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Allelic fractions for all variants detected in tDNA and ctDNA* in patients for whom both plasma and tissue samples were obtained (n=50)

Summary of driver and resistance mutations in EGFR and ALK detected in ctDNA, tDNA, and both ctDNA and tDNA

Tissue next-generation sequencing gene coverage. A: Illumina TruSeq panel (47 genes), and B: Penn Precision Panel (20 genes)

Analysis of discordant EGFR driver and resistance mutations detected in tDNA or ctDNA

All mutations detected in patient ctDNA (n=102)

Circulating tumor DNA next-generation sequencing gene coverage

Total amount of cfDNA extracted from each patient sample

Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS.Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible.Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible.Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.

INTRODUCTION Real-world clinical outcomes in patients with advanced NSCLC harboring EGFR exon 20 insertion (exon20ins) mutations have not been extensively studied. We conducted a retrospective cohort study to assess the clinical outcomes of EGFR exon20ins compared with common EGFR (cEGFR) mutations. METHODS Adults with advanced NSCLC harboring any EGFR mutations in the NSCLC Flatiron registry (2011 through May 2020) were included. To compare the relative prognosis (prognostic value) of exon20ins vs cEGFR, real-world overall survival (rwOS) was the primary endpoint. Separately, to compare the relative response to tyrosine kinase inhibitor (TKI) treatment (predictive value), real-world progression-free survival (rwPFS) was the primary endpoint. RESULTS For the prognostic value analysis, 3014 patients with EGFR mutant NSCLC (cEGFR, n = 2833; EGFR exon20ins, n = 181) were eligible. The median (95% CI) rwOS was 16.2 (11.04-19.38) months in the EGFR exon20ins cohort vs 25.5 (24.48-27.04) months in the cEGFR cohort (adjusted HR, 1.75 [1.45-2.13]; p

PURPOSEAlthough the majority of patients with metastatic non–small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging.MATERIALS AND METHODSPatients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded.RESULTSAmong 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders.CONCLUSIONMolecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies.

PURPOSE Non–small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell–directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site. METHODS CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with EGFR Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5. RESULTS In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively. CONCLUSION Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy.

BACKGROUND Patients with oropharyngeal cancer who undergo transoral robotic surgery (TORS) and have high-risk features generally receive adjuvant chemoradiotherapy or trimodality therapy (TMT). The notion that TMT leads to high toxicity is largely based on studies that included human papilloma virus (HPV)-negative cancers and/or nonrobotic surgery; we sought to describe outcomes in HPV-associated oropharyngeal squamous cell cancer (HPV + OPSCC) undergoing TORS-TMT. METHODS In consecutive patients with HPV + OPSCC receiving TMT at an academic center from 2010 to 2017, survival was estimated using Kaplan-Meier methodology, and toxicities were ascertained via chart review. RESULTS In our cohort of 178 patients, 5-year survival was 93.6%. Feeding tube rates were 25.8% at therapy completion and 0.7% at 1 year. Rates of grade ≥ 3 kidney injury, anemia, and neutropenia in cisplatin-treated patients were 2.7%, 3.4%, and 11.0%, respectively. CONCLUSIONS Patients with HPV + OPSCC who underwent TORS-TMT had excellent survival and low rates of toxicity and feeding tube dependence. These outcomes compare favorably to historical cohorts treated with definitive chemoradiotherapy.

OBJECTIVES: Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation. MATERIALS AND METHODS: KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated. RESULTS: Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing. CONCLUSION: Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib. ispartof: Lung Cancer vol:166 pages:270-278 ispartof: location:Ireland status: published

Coronavirus disease 2019 (COVID-19) has had a devastating impact around the world. With high rates of transmission and no curative therapies or vaccine yet available, the current cornerstone of management focuses on prevention by social distancing. This includes decreased health care contact for patients. Patients with lung cancer are a particularly vulnerable population, where the risk of mortality from cancer must now be balanced by the potential risk of a life-threatening infection. In these unprecedented times, a collaborative and multidisciplinary approach is required to streamline but not compromise care. We have developed guidelines at our academic cancer center to standardize management of patients with lung cancer across our health care system and provide guidance to the larger oncology community. We recommend that general principles of lung cancer treatment continue to be followed in most cases where delays could result in rapid cancer progression. We recognize that our recommendations may change over time based on clinical resources and the evolving nature of the COVID-19 pandemic. In principle, however, treatment paradigms must continue to be individualized, with careful consideration of risks and benefits of continuing or altering lung cancer–directed therapy.

At JADPRO Live 2019, Joshua Bauml, MD, and Christina Knepley, CRNP, discussed how to devise treatment plans for patients with metastatic non–small cell lung cancer, including using biomarkers to guide treatment selection, understanding clinical data supporting the use of targeted and immune checkpoint inhibitor therapies, and managing adverse events.

