IMPORTANCE Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent.OBJECTIVE To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTSThe NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. INTERVENTIONS Chemoradiation and consolidation chemotherapy with or without metformin.MAIN OUTCOMES AND MEASURES The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03.RESULTS A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC.

Five women with hypothalamic amenorrhea were treated with LH-RH (10-15 microg i.v. at 90 min intervals for 17-20 days). In all women this chronic intermittent LH-RH administration resulted in a normalization of serum gonadotropin levels. Four women exhibited preovulatory estradiol serum levels with subsequent LH peaks. In three women the LH peaks were followed by normal luteal phase serum progesterone levels. One woman with hyperprolactinemic amenorrhea was also treated with the same therapeutic regimen which induced ovulation as judged from normal luteal phase serum progesterone levels. The results indicate that normal pituitary-ovarian function can be established in hypothalamic amenorrhea by chronic intermittent administration of LH-RH. They also suggest that in the human female hypothalamic LH-RH function may be only permissive in that the cyclicity of endocrine events during the menstrual cycle is regulated on pituitary and ovarian levels. Hyperproactinemic amenorrhea appears to be associated with insufficient endogenous LH-RH secretion which can be substituted by exogenous chronic intermittent administration of LH-RH. Elevated prolactin levels per se do not interfere with the pituitary positive feedback mechanisms nor with the gonadotropin action on the ovarian level.

2501 Background: MTX-based chemoradiotherapy is effective in PCNSL, but carries a risk of severe neurotoxicity (NT), especially in the elderly. In a phase II single arm study, R-MPV-A chemotherapy was combined with substantially reduced doses of radiotherapy (23.4 Gy), achieving prolonged progression free survival (PFS) and overall survival (OS) with acceptable NT. Because R-MPV-A had never been tested without radiotherapy, we conducted a randomized study to determine if the low doses of radiation played a role in the observed disease control, and to characterize NT as compared to chemotherapy alone. Methods: Patients were stratified by MSK RPA class and randomized to receive R-MPV-A with LD-WBRT (chemoRT arm) versus R-MPV-A alone (chemo arm). MTX dose was 3.5g/m2 infused over 2 hours. Filgrastim and pegfilgrastim support was given to all patients. LD-WBRT dose was 23.4 Gy (1.8 Gy X 13). The primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63, with one-sided alpha level of 0.15. Results: A total of 91 patients were randomized, of whom 4 were ineligible. Among eligible patients, 43 were enrolled in the chemoRT arm and 44 in the chemo arm. Median age was 66 (chemoRT) and 59 (chemo). Median KPS was 80 for both arms. Response rates following R-MPV were 81% (chemoRT) and 83% (chemo). In the chemoRT arm, 37 patients (86%) received LD-WBRT. After median follow-up of 55 months (m), the median ITT PFS was 25 m in the chemo arm and not reached in the chemoRT arm (HR 0.51; 95% CI [0.27, 0.95]; p = 0.015). The 2-year PFS was 54% (chemo) and 78% (chemoRT). Salvage radiotherapy has been given to 11 patients in the chemo arm. Median OS was not reached in either arm, with data still maturing. In both arms, most common grades 3 or 4 toxicities were anemia (27%), lymphopenia (41%), neutropenia (35%), thrombocytopenia (26%), ALT (23%) and AST (13%). One patient died from sepsis (chemo arm). As per investigators’ assessment, the rate of clinically defined moderate to severe NT was 11.4% (chemo) and 14% (chemoRT), p = 0.75. Conclusions: The study met the primary endpoint, demonstrating the addition of LD-WBRT to R-MPV-A improves PFS in newly diagnosed PCNSL. As per investigator’s assessment, NT rates were not statistically significantly increased, but further neuropsychological testing and neuroimaging analyses are ongoing to characterize cognitive decline and how it compares to other consolidation treatments. Clinical trial information: NCT01399372 .

No abstract

8502 Background: Metformin, a diabetes agent that inhibits mitochondria complex I, enhances radiotherapy and chemotherapy responses in pre-clinical models of NSCLC. NRG-LU001 examined whether metformin can improve outcomes of curative CRT in locally advanced (LA)-NSCLC. Methods: The primary endpoint of this trial was 1-year progression free survival (PFS). Unresected, non-diabetic, stage IIIA/B NSCLC patients were randomized (1:1) to either carboplatin-paclitaxel chemotherapy concurrent with chest RT (60Gy), followed by consolidation carboplatin-paclitaxel chemotherapy (Control Arm) or the same and oral metformin (2000mg daily) during cytotoxic therapy (Experimental Arm). PFS and overall survival (OS) were estimated with the Kaplan-Meier method; time to local-regional progression (TTLRP), time to distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded with CTCAE v.4.0. Results: Between Aug.2014 and Dec.2016, 170 patients were accrued. Analysis was planned at 102 PFS events (Feb. 2019). There was no significant difference in rates or grade of toxicity between the two arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Metformin arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP or TTDM. Conclusions: NRG-LU001 center reported outcomes show that oral daily metformin was well-tolerated in combination with CRT treatment for LA-NSCLC. However, metformin did not improve PFS and OS and did not alter the rates of local-regional failure or distant metastasis. Acknowledgements: TT and HS are Co-Principal Investigators. This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). Clinical trial information: NCT02186847.