Ben Solomon

Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer

FGFR1 amplification provides a therapeutic target for squamous cell lung cancer, which is resistant to other targeted lung cancer drugs. A Smoking Gun for Lung Cancer Detectives and scientists alike need strong evidence to take their cases to the judge, who for scientists is often a patient with a deadly disease. Yet, new culprits are sometimes found that can break a case wide open. Lung cancer, which accounts for more than 10% of the global cancer burden, has a poor prognosis and inadequately responds to chemotherapy and radiotherapy. New targeted treatments for lung adenocarcinomas inhibit the oncogenic versions of signaling protein kinases that arise from mutations typically found in lung cancer patients who have never smoked. However, smokers frequently suffer from a different deviant, squamous cell lung cancers, for which there are no known molecular genetic targets for therapy. Now, Weiss et al. have fingered a new suspect in smoking-related lung cancer: amplification of the FGFR1 gene, which encodes the fibroblast growth factor receptor 1 tyrosine kinase (FGFR1). To identify therapeutically viable genetic alterations that may influence squamous cell lung cancer, Weiss et al. performed genomic profiles on a large set of lung cancer specimens. Squamous cell lung cancer samples showed FGFR1 amplification, which was not found in other lung cancer subtypes. The authors then determined that a molecule that broadly inhibits FGF receptor function could block tumor growth and cause cell death in the cancers that expressed high amounts of the FGFR1 gene product in a manner that was dependent on FGFR1 expression. Moreover, FGFR1 inhibition resulted in a considerable decrease in tumor size in a mouse model of FGFR1-amplified lung cancer. This culmination of evidence implies that inhibition of this receptor tyrosine kinase should be explored as a candidate therapy for corralling squamous cell lung cancer in smokers. Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases). Using cell-based screening with the FGFR inhibitor PD173074 in a large (n = 83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (FGFR1V561M), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally, we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Thus, focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.

Prognostic Significance of p16INK4A and Human Papillomavirus in Patients With Oropharyngeal Cancer Treated on TROG 02.02 Phase III Trial

PURPOSE To determine the prognostic importance of p16 and human papillomavirus (HPV) in patients with oropharyngeal cancer treated on a phase III concurrent chemoradiotherapy trial. PATIENTS AND METHODS Patients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. In this substudy, analyses were restricted to patients with oropharyngeal cancer. p16 was detected by immunohistochemistry, and HPV was detected by in situ hybridization and polymerase chain reaction. RESULTS Slides were available for p16 assay in 206 of 465 patients, of which 185 were eligible, and p16 and HPV were evaluable in 172 patients. One hundred six (57%) of 185 were p16-positive, and in patients evaluable for both p16 and HPV, 88 (86%) of 102 p16-positive patients were also HPV-positive. Patients who were p16-positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. p16-positive tumors compared with p16-negative tumors were associated with better 2-year overall survival (91% v 74%; hazard ratio [HR], 0.36; 95% CI, 0.17 to 0.74; P = .004) and failure-free survival (87% v 72%; HR, 0.39; 95% CI, 0.20 to 0.74; P = .003). p16 was a significant prognostic factor on multivariable analysis (HR, 0.45; 95% CI, 0.21 to 0.96; P = .04). p16-positive patients had lower rates of locoregional failure and deaths due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33; 95% CI, 0.09 to 1.24; P = .13). CONCLUSION HPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.

Correlation of p16 status, hypoxic imaging using [18F]-misonidazole positron emission tomography and outcome in patients with loco-regionally advanced head and neck cancer

We investigated the relationship between hypoxia, human papillomavirus (HPV) status and outcome in head and neck squamous cell carcinoma.

