusion within a few hours of onset of symptoms. Since intravenous streptokinase could be widely applied if effective, we and others have wondered whether high-dose, brief-duration intravenous streptokinase infusion given early in myocardial infarction would lyse coronary clots without bleeding. To date we have treated 13 patients within 6 hours of onset of symptoms and with ECG and angiographic evidence of typical myocardial infarction caused by coronary clot. Clot lysis and angiographically proved coronary reperfusion were achieved in 6 patients within 1 hour of starting a systemic intravenous infusion of 850,000 IU of streptokinase. Schroeder et al., in Berlin, West Germany, achieved angiographically proved coronary reperfusion in 11 of 21 patients with acute myocardial infarction following a 30-minute intravenous streptokinase infusion of 500,000 IU. Neuhaus et al., in Göttinen, West Germany, achieved angiographically proved coronary reperfusion in 24 of 39 similar patients within 48 minutes by intravenous infusion of 1,700,000 IU of streptokinase. In these three studies, no serious bleeding occured; left ventricular function was improved in patients who achieved coronary reperfusion. We conclude that rapid intracoronary clot lysis and coronary reperfusion can be achieved early in myocardial infarction by brief-duration systemic intravenous infusion of high-dose streptokinase without a high incidence of serious bleeding.

Determinants of cardiac performance in severe aortic stenosis.

Left ventricular (LV) myocardial function and the influence on LV pump performance of associated coronary arterial disease, of outflow obstruction and its consequences, and of altered ventricular pressure-volume characteristics were examined in a representative group of 28 adult patients with symptomatic severe aortic stenosis (valvular orifice area less than 0.50 sq cm/sq m). Eighteen patients (64%) exhibited depressed LV pump performance with levels of ejection fraction less than 0.50. In seven patients, coronary arterial disease documented by either arteriographic studies or postmortem analyses was associated with a segmental (i.e., nonhomogeneous) LV contractile disorder consistent with previous myocardial infarction. In the remaining 11 patients a homogeneous LV contractile disorder was the result of chronic outflow obstruction and its consequences. The possibility that reduced ventricular performance might be accounted for by increased afterload could not be supported by significant correlation between LV contractile characteristics (estimated from the ejection fraction and the mean circumferential fiber shortening rate) and indices of afterload (including LV systolic pressure, aortic valvular orifice area, and mean systolic wall tension). This observation suggested that myocardial hypertrophy and other consequences of longstanding obstruction to outflow played a primary role in depression of LV performance in these patients. Left ventricular end-diastolic volume was abnormal in all but three patients with depressed LV function; this increase was accompanied by a disproportionately greater increment in end-diastolic pressure, suggesting that reduced distensibility limited the ability of the ventricle to compensate for reduced contractile performance by means of the Starling mechanism.

The anginal syndrome without evidence of coronary artery disease.

It is apparent that a variety of factors may be responsible for myocardial ischemia, and even infarction, in the absence of occlusive major vessel coronary disease. In particular, it must be emphasized than angina-like chest pain may well have its origin in myocardial ischemia, even in younger patients with unusual patterns of chest pain but without predisposition to premature CAD. Increasing awareness of disorders such as coronary arterial spasm, functional impairment of subendocardial blood flow and the possible role of variant patterns of anatomic distribution of the coronary arterial tree, will provide a better understanding of their significance as determining or contributing factors in patients with the anginal syndrome.

Congenital absence of the left circumflex coronary artery in the systolic click syndrome.

The anatomy of the coronary artery circulation was examined by means of selective coronary arteriography in 19 patients, evaluated because of disabling chest pain and ECG abnormalities, with typical clinical findings of the systolic click syndrome (SCS). In 17 (89.5%), the elft circumflex coronary artery (LCCA) was absent; a single marginal branch arose from the left main vessel, but no vessel was present in or near the atrioventricular (A-V) groove. In contrast, the LCCA was identified in 74 of 78 control patients (94.9%) considered to have representative normal distribution of coronary artery branches, All but two patients with SCS exhibited reduced contraction of the segment of left ventricular (LV) myocardium surrounding the mitral valve ring (extent of systolic diameter decrease 1.4 +/- 3.1% vs normal 31.8 +/- 3.4%, P lwss than 0.001), as well as of the LV inflow tract (diameter decreasce 16.2 +/- 2.5% vs normal 38.6 +/- 1.8% P less than 0.001); both of these regions of the left ventricle derive their vascular supply from the LCCA, An identical segmental LV contraction disorder was observed in seven patients with functionally single vessel occlusive coronary artery disease involving the LCCA, An identical finding in this study was a relatively high incidence of absent LCCA (42%) in 19 patients with atypical angina and normal coronary arteriograms. It is concluded that a congenital anomaly of the coronary circulation, with absent LCCA, may be responsible for segmental myocardial dysfunction in some patients with SCS. In turn, this segmental contraction disorder may determine functional abnormality of the mitral valve apparatus.