Purpose This trial tested the safety and efficacy of a novel, deintensified radiation therapy (RT) approach after initial surgical resection for patients with human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods and Materials This single-arm phase 2 prospective clinical trial enrolled 60 patients with stage pT1-pT2 N1-3 HPV-associated OPSCC treated with transoral robotic surgery (TORS) and selective neck dissection at a single institution between May 2014 and September 2017. Patients had favorable features at the primary site (negative surgical margins ≥2 mm, no perineural invasion, and no lymphovascular invasion) but required adjuvant therapy based on lymph node involvement. Surgeries were all performed at a high-volume head and neck cancer center with expertise in TORS. Patients received postoperative RT to at-risk areas in the involved neck (60-66 Gy) and uninvolved neck (54 Gy). The resected primary site was treated as an active avoidance structure in the treatment planning of postoperative RT. Concurrent chemotherapy was administered for patients with extranodal extension. Results Median follow-up of the 60 patients enrolled was 2.4 years (range, 8.5-53.8 months). A single patient recurred at the primary site, for 2-year local control of 98.3%. One patient (1.7%) developed a regional neck recurrence, and 2 patients (3.3%) developed distant metastases. Measured 2-year local recurrence–free survival was 97.9% (95% confidence interval, 86.1%-99.7%). Overall survival was 100% at the time of analysis. The mean radiation dose to the primary site was 36.9 Gy (standard deviation, 10.3 Gy). Two patients (3.3%) experienced late soft tissue necrosis in the primary site surgical bed that resolved within 2 months. Feeding tube dependence rates were 0% during RT, 3.3% temporarily during follow-up, and 0% at last follow-up. Conclusions Deintensified postoperative RT that avoids the resected primary tumor site and targets only the at-risk neck after TORS for selected patients with HPV-associated OPSCC may be safe and is worthy of further study.

PURPOSE The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non–small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations. METHODS We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). RESULTS From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/ KRAS, 18 had STK11/ TP53, and seven had STK11/ KRAS/ TP53. Patients with STK11/ KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/ TP53 (4.3 months; log-rank P = .043), and STK11/ KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/ KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/ TP53 (28.3 months; log-rank P < .001), and STK11/ KRAS/ TP53 (22 months; log-rank P = .025). CONCLUSION Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis.

Objectives Sex differences in surgically treated HPV-associated oropharyngeal squamous cell carcinoma are not defined due to the low number of affected women. We explored the oncologic outcomes of men and women with p16-positive oropharyngeal squamous cell carinoma treated with primary surgery. Materials and Methods Retrospective analysis of patients with HPV-related oropharyngeal cancer treated with surgery and pathology guided adjuvant therapy from 2007 to 2017. Primary end point was recurrence-free and overall survival. Results Of 468 men (86.7%) and 72 women (13.3%), women presented more often with clinical N0 nodal disease (25% vs 12.2%). There were no differences in adverse pathologic features or T stage, although women were more likely to present with N0 disease (16.7% vs 10%), less N2 disease (6.9% vs 17.7%, p = 0.03), and more stage I disease (88.9% vs 75%). As a result, women were more likely to undergo surgery alone (30.6% vs 14.1%) while men were more likely to require adjuvant radiation therapy (47.2% vs 36.1%). Four women (5.6%) and 30 men (6.4%, p = 0.8) died during follow-up. Multivariate analysis controlling for age, sex, treatment, and pathologic stage demonstrated no differences in overall survival between men and women. There were no differences in recurrence-free or overall survival between men and women at two and five years. Conclusions Although women undergoing transoral robotic surgery for HPV+ oropharyngeal squamous cell carcinoma may have less advanced disease, upfront surgery with pathology-guided adjuvant therapy produces similar oncologic results in men and women while accounting for disease burden.

OBJECTIVE To analyze the patterns, risk factors, and salvage outcomes for locoregional recurrences (LRR) after treatment with transoral robotic surgery (TORS) for HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC). STUDY DESIGN Retrospective analysis of HPV+ OPSCC patients completing primary TORS, neck dissection, and NCCN-guideline-compliant adjuvant therapy at a single institution from 2007 to 2017. METHODS Features associated with LRR, detailed patterns of LRR, and outcomes of salvage therapy were analyzed. Disease-free survival (DFS) and overall survival (OS) were calculated for subgroups of patients receiving distinct adjuvant treatments. RESULTS Of 541 patients who completed guideline-indicated therapy, the estimated 5-year LRR rate was 4.5%. There were no identifiable clinical or pathologic features associated with LRR. Compared to patients not receiving adjuvant therapy, those who received indicated adjuvant radiation alone had a lower risk of LRR (HR 0.28, 95% CI [0.09-0.83], P = .023), but there was no difference in DFS (P = .21) and OS (P = .86) between adjuvant therapy groups. The 5-year OS for patients who developed LRR was 67.1% vs. 93.9% for those without LRR (P