Effect of Platinum-Based Chemoradiotherapy on Cellular Proliferation in Bone Marrow and Spleen, Estimated by 18 F- FLT PET/CT in Patients with Locally Advanced Non-Small Cell Lung Cancer

Historically, it has been difficult to monitor the acute impact of anticancer therapies on hematopoietic organs on a whole-body scale. Deeper understanding of the effect of treatments on bone marrow would be of great potential value in the rational design of intensive treatment regimens. 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) is a functional radiotracer used to study cellular proliferation. It is trapped in cells in proportion to thymidine-kinase 1 enzyme expression, which is upregulated during DNA synthesis. This study investigates the potential of 18F-FLT to monitor acute effects of chemotherapy on cellular proliferation and its recovery in bone marrow, spleen, and liver during treatment with 2 different chemotherapy regimens. Methods: Sixty patients with non–small cell lung cancer underwent concurrent radical chemoradiotherapy to 60 Gy in 6 wk with either cisplatin/etoposide (C/E, n = 28) weeks 1 and 5 or weekly carboplatin/paclitaxel (C/P, n = 32) regimens. 18F-FLT and 18F-FDG PET with CT were performed at baseline, week 2 (day 9 for 18F-FLT and day 10 for 18F-FDG PET), and week 4 (day 23 for 18F-FLT and day 24 for 18F-FDG PET). Visual and semiquantitative standardized uptake value (SUV) measurements were performed in bone marrow outside the radiotherapy field, liver, spleen, and small bowel. These were correlated to blood counts and smears in a subset of patients. Results: The C/E group exhibited a drop in bone marrow 18F-FLT uptake at week 2 (median SUVmax [maximum SUV] decrease to 31%, 8.7–6.0, P < 0.001), with recovery at week 4, reflecting the absence of chemotherapy between these times. By contrast, the weekly C/P group showed gradually declining bone marrow uptake (P > 0.05). Spleen uptake in both cohorts decreased at week 2, with intense rebound activity at week 4 (SUVmax week 4 at 58% above baseline: 2.4–3.8, for C/E, respectively, 30% for C/P: 2.7–3.5, P < 0.001). Liver uptake changed little. 18F-FLT changes preceded neutrophil count reductions. 18F-FDG uptake in marrow liver and spleen changed much less than 18F-FLT. Conclusion: 18F-FLT imaging may be used to quantify impairment and recovery of bone marrow by specific chemotherapy regimens and may also enable imaging of organ-specific processes such as spleen activation. 18F-FLT is superior to 18F-FDG for this purpose. This technology may support novel treatment planning and monitoring approaches in oncology patients.

Treatment response in the neck: p16+ versus p16− oropharyngeal cancer

To compare nodal response rates following chemoradiotherapy in patients with p16+ and p16− oropharyngeal squamous cell carcinoma (OPSCC).

Weekly cisplatin and radiotherapy for low risk, locoregionally advanced human papillomavirus–positive oropharyngeal squamous cell carcinoma

There is interest in different treatment strategies, including deintensification in good prognosis human papillomavirus‐positive (HPV(+)) oropharyngeal squamous cell carcinoma (SCC). We reviewed our experience with weekly cisplatin in low‐risk, locoregionally advanced HPV(+) oropharyngeal SCC since late 2009.Background There is interest in different treatment strategies, including deintensification in good prognosis human papillomavirus-positive (HPV(+)) oropharyngeal squamous cell carcinoma (SCC). We reviewed our experience with weekly cisplatin in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC since late 2009. Methods Data from patients with low-risk HPV(+) oropharyngeal SCC treated with weekly cisplatin (40 mg/m2) and 70 Gy radiotherapy were collected. Low risk was defined as stage III to IV oropharyngeal SCC excluding T1-2N1, T4 or N3 disease, or N2b to N2c disease in patients with >10 pack-year smoking history. Results Of 31 patients, the median age was 56 years (range, 41–69 years). All patients completed 70 Gy radiotherapy within 51 days and 84% completed at least 5 cycles of cisplatin. Grade 3 mucositis occurred in 22 patients (71%) and grade 3 febrile neutropenia in 6 patients (19%). No patients required enteral feeding at 12 months. The median follow-up was 30 months (range, 21–57 months) with no recurrences or deaths. Conclusion Concurrent weekly cisplatin is relatively well-tolerated and associated with excellent disease control in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC.

Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the INK4/ARF locus in non–small cell lung cancer

E6AP exhibits tumor suppressor activity that may help stratify NSCLC patients. INK4/ARF repression in lung cancer by loss of E6AP The abundance of the cell cycle decelerator p16INK4a, encoded at the INK4/ARF locus, is decreased in various cancers. Gamell et al. found that the absence of p16INK4a in some patients is explained by the lack of the E3 ubiquitin ligase E6AP. E6AP bound to and inhibited the activity of transcription factor E2F1; a decrease in E6AP abundance enabled E2F1-mediated expression of the cell cycle promoter CDC6, which encodes a transcriptional regulator that represses INK4/ARF expression. The findings identify a tumor-suppressive role for E6AP in lung cancer and suggest that targeting the E2F1-CDC6 pathway might slow tumor growth in some NSCLC patients. The tumor suppressor p16INK4a, one protein encoded by the INK4/ARF locus, is frequently absent in multiple cancers, including non–small cell lung cancer (NSCLC). Whereas increased methylation of the encoding gene (CDKN2A) accounts for its loss in a third of patients, no molecular explanation exists for the remainder. We unraveled an alternative mechanism for the silencing of the INK4/ARF locus involving the E3 ubiquitin ligase and transcriptional cofactor E6AP (also known as UBE3A). We found that the expression of three tumor suppressor genes encoded in the INK4/ARF locus (p15INK4b, p16INK4a, and p19ARF) was decreased in E6AP−/− mouse embryo fibroblasts. E6AP induced the expression of the INK4/ARF locus at the transcriptional level by inhibiting CDC6 transcription, a gene encoding a key repressor of the locus. Luciferase assays revealed that E6AP inhibited CDC6 expression by reducing its E2F1-dependent transcription. Chromatin immunoprecipitation analysis indicated that E6AP reduced the amount of E2F1 at the CDC6 promoter. In a subset of NSCLC samples, an E6AP-low/CDC6-high/p16INK4a-low protein abundance profile correlated with low methylation of the gene encoding p16INK4a (CDKN2A) and poor patient prognosis. These findings define a previously unrecognized tumor-suppressive role for E6AP in NSCLC, reveal an alternative silencing mechanism of the INK4/ARF locus, and reveal E6AP as a potential prognostic marker in NSCLC.

Abstract CT005: Phase I study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors

Background: BGB-283 is a novel inhibitor of the RAF dimer with potent and reversible inhibitory activities against RAF family kinases including wild type A-RAF, B-RAF, C-RAF and B-RAF V600E, as well as EGFR. BGB-283 demonstrated acceptable safety and early clinical activity in its Phase 1A study. In this Phase IB dose expansion study, we further evaluated safety and tolerability of BGB-283 and investigated efficacy in pre-selected patients (pts) with B-RAF or K-RAS/N-RAS-mutated solid tumors. Methods: This Phase 1B study was a multicenter, open-label, multiple-arm, dose expansion study. Pts were treated at the RP2D of BGB-283 at 30 mg/day. There were 10 different expansion arms for: B-RAF V600-mutated melanoma (not previously treated with a B-RAF or MEK inhibitor, and B-RAF and/or MEK inhibitor-resistant pts), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), papillary thyroid cancer (PTC) and other solid tumors with B-RAF mutations; K-RAS/N-RAS-mutated endometrial cancer, NSCLC, CRC, and other solid tumors with K-RAS/N-RAS or NF-1 mutations. The primary end point was the response rate based on RECIST Version 1.1. Adverse events (AEs) are reported per CTCAE V4.03. Results: As of 19th Sep 2016, 96 pts were enrolled: median age was 63 years (range: 20 to 82 years) with all pts having baseline ECOG PS of 0 or 1. Forty-seven (49.0%) subjects had received ≥3 prior lines of treatment, 22 (22.9%) had received 2 prior lines of treatment, and 18 (18.8%) had received 1 prior line of treatment. BGB-283 was generally well-tolerated. Drug-related AEs were mostly Grade 1/2 in severity; the most common were fatigue in 37 (38.5%) subjects, nausea in 16 (16.7%), decreased appetite in 21 (21.9%), and diarrhea in 17 (17.7%). A total of 34 (35.4%) subjects experienced study drug-related Grade 3/4 AEs, notably drug-related thrombocytopenia (6.3%), palmar-plantar erythrodysesthesia syndrome (1.0%) and hypertension (8.3%). In the cohorts with previously-untreated B-RAF V600-mutated melanoma (n=7), PTC with B-RAF mutation (n=3) and NSCLC with K-RAS mutation (n=6), the response rates were 42.9% (95% confidence interval [CI], 9.9, 81.6), 33.3% (95% CI, 0.8, 90.6) and 16.7% (95% [0.4, 64.1]), respectively. Confirmed PR was seen in the single case of ovarian cancer with B-RAF mutation enrolled and also in one of 4 melanoma subjects with a confirmed B-RAF V600 mutation, who had not responded to B-RAF and/or MEK inhibitor(s). One unconfirmed PR was found in two NSCLC subjects with a B-RAF mutation. Conclusions: BGB-283 was generally well-tolerated during the Phase 1B stage of the study. Antitumor activity was not only observed in subjects with B-RAF V600-mutated solid tumors including melanoma, PTC, and ovarian cancer, but also in subjects with K-RAS-mutated NSCLC. When added to the efficacy data in the Phase IA portion of this study, with objective responses noted in these tumor subtypes as well as in K-RAS-mutated endometrial carcinoma, BGB-283 demonstrated a desirable risk-benefit profile for further efficacy and safety investigation. Citation Format: Jayesh Desai, Hui Gan, Catherine Barrow, Michael B. Jameson, Ben Solomon, Victoria Atkinson, Andrew Haydon, Michael Millward, Stephen Begbie, Michael Brown, Benjamin Markman, William Patterson, Andrew Hill, Lisa Horvath, Adnan Nagrial, Gary Richardson, Christopher Jackson, Michael Friedlander, David Gibbs, Phillip Parente, Jason Yang, Lai Wang, Yunxin Chen, Lusong Luo. A Phase IB study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT002. doi:10.1158/1538-7445.AM2017-CT002

Unilateral radiotherapy treatment for p16/human papillomavirus-positive squamous cell carcinoma of unknown primary in the head and neck: Radiotherapy for p16 + Unknown Primary

The outcomes of unilateral radiotherapy treatment for patients with p16/HPV‐positive squamous cell carcinomas of unknown primary (SCCUP) affecting cervical lymph nodes are under‐reported. Compared to radiating large volumes of the pharyngeal axis (the more common approach), this is potentially a much less toxic treatment for a good prognosis group.

Weekly cisplatin and radiotherapy for low risk, locoregionally advanced human papillomavirus-positive oropharyngeal squamous cell carcinoma: Weekly Cisplatin and RT in HPV(+) OP SCC

There is interest in different treatment strategies, including deintensification in good prognosis human papillomavirus‐positive (HPV(+)) oropharyngeal squamous cell carcinoma (SCC). We reviewed our experience with weekly cisplatin in low‐risk, locoregionally advanced HPV(+) oropharyngeal SCC since late 2009.Background There is interest in different treatment strategies, including deintensification in good prognosis human papillomavirus-positive (HPV(+)) oropharyngeal squamous cell carcinoma (SCC). We reviewed our experience with weekly cisplatin in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC since late 2009. Methods Data from patients with low-risk HPV(+) oropharyngeal SCC treated with weekly cisplatin (40 mg/m2) and 70 Gy radiotherapy were collected. Low risk was defined as stage III to IV oropharyngeal SCC excluding T1-2N1, T4 or N3 disease, or N2b to N2c disease in patients with >10 pack-year smoking history. Results Of 31 patients, the median age was 56 years (range, 41–69 years). All patients completed 70 Gy radiotherapy within 51 days and 84% completed at least 5 cycles of cisplatin. Grade 3 mucositis occurred in 22 patients (71%) and grade 3 febrile neutropenia in 6 patients (19%). No patients required enteral feeding at 12 months. The median follow-up was 30 months (range, 21–57 months) with no recurrences or deaths. Conclusion Concurrent weekly cisplatin is relatively well-tolerated and associated with excellent disease control in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC.