The rexinoid bexarotene represses cyclin D1 by causing its proteasomal degradation. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib represses cyclin D1 via different mechanisms. We conducted a preclinical study and two clinical/translational trials (a window-of-opportunity and phase II) of bexarotene plus erlotinib. The combination repressed growth and cyclin D1 expression in cyclin-E– and KRAS/p53–driven transgenic lung cancer cells. The window-of-opportunity trial in early-stage non-small-cell lung cancer (NSCLC) patients (10 evaluable) repressed cyclin D1 (in tumor biopsies and buccal swabs) and induced necrosis and inflammatory responses including in cases with KRAS mutations. The phase II trial in heavily pre-treated, advanced NSCLC patients (40 evaluable; a median of two prior relapses per patient [range, 0–5]; 21% with prior EGFR-inhibitor therapy) produced three major clinical responses in patients with prolonged progression-free survival (583, 665, and 1460-plus days). Median overall survival was 22 weeks. Hypertriglyceridemia was associated with an increased median overall survival (P = 0.001). Early PET response did not reliably predict clinical response. The combination was generally well tolerated, with toxicities similar to those of the single agents. In conclusion, bexarotene plus erlotinib was active in KRAS-driven lung cancer cells, was biologically active in early-stage mutant-KRAS NSCLC, and was clinically active in advanced, chemotherapy-refractory mutant-KRAS tumors in this study and previous trials. Additional lung cancer therapy or prevention trials with this oral regimen are warranted.

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Background Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue of children and young adults. Patients with ES are treated with intensive chemotherapy regimens. We describe predictors of acute chemotherapy-associated toxicity in this population. Procedure In this retrospective cohort study, records of ES patients treated at two academic medical centers between 1980 and 2010 were reviewed. Grade 3 and 4 non-hematologic chemotherapy-associated toxicities during frontline therapy were recorded for each patient, along with potential clinical and demographic predictors of toxicity. Bivariate analyses were performed using the Fisher exact test. Multivariate analysis was performed using logistic regression. Results The cohort included 142 patients with ES and toxicity data. In bivariate analyses, age <12 years at diagnosis, Latino ethnicity, low family income, and treatment on a clinical trial were associated with higher incidence of toxicity (p <0.01). Tumor size, site, stage, mode of local control, body mass index, overall chemotherapy exposure and dose-intensity were not associated with toxicity. In multivariate analysis, low income (odds ratio (OR) 4.97, 95% CI 1.9–13.1), clinical trial enrollment (OR 3.67, 95% CI 1.2–10.9), pelvic tumor site (OR 3.88, 95% CI 1.17–12.88), and age <12 years (OR 2.8, 95% CI 1.0–7.5) were independent predictors of toxicity. Conclusion ES patients who are younger, of Latino ethnicity, have pelvic tumors or low income have higher rates of toxicity that may require increased supportive care. Treatment on a clinical trial was also associated with higher rates of toxicity, though this finding may reflect better reporting in these patients.

Background: The incidence of Ewing sarcoma varies by race, with very low rates among persons of African and East Asian ancestry. The incidence by race of other mesenchymal tumors that also harbor EWSR1 translocations has not been studied.Methods: The SEER database was queried to find cases of mesenchymal tumors associated with EWSR1 translocations: Ewing sarcoma; clear cell sarcoma; extraskeletal myxoid chondrosarcoma; myxoid liposarcoma; desmoplastic small round cell tumor; and myoepithelial tumor. Age-adjusted incidence rates were calculated for white, African American, and Asian/Native American populations and compared statistically.Results: Ewing sarcoma was significantly less common in the African American and Asian/Native American populations compared with the white population, with incidence rate ratios of 0.12 (95% CI, 0.08-0.20; P < 0.001) and 0.54 (95% CI, 0.41-0.69; P < 0.001), respectively. Desmoplastic small round cell tumor was significantly more common in the African American population compared with the white population (incidence rate ratio ¼ 3.0; 95% CI, 1.62-5.49; P < 0.001). Myxoid liposarcoma was significantly less common in the Asian/Native American population compared with the white population (incidence rate ratio ¼ 0.72; 95% CI, 0.56-0.92; P ¼ 0.006). The incidence rates for extraskeletal myxoid chondrosarcoma, myoepithelial tumors, and clear cell sarcoma did not differ significantly by race.Conclusions: Tumors associated with EWSR1 translocation are not uniformly more common in people of European ancestry.Impact: The relationship between race and EWSR1 somatic translocation is complex. Future studies investigating the genetic epidemiology of EWSR1 translocated tumors are required. Cancer Epidemiol Biomarkers Prev; 20(3); 449-53. Ó2011 AACR.

