A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.

BACKGROUND: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

Clinical outcomes and immune phenotypes associated with STK11 co-occurring mutations in non-small cell lung cancer.

Background: STK11 mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis. Methods: Forty-one patients with STK11-mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis. Data from the Cancer Genome Atlas (TCGA) was used for survival and immune gene expression analysis. Overall and progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared using a log-rank test. Results: In the 41 patients included, common co-occurring alterations with STK11 were KRAS (54%), TP53 (44%), CDKN2A (37%) and KEAP1 (27%). Overall 17 patients received locoregional therapy with surgery or radiation with median OS of 8.6 years and there was no significant difference in clinical outcomes with KRAS and TP53 co-occurring mutations. Response to both chemotherapy and immunotherapy was poor across all co-occurring mutations. However, TP53 co-mutation was associated with improved clinical benefit with immunotherapy. Patients with higher TMB had longer PFS with immunotherapy. In TCGA survival analysis, tumors with STK11 mutation with or without KRAS co-mutation were associated with worse survival (P<0.05) but tumors with STK11/TP53 co-mutation did not have worst survival compared to STK11 wild type tumors. Moreover, co-occurring mutations had significant effect on intratumoral immune status with both STK11 alone and STK11/KRAS co-mutated tumors showing more enrichment for wound healing immune subtype while STK11/TP53 co-mutated tumors showed more enrichment for IFN-g immune subtype. Conclusions: Our retrospective analysis in patients with STK11-mutated NSCLC found that both TMB and co-occurring mutations may be predictors for response to immunotherapy with worse outcomes in patients with low TMB or KRAS co-mutation and improved outcomes with TP53 co-mutation. Patients with STK11-mutated NSCLC also demonstrate chemotherapy resistance but have similar outcomes with localized treatment compared to STK11 wild type tumors. Moreover, co-mutations with KRAS or TP53 significantly alter tumor immune landscape of STK11-mutated tumors and therefore response to immunotherapy.

A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies.

PURPOSE: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS: Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION: V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.

Overexpression of excision repair cross-complementing 1 gene associates with higher risk of therapeutic failure after definitive chemoradiation for unresectable non-small cell lung cancer.

BACKGROUND: Locally advanced non-small cell lung cancer (NSCLC) is typically treated with concurrent chemoradiation (CRT). Excision Repair Cross-Complementing 1 (ERCC1) is a protein involved in DNA damage repair. The objective of this study was to assess whether higher tumoral ERCC1 expression would associate with worse clinical outcomes in NSCLC treated with CRT. METHODS: Twenty-five patients were included. Relative expression levels of messenger RNA (mRNA) for ERCC1 were measured with a quantitative reverse transcription polymerase chain reaction (qRT-PCR) and expressed as scaled ERCC1 mRNA gene expression value. Patients were followed every 3 months with history, physical exam, and imaging to assess clinical outcomes. We evaluated the associations between ERCC1, as well as other prognostic variables including stage, age, gender, race, histology, RT dose, performance status, and progression free survival (PFS) and overall survival (OS) with Kaplan-Meier method and Cox regression. RESULTS: Recursive partitioning analysis identified a GeneExp cutoff of 1.54. Higher ERCC1 expression was associated with worse PFS [hazard ratio (HR) =1.70, P=0.04] and trended towards worse OS (HR =1.53, P=0.11). Increasing tumor volume (HR =1.001, P=0.055), squamous cell (HR =7.86, P=0.008) and poorly differentiated histology (HR =5.25, P=0.06) also associated with worse OS. The cumulative incidence of local recurrence at 1 year trended higher with ERCC1 GeneExp ≥1.54 (78.1%) compared to ERCC1 GeneExp <1.54 (14.9%, P=0.08). Distant relapse at 1 year was 72% with tumor ERCC1 expression ≥1.54 and 52% with ERCC1 expression <1.54 (P=0.28). CONCLUSIONS: Higher ERCC1 expression by qRT-PCR appears to correlate with worse PFS in locally advanced NSCLC treated with CRT. However, the overall sample size of the population was small; thus, larger studies are warranted to integrate molecular biomarkers to identify patients who might benefit from treatment intensification.

Combining radiation therapy and immunotherapy for lung cancers: a narrative review.

