Genentech Foundation

PURPOSE: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non-small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO. EXPERIMENTAL DESIGN: This retrospective study included 221 patients from a phase III trial of atezolizumab+carboplatin+nab-paclitaxel versus carboplatin+nab-paclitaxel in squamous NSCLC (IMpower131). ctDNA monitoring used the FoundationOne Tracker involving comprehensive genomic profiling of pretreatment tumor tissue, variant selection using an algorithm to exclude nontumor variants, and multiplex PCR of up to 16 variants to detect and quantify ctDNA. RESULTS: ctDNA was detected (ctDNA+) in 96% of pretreatment samples (median, 93 mean tumor molecules/mL), and similar ctDNA dynamics were noted across treatment arms during chemoIO. ctDNA decrease from baseline to C4D1 was associated with improved outcomes across multiple cutoffs for patients treated with chemoIO. When including patients with missing plasma or ctDNA- at baseline, patients with ctDNA- at C4D1 (clearance), had more favorable progression-free survival (median 8.8 vs. 3.5 months; HR, 0.32;0.20-0.52) and OS (median not reached vs. 8.9 months; HR, 0.22; 0.12-0.39) from C4D1 than ctDNA+ patients. CONCLUSIONS: ctDNA monitoring during induction chemoIO can inform treatment outcomes in patients with advanced NSCLC. Importantly, monitoring remains feasible and informative for patients missing baseline ctDNA. ctDNA testing during induction chemoIO identifies patients at higher risk for disease progression and may inform patient selection for novel personalized maintenance or second-line treatment strategies.

To determine how accurately the Roche-Wainer-Thissen (RWT), Tanner-Whitehouse (TW2), and Bayley-Pinneau (BP) prediction models estimated adult height, serial height predictions were made for 23 healthy boys (mean initial age 10.4 ± 1.1 years) every 8 months from 8-15 years of age. The RWT model was tested using Greulich-Pyle (RWT-GP) and Fels (RWT-Fels) bone ages. Stature was measured every 4 months until near final height was attained (growth rate <1cm · 8 mo-1). Mean age at near final height was 18.4 ± 1.4 years. To assure that the predictions were as accurate and precise as possible, bone age assessments were made by experts in each method. To investigate the influence of maturation on the predictions, the boys were grouped by Fels bone ages: <11 yr, 11-13.99 yr, and 14-14.99 yr. Comparison of the prediction bias and of the root mean square errors (RMSE) showed that the TW2 model gave the most accurate results, followed by the RWT and BP models. The adult height was generally underpredicted by the TW2 model and overpredicted by the RWT and BP models. The RMSE was reduced for each of the models as the bone age approached maturity. The TW2 model had the smallest average RMSE in all bone age groups. In the <11 yr bone age group, the RWT-Fels, RWT-GP, and BP models produced RMSEs that were 16.4%, 18.4%, 62.1%, respectively, greater than the TW2 model. For the 11-13.99 yr group, RMSE by the RWT-Fels, RWT-GP, and BP models were 7.5%, 18.0%, and 15.2%, respectively, greater than the TW2 model. In the 14-14.99 yr group the RWT-GP model had a 45.5% greater RMSE than the TW2 model, whereas the RWT-Fels model produced a RMSE only 15.2% greater than TW2. The RWT-Fels model produced a lower RMSE than the RWT-GP model for all bone age groups. Although the data are probably as accurate and precise as presently possible, biologically significant error remains, especially with overprediction of adult height in normally growing boys by the BP and RWT models. It is recommended that regardless of the prediction model implemented, caution be used when advising patients of their predicted adult height since all of the models tested had outlying predictions. Am. J. Hum. Biol. 9:371-380, 1997. © 1997 Wiley-Liss, Inc.

696 We have administered recombinant human growth hormone (rhGH) 0.3 mg/kg/wk SQ to six patients with severe growth failure after cardiac transplantation. The average age of the patients at first transplant was 6.4 yrs (range 14 mos to 13 yrs). Three patients had a second transplant 2° to rejection at 4.8, 5.2 and 8 yrs, respectively, after their first, all before study entry. All were on a triple drug immunosuppression regimen that included cyclosporine, azathioprine and prednisone (dose range .09 to .19 mg/kg/d). Average growth velocity (GV) for the year prior to rhGH therapy was 3.0 cm/yr (range zero to 5.1). Peak serum GH levels ranged from 1.7 to 14.2 ng/ml on standard double agent stimulation testing; four of the six were considered to be GH deficient. At the start of rhGH therapy, the average height standard deviation score (hSDS) was −4.3 (−2.8 to −6.4). The patients have been treated for 4 mos to 2.5 yrs. Two patients followed for more than two yrs grew 10.7 and 11.6 cm respectively the first yr and 13.4 and 11.4 cm the second year. Their SDS height scores have improved from −4.0 to −2.8 and −6.4 to −3.2. One patient has been on rhGH for one year during which he has grown 9.2 cm. Three patients followed for 6 mos have increased their GV from 0.2 to 8.9, 2.1 to 9.7 and 5.1 to 16.4 cm/yr, respectively. One patient, who had the lowest GH response to stimulation, and ultimately underwent a renal allograft for chronic renal failure, did not grow despite 16 mos on rhGH. Adverse effects possibly related to rhGH included two rejection episodes during the treatment period. One patient had grade 1B rejection following a rapid increase in height that responded to adjusting his immunosuppression for his increased size. Another patient had a hemodynamically significant rejection felt to be secondary to noncompliance with the medical regimen. Persistent tachycardia with a normal biopsy was seen in one patient after 9 mos of therapy; it resolved after stopping rhGH. No other patients had clinical or pathologic evidence of rejection. A patient with pre-existing scoliosis required surgical repair after 20 mos on rhGH. There were no serious infections. Except for the patient with worsening renal function, all laboratory parameters remained stable on rhGH, including fasting blood sugar and glycosylated hemoglobin. In conclusion, there has thus far been one serious rejection episode; other sequelae were related to rapid growth: worsening scoliosis, and the need for dosage adjustment for changing body size. Cardiac findings (e.g. tachycardia) have to be carefully followed. We conclude that preliminary data indicate that excellent growth may be safely achieved using rhGH in very slow growing children after heart transplantation.