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Background: Safe, effective treatment options for advanced melanoma that progressed on a PD-1/PD-L1 inhibitor is an unmet medical need. Results of the phase 1b KEYNOTE-029 trial showed promising antitumor activity in advanced melanoma with pembro combined with a CTLA-4 inhibitor. This ongoing, open-label, multiarm phase 1/2 study (NCT03179436) evaluating the CTLA-4 inhibitor Qmab + pembro showed antitumor activity as first-line treatment for advanced NSCLC and for previously treated extensive-stage SCLC. Data from the efficacy expansion phase in pts with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor are presented. Methods: Pts with unresectable stage III-IV melanoma and confirmed progressive disease (PD) per iRECIST within 12 wk of the last dose of a PD-1/PD-L1 inhibitor given alone or in combination for ≥2 doses (combinations with CTLA-4 inhibitors were not allowed) were randomly assigned (1:1) to receive Qmab 25 mg IV Q6W with or without pembro 400 mg IV Q6W; 100 pts in the Qmab + pembro arm and 40 pts in the Qmab monotherapy arm were planned for enrollment. Treatment in both arms was given for up to 18 cycles (~2 y) or until PD, toxicity, or pt withdrawal. Pts who had PD after ≥2 Qmab monotherapy cycles could crossover to Qmab + pembro. Tumor imaging was assessed Q9W to wk 54 and Q12W thereafter. Primary end points were safety and ORR by BICR per RECIST v1.1. Secondary and exploratory end points included DOR and PFS by BICR per RECIST v1.1 and OS. Results: 151 pts were enrolled (n = 111, Qmab + pembro; n = 40, Qmab monotherapy); median time from first dose to database cutoff was 7.7 mo. In all pts, median age was 64 y; 66% of pts were male, 33% had BRAF-mutant tumors, and 50% had elevated LDH. Treatment-related adverse events (TRAEs) were reported in 87 pts (78%) in the Qmab + pembro arm and 24 pts (60%) in the Qmab monotherapy arm; grade 3/4 TRAEs were reported in 16 pts (14%) and 3 pts (8%), respectively. The most common TRAEs were pruritus (26%), fatigue (14%), diarrhea (14%), and rash (13%). No treatment-related deaths occurred in either arm; 5% of pts discontinued because of TRAEs. Confirmed ORR was 9% (95% CI, 4.4-15.9) with Qmab + pembro (1 CR, 9 PRs) and 3% (95% CI, 0.1-13.2) with Qmab monotherapy (1 PR). Median DOR was not reached (NR; range, 2.0+ to 13.8+ mo) with Qmab + pembro. DOR was 1.9+ with Qmab monotherapy. Median PFS was 2.1 mo (95% CI, 2.1-3.2) with Qmab + pembro and 2.1 mo (95% CI, 2.1-2.5) with Qmab monotherapy; 6-mo PFS rates were 21% and 13%, respectively. Median OS was NR (95% CI, 11.2 mo to NR) with Qmab + pembro and 7.8 mo (95% CI, 6.3 to NR) with Qmab monotherapy; 6-mo OS rates were 74% and 73%, respectively. Conclusions: Qmab + pembro was generally well tolerated and provided modest antitumor activity in pts with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor. This combination and a coformulation of Qmab + pembro will be further investigated in the KEYMAKER-U02 study. Citation Format: Sanjeev Deva, Jacek Mackiewicz, Stephane Dalle, Helen Gogas, Iwona Lugowska, Alfonso Berrocal, Alexander M. Menzies, Michele Maio, Adnan Nagrial, Karmele Mujika Eizmendi, Jean-Jacques Grob, Christian Caglevic, Megan Lyle, Juan Martin-Liberal, Rachel Altura, Yixin Ren, Anuradha Khilnani, Jobin Cyrus, Shabana Siddiqi, Michal Lotem. Phase 1/2 study of quavonlimab (Qmab) + pembrolizumab (pembro) in patients (pts) with advanced melanoma that progressed on a PD-1/PD-L1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT557.

Lung cancer is the leading cause of cancer-related mortality in the United States. Improved ways to treat and prevent lung cancer are needed. Increased epidermal growth factor receptor (EGFR) expression frequently occurs in lung carcinogenesis. Treatment with the EGFR-tyrosine kinase inhibitor (EGFR-TKI) erlotinib prolongs survival, especially in patients whose lung cancers harbor activating EGFR mutations. However, patients with non-small cell lung cancers (NSCLCs) that harbor KRAS mutations can be less responsive. Therefore, there is a need for improved NSCLC treatments irrespective of KRAS or EGFR mutation status. Previous studies showed that the rexinoid bexarotene causes cyclin D1 proteasomal degradation. The EGFR-TKI erlotinib also represses cyclin D1, but via different mechanisms. The combination of bexarotene with erlotinib was explored. Initial effects of this combination on tumor growth and cyclin D1 expression were examined in murine transgenic lung cancer cell models with or without KRAS/p53 mutations. Findings were translated into both early stage window of opportunity (14 patients enrolled) and advanced stage (42 patients enrolled) phase II NSCLC trials. In the window of opportunity trial, cyclin D1 was measured in pre-versus post-treatment NSCLC biopsies and in buccal swabs. EGFR and phospho-EGFR immunohistochemical expression was assessed in the paired tumor biopsies. KRAS and EGFR mutations were also examined. A phase II trial in heavily pre-treated stage IV NSCLC cases was performed with early PET responses evaluated. Findings reveal significant repression of cyclin D1 expression and lung cancer cell growth. Intriguingly, cyclin D1, EGFR and phospho-EGFR immunohistochemical expression profiles were reduced while necrosis and inflammatory cellular responses were induced in the window of opportunity trial independent of the presence of KRAS or EGFR mutations. Cyclin D1 was repressed in post-treatment buccal swabs. The refractory NSCLC trial (2 median relapses, 21% with prior EGFR-inhibitor therapies) had 3 major clinical responses (2 had KRAS or EGFR mutations) with prolonged survival (583, 665, and 1460+ days). Median survival was 22 weeks (16 weeks for controls). Hypertriglyceridemia or rash significantly increased median overall survival to 24 weeks. Early PET response did not reliably predict clinical response. In summary, combining bexarotene with erlotinib can repress cyclin D1 and confer in vitro and clinical anti-tumor responses (including induced tumor necrosis and inflammatory changes) independent of EGFR or KRAS mutations present in the lung cancers. Notably, survival increased in the treated stage IV NSCLC patients when hypertriglyceridemia or rash developed. Clinical activity of this regimen is encouraging and warrants further study for lung cancer therapy or chemoprevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-412. doi:10.1158/1538-7445.AM2011-LB-412

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