Lung cancer remains the leading cause of cancer morbidity and mortality worldwide among both men and women. While surgical resection remains the standard of care for early stage NSCLC, chemoradiation has been a mainstay of treatment for locally advanced non-small-cell lung cancer (LA-NSCLC) patients for decades. Consolidation immunotherapy has improved survival in this subset of patients after conventional chemoradiation, and has emerged as the new standard. The synergy between immunotherapy and radiation, as well as ongoing research on the effects of radiation on the immune system, allows for the exploration of new avenues in the treatment of LA-NSCLC. In addition to the use of durvalumab as consolidative systemic therapy after concurrent chemoradiotherapy for Stage III NSCLC, other combination regimens have been shown to be effective in various disease stages in preclinical and clinical studies. These regimens include CTLA-4 and PD/PDL-1 checkpoint inhibitors combined with radiation treatment. While these combined regimens have demonstrated efficacy, they are not without toxicity, and require additional evaluation when combined with radiation. In this review, we have summarized the immunostimulatory and immunosuppressive effects of radiation therapy. We also evaluate the current evidence and ongoing research supporting the combination of radiotherapy and immunotherapy across early to LA-NSCLC.

Genomic characterization of malignant pleural mesothelioma and associated clinical outcomes.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare malignancy with a poor prognosis. While treatment with a platinum-based chemotherapy is the standard of care, many patients have rapid progression of disease with a median overall survival of ~12 months. Limited data exist about the genomic alterations associated with MPM and their clinical implications. METHODS: We report genomic alterations and clinical data for 17 patients with MPM who had next generation sequencing performed. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier method. RESULTS: Median age at diagnosis was 70 years (range 55-85), and 47% of the patients were male. The most common genomic alterations in the 17 patients were NF2 (53%), BAP1 (41%), CDKN2A (41%) and TP53 (29%). The median OS was 10.8 months. When stratified by mutational status, patients had better median OS if they had a BAP1 alteration compared to TP53 alteration (median OS 14.5 vs 7.2 months). Median PFS with first-line chemotherapy was 7 months (SD ± 3.3). However, patients with TP53 mutations had worse PFS with chemotherapy with median of only 3.9 months. Tumor mutation burden (TMB) was available for 12 patients and all had low TMB (range 1 to 8.1 mutation/Mb). Median PFS with immunotherapy was poor with at 1.5 months (SD ±0.4) and there was no significant difference in PFS with immunotherapy based on molecular profile. CONCLUSION: Our study has identified that TP53 confers worse survival and response to platinum chemotherapy compared to BAP1. Overall PDL1 expression and TMB is low in patients with MPM resulting in limited benefit from single agent PD-1/PD-L1 agent.

Tumor volume reduction evaluated by cone beam computed tomography during stereotactic body radiotherapy for early stage non-small cell lung cancer.

BACKGROUND: We hypothesized that significant tumor volume reduction (TVR) occurs over the course of stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC), and that TVR correlates with clinical outcomes. METHODS: We conducted a retrospective review of patients treated with SBRT for early stage NSCLC across two academic centers. For each patient, we contoured the tumor volume (TV) on cone beam computed tomography (CBCT) images obtained before each treatment fraction. We then calculated TVR based on the TV from the first and last days of treatment. We used log-rank tests to quantify differences in overall survival (OS), progression-free survival (PFS) and recurrence based on TVR. RESULTS: Data from 69 patients and a total of 73 treated tumors were analyzed. The median follow-up for survivors was 51.8 months (range, 6.9 to 80.0 months). The median TVR for the cohort was 10.1% (range, -5.7% to 43.5%). There was no significant difference in either OS (median 33.4 vs. 29.1 months, P=0.79) or PFS (median 26.3 vs. 12.3 months, P=0.43) for those with high TVRs (≥10.1%) vs. low TVRs (<10.1%), respectively. There was a trend toward superior 2-year PFS in the high TVR group (52.2% vs. 36.7%, P=0.062), but this effect diminished on longer follow-up (4-year PFS 31.9% vs. 26.7%, P=0.15). No associations were observed between TVR and local, regional or distant recurrence. CONCLUSIONS: We were not able to demonstrate that TVR is a reliable predictive imaging marker for stage I/II NSCLC treated with SBRT. Future studies with larger sample sizes are needed to clarify a potential relationship between TVR and early outcomes.