Introduction This study aims to determine whether advanced ROS1 gene-rearranged NSCLC (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate. Methods Venous and arterial TEEs within ±365 days of diagnosis of ROS1+, ALK+, EGFR+, or KRAS+ advanced NSCLC at five academic centers in the United States and China were captured (October 2002–April 2018). The primary endpoint was incidence of TEE in ROS1+ compared to anaplastic lymphoma kinase (ALK)+, EGFR+, and KRAS+ NSCLC within ±90 days of diagnosis. Logistic regression was used to assess if the odds of TEE differed among oncogene drivers. Results Eligible data from 95 ROS1+, 193 ALK+, 300 EGFR+, and 152 KRAS+ NSCLC patients were analyzed. The incidence rate of TEE was 34.7% (n = 33), 22.3% (n = 43), 13.7% (n = 41), and 18.4% (n = 28), respectively. In univariate analysis, the odds of a TEE in ROS1+ NSCLC were higher than ALK+, EGFR+, and KRAS+ cohorts. In multivariable analysis, the odds of a TEE were significantly higher for ROS1+ compared to EGFR+ and KRAS+ cohorts, the odds ratio (OR) was 2.44, with a 95% confidence interval of 1.31–4.57 (p = 0.005), and OR: 2.62, with a 95% confidence interval of 1.26–5.46 (p = 0.01), respectively. Although numerically superior, the odds for a TEE with ROS1+ compared to ALK+ was not statistically significant (OR: 1.45, p = 0.229). Overall survival was not significantly different in patients with or without TEE within ±90 days of diagnosis in the overall study cohort or within each molecular group. Conclusions The risk of peridiagnostic TEEs is significantly elevated in patients with advanced ROS+ NSCLC compared to EGFR+ and KRAS+ cases. TEE risk may be similarly elevated in ALK+ NSCLC.

Purpose Treatment with anti-programmed death receptor-1 (PD-1) therapeutics can lead to unconventional responses and side effect profiles due to their potentiating effects on the immune system. Here we evaluate the radiologic manifestations of anti-PD-1 therapy in the chest in patients with non-small cell lung cancer (NSCLC) receiving anti-PD-1 therapy. Materials and Methods A retrospective review of real-world clinical practice was conducted of all the patients with NSCLC receiving anti-PD-1 therapy at our institution between 2013 and 2016. All patients without adequate clinical or radiologic follow-up data in the electronic medical records were excluded. Imaging examinations for all patients deemed by their thoracic oncologists to have radiologic pseudoprogression or therapy-associated pneumonitis were reviewed by experienced thoracic radiologists. Results A total of 166 patients with NSCLC had available clinical and imaging data for retrospective review. Of these patients, 4 (2%) were considered to have radiologic pseudoprogression, 3 of which manifested as increased tumor size and 1 of which manifested with new lesions. A total of 5 patients (3%) were clinically deemed to have pneumonitis attributable to anti-PD-1 therapy, 4 of which had radiologic manifestations on computed tomography. Conclusion Radiologic pseudoprogression and drug-induced pneumonitis are uncommon but important manifestations of anti-PD-1 therapy on thoracic imaging.

Purpose: Clinical responses with programmed death (PD-1) receptor–directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition. Patients and Methods: We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3–5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/106 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti–PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.

Background To ensure safe delivery of oncologic care during the COVID-19 pandemic, telemedicine has been rapidly adopted. However, little data exist on the impact of telemedicine on quality and accessibility of oncologic care. This study assessed whether conducting an office visit for thoracic oncology patients via telemedicine affected time to treatment initiation and accessibility. Methods This was a retrospective cohort study of patients with thoracic malignancies seen by a multidisciplinary team during the first surge of COVID-19 cases in Philadelphia (March 1 to June 30, 2020). Patients with an index visit for a new phase of care, defined as a new diagnosis, local recurrence, or newly discovered metastatic disease, were included. Results 240 distinct patients with thoracic malignancies were seen: 132 patients (55.0%) were seen initially in-person vs 108 (45.0%) via telemedicine. The majority of visits were for a diagnosis of a new thoracic cancer (87.5%). Among newly diagnosed patients referred to the thoracic oncology team, the median time from referral to initial visit was significantly shorter amongst the patients seen via telemedicine vs. in-person (median 5.0 vs. 6.5 days, p p = 0.47), radiation (27.5 vs 27.5 days, p = 0.86, systemic therapy (15 vs 13 days, p = 0.45). Conclusions Rapid adoption of telemedicine allowed timely delivery of oncologic care during the initial surge of the COVID19 pandemic by a thoracic oncology multi-disciplinary clinic.

Background Patients with human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) continue to experience disappointing outcomes following chemoradiotherapy (CRT) and appreciable morbidity following historical surgical approaches. We aimed to investigate the oncologic outcomes and perioperative morbidity of a transoral robotic surgery (TORS) approach to surgically resectable HPV-negative OPSCC. Methods Retrospective analysis HPV-negative OPSCC patients who underwent TORS, neck dissection and pathology-guided adjuvant therapy (2005-2017). Results Fifty-six patients (91.1% stage III/IV) were included. Three-year overall survival, locoregional control, and disease-free survival were 85.5%, 84.4%, and 73.6%, respectively (median follow-up 30.6 months, interquartile range 18.4-66.6). Eighteen (32.1%) patients underwent adjuvant radiotherapy and 20 (39.3%) underwent adjuvant CRT. Perioperative mortality occurred in one (1.8%) patient and hemorrhage occurred in two (3.6%) patients. Long-term gastrostomy and tracheostomy rates were 5.4% and 0.0%, respectively. Conclusion The TORS approach for resectable HPV-negative OPSCC can achieve encouraging oncologic outcomes with infrequent morbidity.