Correction to: Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer.

In the original publication of the article the author has found few incorrect values in the Table 1.

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

Importance: Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non-small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy. Objective: To determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC. Design, Setting, and Participants: This phase 1 prospective multicenter nonrandomized controlled trial using a 3 plus 3 design was performed from August 30, 2016, to October 24, 2018, with a median follow-up of 16.0 (95% CI, 12.0-22.6) months and data locked on July 25, 2019. Twenty-one participants had locally advanced, unresectable, stage III NSCLC as determined by multidisciplinary review, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function. Data were analyzed from October 17, 2016, to July 19, 2019. Interventions: Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Dose cohorts evaluated included full-dose pembrolizumab (200 mg intravenously every 3 weeks) 2 to 6 weeks after chemoradiotherapy (cohort 1); reduced-dose pembrolizumab (100 mg intravenously every 3 weeks) starting day 29 of chemoradiotherapy (cohort 2); full-dose pembrolizumab starting day 29 of chemoradiotherapy (cohort 3); reduced-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 4); and full-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 5). A safety expansion cohort of 6 patients was planned based on the maximum tolerated dose of pembrolizumab. Dose-limiting toxic effects were defined as pneumonitis of at least grade 4 within cycle 1 of pembrolizumab treatment. Main Outcomes and Measures: Safety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates. Results: Among the 21 patients included in the analysis (11 female [52%]; median age, 69.5 [range, 53.0-85.0] years), no dose-limiting toxic effects in any cohort were observed. One case of grade 5 pneumonitis occurred in the safety expansion cohort with the cohort 5 regimen. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median PFS for patients who received at least 1 dose of pembrolizumab (n = 21) was 18.7 (95% CI, 11.8-29.4) months, and 6- and 12-month PFS were 81.0% (95% CI, 64.1%-97.7%) and 69.7% (95% CI, 49.3%-90.2%), respectively. Median PFS for patients who received at least 2 doses of pembrolizumab (n = 19) was 21.0 (95% CI, 15.3 to infinity) months. Conclusions and Relevance: These findings suggest that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS of 69.7% at 12 months, and requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT02621398.

Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer.

PURPOSE: CC-486 is an oral formulation of azacitidine that allows for extended dosing schedules to prolong azacitidine exposure to malignant cells and maximize clinical activity. CC-486 300 mg daily, administered for 14 or 21 days of 28-day treatment cycles, is currently under investigation in two ongoing phase III trials. The 300-mg daily dose in these studies is administered as two 150-mg tablets (Formulation A). METHODS: We evaluated the bioequivalence of one 300-mg CC-486 tablet (Formulation B) with Formulation A and food effect on Formulation B, in adult patients with cancer in a 2-stage crossover design study. RESULTS: The ratios of the geometric means of the maximum azacitidine plasma concentration (Cmax) and of the area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞) were 101.5% and 105.7%, demonstrating the bioequivalence of Formulations A and B. Formulation B was rapidly absorbed under fasted and fed conditions. The geometric mean of Cmax was significantly decreased by ~ 21% in the fed state. Median Tmax was reached at 2 h and 1 h post-dose in fed and fasted states, respectively (P < 0.001). Nevertheless, systemic drug exposure (AUC) in fed and fasted states was within the 80-125% boundaries of bioequivalence and differences in Cmax and Tmax are not expected to have a clinical impact. CONCLUSION: The single 300-mg CC-486 tablet was bioequivalent to two 150-mg tablets, which have shown to be efficacious and generally well-tolerated in clinical trials, and can be taken with or without food.

Paravertebral Nerve Block With Liposomal Bupivacaine for Pain Control Following Video-Assisted Thoracoscopic Surgery and Thoracotomy.

BACKGROUND: Some surgeons have adopted the use of video-assisted thoracoscopic surgery (VATS) or robotic surgery to perform resections for lung cancer. VATS is associated with less pain and a decrease in pulmonary complications compared with open thoracotomies. Long-acting liposomal bupivacaine (LB) intercostal nerve blocks are reported to provide superior pain relief compared with epidural catheters in the first 3 d after a thoracotomy. This study examined whether LB improves pain after VATS and if it provides effective analgesia after a thoracotomy. MATERIALS AND METHODS: A retrospective review was performed on 151 consecutive patients undergoing a VATS or thoracotomy who received paravertebral nerve blocks. VATS patients received paravertebral nerve blocks with LB (VATS-LB) or 0.25% bupivacaine with epinephrine (BE; VATS-BE). Thoracotomy patients received paravertebral nerve blocks via LB injections. Pain scores, narcotic utilization, complications, and hospital length of stay were examined. RESULTS: Fifty patients underwent a VATS-LB, 53 underwent a VATS-BE, and 32 underwent a thoracotomy. Thoracotomy and VATS-LB patients had pain scores lower than VATS-BE patients in the first 48 h after surgery (P < 0.004). Opioid use was not significantly different between the thoracotomy and VATS-LB patients throughout the first 2 wk postoperatively. CONCLUSIONS: LB paravertebral blocks significantly improve postoperative pain in comparison with 0.25% BE blocks in VATS patients. LB paravertebral blocks also provide effective analgesia in patients undergoing thoracotomies.

Phase I neoadjuvant study of intravesical recombinant fowlpox-GM-CSF (rF-GM-CSF) or fowlpox-TRICOM (rF-TRICOM) in patients with bladder carcinoma.

Intravesical BCG is a highly effective treatment for high-grade nonmuscle invasive bladder cancer and carcinoma in situ (CIS); however, for patients who are either resistant or become unresponsive to BCG therapy there is a need for alternative treatment approaches. This study examined the safety and feasibility of intravesically administered recombinant fowlpox virus encoding GM-CSF (Arm A) or TRICOM (Arm B); and the local and systemic immunologic responses generated to the vector(s). Twenty bladder cancer patients scheduled for cystectomy as their standard of care received preoperatively four weekly doses of intravesical recombinant fowlpox. Treatment was well tolerated, however, three patients experienced transient elevations of liver transaminases, with one rising to the level of a DLT. Cystectomy derived tumor and normal bladder mucosa demonstrated mRNA for the virally encoded LacZ gene supporting effective infection/transfection. Detected serum antibody to the LacZ encoding ß-galactosidase indicated successful expression of vector-encoding gene products and the ability to immunize via the bladder site. H&E and IHC using a panel of immune cell specific antigens demonstrated immune cell infiltration of the bladder wall. These findings demonstrate good safety profile, successful infection/transfection, ability to generate systemic immune response, and local recruitment of immune cell populations with intravesical administration of fowlpox-based constructs encoding for GM-CSF(rF-GM-CSF) or TRICOM (rF-TRICOM), and support further evaluation of this treatment modality for bladder cancer.

A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors.

Background AT-101 is a BH3 mimetic that inhibits the heterodimerization of Bcl-2, Bcl-xL, Bcl-W, and Mcl-1 with pro-apoptotic proteins, thereby lowering the threshold for apoptosis. This phase I trial investigated the MTD of AT-101 in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods Patients were treated with AT-101 (40 mg) every 12 h on days 1, 2 and 3 of each cycle combined with varying dose levels (DL) of paclitaxel and carboplatin [DL1: paclitaxel (150 mg/m2) and carboplatin (AUC 5) on day 1 of each cycle; DL2: paclitaxel (175 mg/m2) and carboplatin (AUC 6) on day 1 of each cycle]. Secondary objectives included characterizing toxicity, efficacy, pharmacokinetics, and pharmacodynamics of the combination. Results Twenty-four patients were treated across two DLs with a planned expansion cohort. The most common tumor type was prostate (N = 11). Two patients experienced DLTs: grade 3 abdominal pain at DL1 and grade 3 ALT increase at DL2; however, the MTD was not determined. Moderate hematologic toxicity was observed. One CR was seen in a patient with esophageal cancer and 4 patients achieved PRs (1 NSCLC, 3 prostate). PD studies did not yield statistically significant decreases in Bcl-2 and caspase 3 protein levels, or increased apoptotic activity induced by AT-101. Conclusion The combination of AT-101 at 40 mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016.

Phase Ib/II study of hydroxychloroquine in combination with chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC).

OBJECTIVES: Activation of cell survival pathways such as autophagy represents a potential resistance mechanism to chemotherapy in NSCLC. Preclinical studies report that autophagy inhibition suppresses lung tumor development and progression. We report the safety and efficacy for adding autophagy inhibitor, hydroxychloroquine, to chemotherapy in a phase Ib/II single-arm study in patients with metastatic NSCLC. PATIENTS AND METHODS: We treated patients with untreated metastatic NSCLC with carboplatin, paclitaxel (and bevacizumab if criteria met) and hydroxychloroquine 200 mg BID. Patients continued on hydroxychloroquine (+/- bevacizumab) maintenance after 4-6 cycles of therapy. RESULTS: We enrolled 40 patients, 8 on phase Ib and 32 on phase II. Forty-three percent were female; 50% with squamous histology. Median age was 62 years (range, 43-73). Thirteen patients developed ≥grade 3 treatment-related adverse event. Common adverse events (all grades) were neutropenia (35%), neuropathy (32.5%), and anemia (32.5%). The objective response rate (ORR) was 33% in the 30 patients (phase II) evaluable for response. Additionally, 20% of the patients demonstrated stable disease (clinical benefit rate of 53%). The median PFS was 3.3 months (95% CI 2.1-6.8 months). In 9 patients with KRAS positive tumors, ORR was 44% and median PFS was higher than expected at 6.4 months (95% CI 1.8-15.6). CONCLUSIONS: Addition of hydroxychloroquine is safe and tolerable with a modest improvement in clinical responses compared to prior studies. Autophagy inhibition may overcome chemotherapy resistance in advanced NSCLC and further study in a more molecularly selected population such as KRAS-positive tumors is warranted.

A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors.

PURPOSE: Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors. METHODS: Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID). RESULTS: Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (N = 18; 51%), fatigue (N = 17; 49%), maculo-papular rash (N = 16; 46%), diarrhea (N = 12; 34%), anorexia (N = 11; 31%), and nausea (N = 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (N = 13) and primarily included fatigue (N = 5; 14%) and maculo-papular rashes (N = 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients. CONCLUSION: The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.

Synchronous Oligometastatic Non-small Cell Lung Cancer Managed With Curative-Intent Chemoradiation Therapy: Long-term Outcomes From a Single Institution.

PURPOSE: We examined long-term clinical outcomes among patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) treated at our institution with definitive thoracic chemoradiation therapy (CRT) and local therapy to all oligometastatic lesions. METHODS AND MATERIALS: A retrospective review identified 38 patients with synchronous oligometastatic NSCLC (≤3 metastatic lesions) who were treated with definitive CRT to the primary tumor and regional lymph nodes between 1999 and 2017 at our institution. Of the 38 patients, 27 patients (71%) received induction chemotherapy, all of whom responded or stabilized with initial systemic therapy before consideration of CRT. Most patients received chemotherapy concurrently with radiation therapy (n = 32; 84%) and local therapy to the metastatic disease site(s) (n = 34; 89%). We assessed patterns of progression or failure, overall survival (OS), progression-free survival (PFS), and toxicities. RESULTS: The median follow-up duration was 54.9 months. Most patients (84%) presented with N2 to N3 disease. The brain or central nervous system was the most common site of disease progression and occurred in 16 of 28 patients (57%) experiencing any progression and 10 of 16 patients (63%) who initially presented with brain oligometastases. Median OS was 21.1 months (95% confidence interval [CI], 15.6-49.0 months), and median PFS 9.7 months (95% CI, 8.2-14.4 months). The 1-, 2-, and 4-year OS rates were 75.7%, 45.0%, and 33.7%, respectively. On multivariate analysis, both locoregional progression (hazard ratio: 5.8; 95% CI, 2.2-15.0; P = .0003) and distant progression (hazard ratio: 6.0; 95% CI, 2.3-15.4; P = .0002), when treated as time-dependent covariates, were associated with inferior OS. Grade ≥3 esophagitis occurred in 9% and grade ≥3 pneumonitis in 5% of patients with evaluable data. CONCLUSIONS: Patients with synchronous oligometastatic NSCLC and a high regional nodal burden treated with definitive thoracic CRT experienced favorable survival outcomes and low toxicity. At our institution, treating oligometastatic disease with CRT after systemic therapy is incorporated into the treatment plan from the onset of therapy, and we monitor the neuraxis closely for progression during and after treatment. Future research should focus on novel treatment combinations, such as immunotherapy or targeted systemic therapy as appropriate to further improve tumor control and survival.