BACKGROUND Some patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) do not receive guideline-recommended postoperative radiation therapy (PORT) following primary transoral robotic surgery (TORS). METHODS Three-hundred and sixty-four patients with treatment-naive, HPV-associated OPSCC were recommended to receive PORT based on clinicopathological features following TORS. Patients were stratified based on if they received PORT. Oncologic outcomes were compared. RESULTS The 3-year locoregional failure (LRF) was 32% in patients who did not receive PORT and 4% in patients who received PORT (P

The APOLLO investigators showed that next-generation sequencing of cerebrospinal fluid can reveal molecular alterations—how should this affect our management approach? See related article by Xing et al., p. 6168

Introduction The COVID‐19 pandemic caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) virus has altered the health care environment for the management of head and neck cancers. The purpose of these guidelines is to provide direction during the pandemic for rational Head and Neck Cancer management in order to achieve a medically and ethically appropriate balance of risks and benefits. Methods Creation of consensus document. Results The process yielded a consensus statement among a wide range of practitioners involved in the management of patients with head and neck cancer in a multihospital tertiary care health system. Conclusions These guidelines support an ethical approach for the management of head and neck cancers during the COVID‐19 epidemic consistent with both the local standard of care as well as the head and neck oncological literature.

Purpose TP53 mutation (MT) in epidermal growth factor receptor ( EGFR) -MT non–small cell lung cancer (NSCLC) is associated with poor response to targeted therapy; however, its impact on survival is not clearly established. Patients and Methods We performed an analysis of patients with stage IV EGFR MT NSCLC with available gene sequencing data. Associations between baseline characteristics; molecular profile, including TP53 MT; and survival outcomes were assessed. Results We identified 131 consecutive patients with EGFR MT; 81 (62%) had a TP53 MT, and 55 (42%) had other coexisting oncogenic MTs. Emergent EGFR T790M MT was observed in 42 patients (32%). Overall survival (OS) was longer for younger patients ( P = .003), never smokers ( P = .002), those with Eastern Cooperative Oncology Group performance status 0 to 1 ( P = .004), and emergent T790M MT ( P = .018). TP53 MT ( P = .021) and other coexisting oncogenic MTs ( P = 0.011) were associated with inferior OS. In a multivariable regression analysis adjusted for age, smoking, Eastern Cooperative Oncology Group performance status, and the presence of TP53 MT ( P = .063) and other coexisting MTs ( P = .064) did not achieve statistical significance. Patients with EGFR T790M /TP53 double MT had worse OS compared with patients with T790M MT alone (46.4 months v 82.9 months). In our series, five patients transformed to small-cell lung cancer (5.6%). All had TP53 MT. In four patients, allelic fraction of TP53 MT increased at the time of transformation. Conclusion The presence of TP53 and other coexisting MTs in EGFR MT NSCLC were associated with inferior OS, including patients with emergent T790M MT. An increase in TP53 mutation allelic fraction may potentially be a useful clinical predictor of small-cell transformation.

BACKGROUND The addition of cisplatin or cetuximab to radiation therapy (RT) improves outcomes in comparison with RT alone in the nonoperative management of head and neck squamous cell carcinoma (HNSCC), but limited data exist for comparing these approaches. Using Veterans Health Affairs data, this study compared the outcomes of patients treated with RT plus cisplatin or cetuximab. METHODS Patients with stage III to IVb HNSCC who had been treated nonsurgically with RT and cisplatin or cetuximab from 2000 to 2016 within the Veterans Health Affairs system were identified. Patients were analyzed by the drug used in the first treatment cycle (intent to treat). Overall survival (OS) was compared by treatment group with Cox regression models, and propensity score (PS) methods were used to account for a treatment allocation bias. The risk of toxicities was determined, with logistic regression models fit into propensity-matched cohorts. RESULTS A total of 4520 patients were included in the analysis with a median follow-up of 3 years: 83% received cisplatin. Cisplatin patients were younger (P < .001) and had fewer comorbidities (P < .001). In an unmatched analysis, cetuximab was associated with inferior OS (P < .001). After PS matching, cetuximab treatment remained statistically significantly associated with inferior OS (1.7 vs 4.1 years; hazard ratio, 1.61; 95% confidence interval, 1.44-1.79; P < .001). These differences remained significant across all primary HNSCC subsites and in comparison with low- and high-dose cisplatin. CONCLUSIONS Cetuximab with RT yields inferior OS in comparison with cisplatin for the nonoperative management of stage III to IVb HNSCC. According to this study, cisplatin may be the most appropriate partner for RT in this setting.

BACKGROUND: Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m(2) cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches. METHODS: We examined outcomes of patients with stage III–IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression. RESULTS: A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m(2)). The mean initial dose of LDC was 40 mg/m(2). After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss. CONCLUSION: In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS.