A Novel Acquired Exon 20 EGFR M766Q Mutation in Lung Adenocarcinoma Mediates Osimertinib Resistance but is Sensitive to Neratinib and Poziotinib.

INTRODUCTION: Osimertinib is an effective third-generation tyrosine kinase inhibitor (TKI) for EGFR-mutant lung cancers. However, treatment for patients with acquired resistance to osimertinib remains challenging. We characterized a novel EGFR mutation in exon 20 that was acquired while on osimertinib. METHODS: A 79-year-old woman had disease progression during third-line treatment with osimertinib for an EGFR L858R/T790M-mutant lung cancer. Sequencing of circulating cell-free DNA showed EGFR L858R, an acquired novel EGFR M766Q mutation in exon 20, and no evidence of EGFR T790M. Homology modeling was performed to investigate the effects of M766Q on binding to osimertinib. L858R and L858R/M766Q mutations were retrovirally introduced into Ba/F3 and NIH/3T3 cells and evaluated for sensitivity to first-generation (erlotinib), second-generation (afatinib, neratinib, and poziotinib), and third-generation TKIs (osimertinib) by cell viability and colony-formation assays. EGFR-mediated signaling pathways were interrogated by western blotting. RESULTS: Modeling suggested that EGFR M766Q could disrupt osimertinib binding. L858R/M766Q double-mutant cells were 12-fold more resistant to osimertinib, and more than 250-fold more resistant to erlotinib and afatinib, as compared to L858R-mutant cells. In contrast, double-mutant cells remained sensitive to neratinib and poziotinib at clinically relevant doses (concentration that inhibits 50%, 4.3 and 1.3 nM, respectively). This was corroborated by the effects of the TKIs on colony formation and EGFR signaling. CONCLUSIONS: Acquisition of EGFR M766Q exon 20 mutation is a novel mechanism of acquired resistance to osimertinib. EGFR-mutant lung cancers with an acquired EGFR M766Q mutation in the setting of osimertinib resistance may be sensitive to neratinib and poziotinib.

A phase 1b, multicenter, open-label, dose-finding study of eribulin in combination with carboplatin in advanced solid tumors and non-small cell lung cancer.

PURPOSE: This phase 1b study investigated the maximum tolerated dose (MTD; primary objective), safety, pharmacokinetics, and antitumor activity (secondary objectives) of eribulin combined with carboplatin in patients with solid tumors and, in particular, non-small cell lung cancer (NSCLC). METHODS: Two dose-escalation schemes were evaluated with carboplatin, at an area under the curve (AUC) of either 5 or 6 mg/mL·min. Eribulin, dose-escalated from 0.7 to 1.4 mg/m2 was administered 1 h before (Schedule A) or after (Schedule B) carboplatin as a 2-5-min bolus infusion on days 1 and 8 of a 21-day cycle. Following tolerability assessment, patients with NSCLC were recruited in an expansion cohort. RESULTS: The MTDs were eribulin 1.4 and 1.1 mg/m2 with carboplatin AUC 5 and AUC 6, respectively. The latter combination was used to treat NSCLC patients in the expansion cohort. Pharmacokinetics of eribulin and carboplatin were generally unaffected by administration sequence (i.e., administration of carboplatin did not significantly affect eribulin Cmax and AUC0-t and the converse was also observed). In the NSCLC cohort, the objective response rate was 27%. Median overall and progression-free survival durations were 12.1 and 4.2 months, respectively. No unexpected safety findings were observed. CONCLUSIONS: The combination of eribulin and carboplatin demonstrated antitumor activity; however, recent therapeutic advances may be more promising approaches for first-line treatment of NSCLC. Clinical trial registration NCT00268905.

Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration.

BACKGROUND: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. METHODS: Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. RESULTS: Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. CONCLUSIONS: Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. TRIAL REGISTRATION: NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).