Purpose: Quality of life (QOL) for patients with oropharyngeal squamous cell cancer is negatively affected by conventional radiation (RT) owing to radiation exposure to normal tissues. Proton therapy, via pencil beam scanning (PBS), can better spare many of these tissues, and may thereby improve QOL. Patients and Methods: Patient-reported outcomes were prospectively collected from patients treated from April 2013 to April 2015. Patients were treated with PBS or intensity-modulated radiation therapy (IMRT) via volumetric arc therapy after transoral robotic surgery. Validated QOL questionnaires were collected before RT, and 3, 6, and 12 months post RT. Results: Sixty-four patients were treated with adjuvant RT after transoral robotic surgery, 33 (52%) with volumetric arc therapy, and 31 (48%) with PBS. Both groups were similar in terms of age, site, stage, and dose delivered. Patients receiving PBS had significantly less dose to many normal structures than those receiving IMRT. These dosimetric advantages with PBS were reflected in higher scores in head and neck specific, as well as general, QOL measures. Most notable was significantly less xerostomia with PBS, on multiple patient-reported outcomes at multiple timepoints (6 and 12 months). Conclusion: Pencil beam scanning, when compared to IMRT, confers a significant dosimetric advantage to many normal organs at risk, with a corresponding benefit in multiple patient-reported QOL parameters in patients receiving adjuvant RT for oropharyngeal squamous cell cancer.

Introduction Anti–programmed cell death protein 1 (PD-1) therapy can lead to unconventional tumor responses, including radiologic pseudoprogression. Here we have determined the real-world incidence of radiologic pseudoprogression in advanced NSCLC and compared radiologic response criteria for assessment of disease response. Methods The electronic medical records of all patients with NSCLC who were receiving anti–PD-1 therapy at our institution over a 3-year period were retrospectively reviewed, and patients with clinically suspected radiologic pseudoprogression were identified. Patients without available follow-up imaging or clinical data were excluded. Imaging examinations were then analyzed to determine whether progression was confirmed on subsequent reimaging. Assessments of tumor response by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (RECIST 1.1), the unidimensional immune-related response criteria (iRRC), and the iRECIST criteria for all patients were performed and compared. Results A total of 228 consecutive patients began receiving anti–PD-1 therapy over a 3-year period. Of the 166 of these patients who were evaluable, most (80%) received nivolumab. Fifteen patients (9%) were clinically suspected of having radiologic pseudoprogression on account of tumor enlargement and/or development of new lesions on computed tomography images during the first 4 to 6 weeks of therapy, and they continued receiving anti–PD-1 therapy. Three of these patients (2%) demonstrated evidence of radiologic pseudoprogression at first reimaging. The iRRC and immune RECIST criteria were more accurate in classifying radiologic pseudoprogression as nonprogression; none of the three cases were deemed progression by the iRRC or immune RECIST, whereas all three cases were determined to be progression according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Conclusions Radiologic pseudoprogression is a clinical challenge but an uncommon occurrence in patients with NSCLC who are receiving anti–PD-1 therapy.

PURPOSE: Patients with cancer frequently experience symptoms such as fatigue and pain that can influence their ability to maintain their usual physical activity (PA). This study aimed to evaluate whether symptoms of fatigue and pain are associated with decreased PA among patients with cancer. METHODS: We recruited patients with a cancer diagnosis from one academic medical center and 11 affiliated community hospitals to participate in a cross-sectional survey. Multivariate logistic regression models were used to examine the association between symptoms, demographics, and clinical characteristics and decreased PA since cancer diagnosis. RESULTS: Among 629 participants, 499 (79%) reported a decreased level of PA since their cancer diagnosis. In the past seven days from the time of the survey, 78% of participants reported moderate to very severe fatigue, and 68% reported a pain level 4 or greater on a scale of 0 to 10. Adjusted for covariates, patients with fatigue (Adjusted Odds Ratio, AOR 4.01, 95% CI 2.41-6.65) and pain (AOR 1.89, 95% CI 1.14-3.12) had higher odds of reporting decreased PA since diagnosis. Receipt of chemotherapy or currently receiving active cancer treatment was also associated with decreased PA (p

Purpose/Objective(s) Patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) generally have a good prognosis, though those with locally advanced (LA) disease are at increased risk of locoregional failure (LRF) and distant metastases (DM). A recent SEER study suggested improvement in overall survival and cancer-specific mortality with trimodality therapy compared to definitive chemoradiation (dCRT) for LA HPV+ OPSCC, but is prone to confounding and lacks pattern of failure data. We therefore performed this retrospective analysis of oncologic outcomes for patients with T3/T4 HPV+ OPSCC treated at a high-volume TORS center with surgery +/- adjuvant therapy compared to dCRT alone. Materials/Methods Included were patients with cT3/T4 HPV+ OPSCC treated with dCRT or upfront TORS +/- adjuvant therapy from 2010-2019 with ≥1 year of follow-up. Patients with DM at diagnosis were excluded. Primary outcomes were freedom from LRF (FF-LRF) and LRF leading to death, defined as LRF directly resulting in death or occurring at the same time or before DM resulting in death. Secondary outcomes were freedom from DM (FF-DM) and cancer-specific survival (CSS). Patients were risk stratified based on criteria in the secondary analysis of RTOG 0129 by Ang et al (NEJM 2010): Low-risk: ≤10 pack-year (py) smoking, or > 10 py and N0–N2a disease (AJCC 7th ed.); Intermediate-risk: > 10 py and N2b-N3 disease. Fisher's exact test was used to compare demographics and Kaplan-Meier estimates to compare endpoints. Results 78 patients were treated with dCRT and 44 with upfront TORS. Significantly more dCRT patients were Intermediate-risk (per RTOG 0129 criteria) compared to TORS patients (35.9% vs 6.8%, P Conclusion This large, single-institution series of patients with T3/T4 HPV+ OPSCC treated with either dCRT or upfront TORS +/- adjuvant therapy shows high FF-LRF and low rates of LRF leading to death regardless of treatment. Even in patients with advanced T stage, dCRT was able to obtain excellent disease outcomes. Future prospective studies are warranted to determine which combinations of multimodality therapy are optimal for LA HPV+ OPSCC, incorporating both oncologic and functional outcome endpoints.

Purpose/Objective(s) This study sought to measure circulating plasma tumor-tissue modified human papilloma virus DNA (TTMV-HPV DNA) and kinetics following trans-oral robotic surgery (TORS), neck dissection, and adjuvant (chemo)radiation for p16+ oropharyngeal squamous cell carcinoma (OPSCC). Materials/Methods Patients with p16+ OPSCC currently enrolled on an ongoing phase II clinical trial investigating radiation dose de-intensification following TORS and neck dissection (TORS version 2.0, NCT03729518) with available post-operative plasma samples were included. Plasma was collected following TORS procedure (∼6 weeks post-operatively), during adjuvant (chemo)radiation, and at treatment completion. Plasma samples were analyzed for TTMV-HPV DNA using a liquid biopsy assay. Multivariate robust linear regression analysis was used to identify clinicopathologic features associated with detectable post-operative TTMV-HPV DNA levels. Results Thirty-four patients were included (median age 59 years, IQR 55-62 years; 94% male). The majority of patients had pT1-2 (n = 32, 94%; 1 pT0,1 pT3) and pN1 (n = 32, 94%; 2 pN0) disease. Other pathologic features included LVI (n = 5, 15%), PNI (n = 2, 6%), close or positive margin (n = 9, 26%), number of positive nodes (median 1.5, IQR 1-2), largest node size (median 3.7 cm, IQR 3.0-4.4 cm), and ENE (n = 8, 24%; 4 macroscopic). The majority of patients had undetectable TTMV-HPV DNA following TORS (n = 31, 91%). Three patients (9%) had detectable TTMV-HPV DNA post-operatively with 2 having very low detectable levels (≤ 10 copies/mL) and 1 having a high detectable level (4421 copies/mL). Largest node size (P = 0.0083) and ENE (P = 0.041) were significantly associated with detectable post-operative TTMV-HPV DNA levels. Of those with initially undetectable TTMV-HPV DNA, levels remained undetectable during and after adjuvant (chemo)radiation with 1 patient developing a very low detectable level (7 copies/mL) following treatment. The 2 patients with low detectable TTMV-HPV DNA levels post-operatively (≤ 10 copies/mL) had complete clearance following adjuvant therapy. There were no locoregional recurrences (median follow-up 15 months, IQR 12-21 months) including the patient who developed a low detectable level (7 copies/mL) following treatment (currently 24 months post-TORS). The patient with the high detectable level post-operatively (4421 copies/mL) developed osseous metastatic disease 5 months post-TORS. Conclusion Tumor-tissue modified HPV DNA can be detected with high sensitivity following definitive surgery for p16+ OPSCC. Further prospective studies are warranted to determine if the observed range of post-operative values allows for stratification of patients into those with distant metastatic disease, persistent locoregional disease that warrants adjuvant therapy, versus active surveillance.

PURPOSE/OBJECTIVE(S) Recent landmark trials have suggested a survival benefit to definitive tumor directed therapies (DTDT) for selected patients with metastatic disease for various malignancies. We sought 1) to confirm the prognostic significance of metachronous oligometastatic burden for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and 2) to evaluate disease outcomes for oligometastatic HPV-associated OPSCC after upfront DTDT versus upfront systemic therapy. MATERIALS/METHODS This was a single institution retrospective observational cohort study of patients with HPV-associated OPSCC who developed metachronous metastases ≥3 months after primary treatment with trans-oral robotic surgery (TORS) from 2008-2017. At metastatic presentation, patients were classified as oligometastatic (≤5 metastases) or polymetastatic (> 5 metastases). Treatment was classified as DTDT (all metastases initially treated with surgery/radiotherapy) or as upfront systemic therapy. Overall survival (OS) was compared using log-rank tests at a significance of P < 0.05. Univariable and multivariable (MV) Cox proportional hazard models were used to assess the association of patient, disease, and treatment characteristics with survival. Variables with P < 0.15 on univariable analysis (initial metastatic treatment, metastatic site, and number of metastases) were included in the multivariable model. RESULTS Of 676 patients undergoing primary surgical management for HPV-associated OPSCC, 36 patients subsequently developed metachronous metastases. For those 36 patients, the median follow-up time after surgery was 27.5 months (range 4.5-127.0), and the median OS was 42.8 months. The median age at distant metastasis was 62 (range 32-86), and most patients were male (86.1%) and Caucasian (97.2%). Overall, 27 patients presented with oligometastasis and 9 with polymetastasis. Oligometastatic patients had improved median OS compared to polymetastatic patients (47.9 vs. 22.7 months, P = 0.020). For the 27 oligometastatic patients, 12 were initially treated with DTDT while 15 received systemic therapy. DTDT was associated with an improved median OS when compared to systemic therapy (median OS not reached for DTDT vs 40.7 months, P = 0.021), with 3 year OS of 90.0% and 55.0% respectively. DTDT was also associated with improved OS on MV Cox regression (hazard ratio = 0.06, 95% CI 0.004-0.73, P = 0.027) compared to systemic therapy when controlling for number of metastases and metastatic site. CONCLUSION Our study findings suggest that the extent of metastatic disease at metastatic presentation is related to prognosis, with oligometastasis associated with improved overall survival compared to polymetastasis. Among patients with oligometastatic disease, initial DTDT is associated with superior overall survival when compared to upfront systemic therapy.

14 Background: Current NCCN guidelines recommend comprehensive molecular profiling for all newly diagnosed patients with metastatic non-squamous NSCLC to enable the delivery of personalized medicine. We have previously demonstrated that incorporation of plasma based next-generation gene sequencing (NGS) improves detection of clinically actionable mutations in patients with advanced NSCLC (Aggarwal et al, JAMA Oncology, 2018). To increase rates of comprehensive molecular testing at our institution, we adapted our clinical practice to include concurrent use of plasma (P) and tissue (T) based NGS upon initial diagnosis. P NGS testing was performed using a commercial 74 gene assay. We analyzed the impact of this practice change on guideline concordant molecular testing at our institution. Methods: A retrospective cohort study of patients with newly diagnosed metastatic non-squamous NSCLC following the implementation of this practice change in 12/2018 was performed. Tiers of NCCN guideline concordant testing were defined, Tier 1: complete EGFR, ALK, BRAF, ROS1, MET, RET, NTRK testing, Tier 2: included above, but with incomplete NTRK testing, Tier 3: > 2 genes tested, Tier 4: single gene testing, Tier 5: no testing. Proportion of patients with comprehensive molecular testing by modality (T NGS vs. T+P NGS) were compared using one-sided Fisher’s exact test. Results: Between 01/2019, and 12/2019, 170 patients with newly diagnosed metastatic non-Sq NSCLC were treated at our institution. Overall, 98.2% (167/170) patients underwent molecular testing, Tier 1: n = 100 (59%), Tier 2: n = 39 (23%), Tier 3/4: n = 28 (16.5%), Tier 5: n = 3 (2%). Amongst these patients, 43.1% (72/167) were tested with T NGS alone, 8% (15/167) with P NGS alone, and 47.9% (80/167) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS: 95.7% (79/80) compared to T alone: 62.5% (45/72), p < 0.0005. Prior to the initiation of first line treatment, 72.4% (123/170) patients underwent molecular testing, Tier 1: n = 73 (59%), Tier 2: n = 27 (22%) and Tier 3/4: n = 23 (18%). Amongst these, 39% (48/123) were tested with T NGS alone, 7% (9/123) with P NGS alone and 53.6% (66/123) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS, 100% (66/66) compared to 52% (25/48) with T NGS alone (p < 0.0005). Conclusions: Incorporation of concurrent T+P NGS testing in treatment naïve metastatic non-Sq NSCLC significantly increased the proportion of patients undergoing guideline concordant molecular testing, including prior to initiation of first-line therapy at our institution. Concurrent T+P NGS should be adopted into institutional pathways and routine clinical practice.

Background: Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but not in those with solid tumors. Macrophages are actively recruited into, and abundantly present in the solid tumor microenvironment (sTME). Tumor- associated macrophages typically evince immunosuppressive behavior, but when engineered to be proinflammatory, may be an ideal vector to administer adoptive cellular therapy in solid tumors. Furthermore, insertion of a CAR confers on the macrophages the ability to selectively recognize and phagocytose antigen overexpressing cancer cells. Additionally, CAR macrophages reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and immune memory. Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in many cancers, including but not limited to breast and gastroesophageal cancers. CT-0508 is a cell product comprised of autologous monocyte-derived pro-inflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies have shown that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden and prolonged survival in relevant models. CT-0508 cells were safe in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. Methods: This is a FIH Phase 1 study to evaluate safety, tolerability, cell manufacturing feasibility, trafficking, and preliminary evidence of efficacy of investigational product CT-0508 in approximately 18 subjects with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2 who have failed available therapies including anti-HER2 therapies when indicated. Filgrastim will be used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. The CT-0508 CAR macrophage product will be manufactured, prepared and cryopreserved from mobilized peripheral blood monocytes. Group 1 subjects will receive CT-0508 infusion split over D1, 3 and 5. Subjects will be continually assessed for acute and cumulative toxicity. Dose limiting toxicities will be observed and addressed by a Safety Review Committee. Group 2 subjects will receive the full CT-0508 infusion on D1. Pre and post treatment biopsies and blood samples will be collected to investigate correlates of safety (immunogenicity), trafficking (PCR, RNA scope), persistence, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Clinical trial registry number: NCT04660929 Citation Format: Joshua Bauml, Debora Barton, Amy Ronczka, Daniel Cushing, Michael Klichinsky, Elizabeth C. Dees. A phase 1, first in human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in subjects with HER2 overexpressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT204.

Introduction The phase 2 CodeBreaK 100 trial evaluated the first-in-class KRASG12C inhibitor, sotorasib, in pts with advanced NSCLC. Pts were enrolled based on the positive KRAS p.G12C status, as determined using tissue-based Qiagen Therascreen KRAS RGQ PCR kit test. Guardant360 (G360) CDx utilizes circulating cfDNA from plasma for sequencing and has been approved by FDA as a companion diagnostic to detect genomic mutations in pts with solid tumors. In this study, we used data from the trial to compare the efficacy of sotorasib in pts positive for KRAS p.G12C by cfDNA with that in the overall population identified by tissue. The concordance between the two assays was evaluated. Methods Key inclusion criteria: centrally confirmed KRAS p.G12C and progression on prior therapies. Primary endpoint was objective response rate (ORR) assessed by central review. Pts who had adequate pretreatment plasma sample were included in the validation. Due to the lack of KRAS p.G12C-negative tissue specimens from the trial population, paired blood and tissue samples from an additional NSCLC cohort of pts were sourced for the concordance study. Results Overall, 126 pts were enrolled based on tissue result. 124 were evaluable for efficacy per central review. 77 of 107 evaluable pts eligible for G360 testing tested positive for KRAS p.G12C. The ORR was 37.1% in pts positive by tissue and 36.4% in those positive by cfDNA (Table). In 189 pts eligible for concordance study, the overall concordance was 81.5%, with positive and negative % agreements of 70.1% and 100.0%, respectively. Conclusions In the phase 2 CodeBreaK 100 trial of sotorasib, efficacy in pts positive for KRAS p.G12C by the plasma-based G360 CDx was comparable to that in the overall population identified by tissue testing, with high concordance demonstrated between the two assays and a negative % agreement of 100%. Plasma cfDNA may be used to identify pts who may benefit from sotorasib. cfDNA by G360 CDx N=77Tissue by Therascreen N=124Best overall response - n (%)Complete response0 (0.0)3 (2.4)Partial response28 (36.4)43 (34.7)Stable disease32 (41.6)54 (43.5)Progressive disease13 (16.9)20 (16.1)Not evaluable/Not done4 (5.2)4 (3.2)Objective response rate - % (95% Cl)36.4 (25.7, 48.1)37.1 (28.6, 46.2) Citation Format: Joshua M. Bauml, Bob T. Li, Vamsidhar Velcheti, Ramaswamy Govindan, Alessandra Curioni Fontecedro, Christophe Dooms, Toshiaki Takahashi, Andrew W. Duda, Justin Odegaard, Fernando Cruz-Guilloty, Liming Jin, Ying Zhang, Ferdinandos Skoulidis. Clinical validation of plasma cell-free DNA (cfDNA) sequencing in the phase 2 trial of sotorasib in patients (pts) with KRAS p.G12C mutated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT181.

Background: Lung cancer is a major cause of death in HIV-infected (HIV+) persons. In this study, we compared the prevalence of tumour EGFR and KRAS mutations in a cohort of lung adenocarcinoma patients by HIV status. Methods: We collected data from 55 HIV+ patients with lung adenocarcinoma matched to 136 uninfected comparators. We compared the prevalence of EGFR and KRAS mutations by HIV status. We then compared survival by HIV status and by cancer mutation status among HIV+ subjects. Results: Presence of KRAS and EGFR genetic alterations did not vary by HIV status (all P>0.1). There was no difference in overall survival by HIV status or by mutation status among HIV+ subjects. Conclusions: We found no major differences in the prevalence of EGFR or KRAS lung adenocarcinoma mutations by HIV status, suggesting that mutational testing should be conducted similarly regardless of the HIV status.

Efficient use of nivolumab in non-small-cell lung cancer (NSCLC) has been limited by the lack of a definitive predictive biomarker. In patients with metastatic melanoma treated with ipilimumab, a pretreatment neutrophil-to-lymphocyte ratio (NLR)5 has been associated with improved survival. This retrospective cohort study aimed to determine whether the pretreatment NLR was associated with outcomes in NSCLC patients treated with nivolumab.We reviewed the medical records of all patients with previously treated advanced NSCLC who received nivolumab between March 2015 and March 2016 outside of a clinical trial at the University of Pennsylvania. Patients were dichotomized according to pretreatment NLR5 vs. ≥5. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment NLR on overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).175 patients were treated. Median age was 68 (range, 33-88); 54% were female. Twenty-five percent of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2; 46% had received ≥2 prior systemic therapies. In multivariate analyses, pretreatment neutrophil-to-lymphocyte ratio (NLR) ≥5 was independently associated with inferior OS (median 5.5 vs. 8.4 months; HR 2.07, 95% CI 1.3-3.3; p=0.002) and inferior PFS (median 1.9 vs. 2.8 months; HR 1.43, 95% CI 1.02-2.0; p=0.04).In a cohort of patients with NSCLC treated with nivolumab in routine practice, pretreatment NLR≥5 was associated with inferior outcomes. It is unclear whether this marker is predictive or prognostic. Prospective studies are warranted to determine the utility of NLR in the context of other biomarkers of programmed death-1 (PD-1) therapy.