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MICROABSTRACT: Effective treatment strategies after immunotherapy are greatly needed in NSCLC. The time off platinum chemotherapy (platinum-free-interval) is one predictor used to select patients for platinum re-exposure in other malignancies, but is not known in NSCLC. We analyzed a retrospective cohort of 751 patients who underwent this approach and did not find that the platinum-free-interval predicted better outcomes after platinum re-exposure. CLINICAL PRACTICE POINTS: Small studies in the era prior to NSCLC immunotherapy have identified a platinum-free-interval of approximately 6 months as predictive of better outcomes with platinum chemotherapy re-treatment. However, in the era of immunotherapy, where patients are on 1(st)-line therapy and maintenance for a longer period of time, the optimal platinum-free-interval has not been evaluated. Unlike other malignancies, we did not find an optimal platinum-free-interval in this setting that predicts benefit from platinum re-exposure. This may have implications on the design of clinical trials evaluating treatments in the salvage setting as well as treatment decisions in patients after disease progression on chemoimmunotherapy. INTRODUCTION: Immunotherapy has prolonged the time that NSCLC patients are off platinum-based (PB) chemotherapy. However, the significance of the platinum-free-interval (PFI) is unclear. We evaluated whether an optimal PFI exists in NSCLC for PB re-exposure in contemporary treatment settings. METHODS: We conducted a retrospective cohort study of patients with metastatic NSCLC treated with 1(st)-line PB chemotherapy with or without immunotherapy. Using multivariable Cox models stratified by treatment strategies, we evaluated whether salvage PB vs nonPB chemotherapy resulted in superior outcomes and whether this was modulated by the PFI. RESULTS: 751 patients treated with salvage chemotherapy after PB chemoimmunotherapy were identified in 2 treatment strategy cohorts: 3(rd)-line after sequential chemotherapy and immunotherapy (Sequential Chemo IO, n=604); 2(nd)line after chemoimmunotherapy (Concurrent ChemoIO, n=147). An optimal PFI of 5 and 6 months was identified in the Sequential Chemo IO and Concurrent ChemoIO cohorts, but there was no overall survival or progression free survival advantage for PB vs nonPB chemotherapy in long or short PFI groups. CONCLUSIONS: An optimal PFI was identified in this contemporary NSCLC cohort treated with two common immunotherapy-containing treatment approaches, but PFI threshold did not predict benefit from platinum re-exposure as it has in other malignancies.

Background In RAS-mutant tumors, combined MEK and autophagy inhibition using chloroquine demonstrated synthetic lethality in preclinical studies. This phase II trial evaluated the safety and activity of the MEK inhibitor binimetinib combined with hydroxychloroquine (HCQ) in patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC). Methods Eligibility criteria included KRAS-mutant NSCLC, progression after first-line therapy, ECOG PS 0-1, and adequate end-organ function. Binimetinib 45 mg was administered orally (p.o.) bid with HCQ 400 mg p.o. bid. The primary endpoint was objective response rate (ORR). A Simon’s 2-stage phase II clinical trial design was used, with an α error of 5% and a power β of 80%, anticipating an ORR of 30% to proceed to the 2-stage expansion. Results Between April 2021 and January 2022, 9 patients were enrolled to stage I: median age 64 years, 44.4% females, 78% smokers. The best response was stable disease in one patient (11.1%). The median progression free survival (PFS) was 1.9 months, and median overall survival (OS) was 5.3 months. Overall, 5 patients (55.6%) developed a grade 3 adverse event (AE). The most common grade 3 toxicity was rash (33%). Pre-specified criteria for stopping the trial early due to lack of efficacy were met. Conclusion The combination of B + HCQ in second- or later-line treatment of patients with advanced KRAS-mutant NSCLC did not show significant antitumor activity. (ClinicalTrials.gov Identifier: NCT04735068).

Available therapies and clinical trials

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.

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.

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.

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.

8523 Background: The PACIFIC trial demonstrated a 10% improvement in 5-year survival with the addition of consolidation durvalumab versus placebo after chemoradiation (CRT) in good performance status patients (pts) with stage III non-small cell lung cancer (NSCLC). However, not all patients who complete CRT go on to receive consolidation durvalumab. We sought to describe real-world use of consolidation durvalumab or other immune checkpoint inhibitors (ICI) in this setting within a single academic health system. Methods: We retrospectively identified pts with unresectable stage III NSCLC treated with definitive CRT between October 2017 and October 2020 within the University of Pennsylvania Health System, including two urban hospitals and two satellite centers. Pts either received consolidation ICI (ICI group) or did not (no ICI group). Baseline characteristics of the groups were compared with the Chi-squared, Fisher exact, or Wilcoxon rank-sum test as appropriate. Overall survival (OS), measured from the last day of CRT, was compared using the Kaplan-Meier method and log-rank test. Results: Of the 148 consecutively treated pts who completed CRT, 108 (73%) received consolidation ICI; 40 (27%) did not. Within the ICI group, 42% completed 1 year (yr) of treatment. Within the no ICI group, reasons for non-receipt included disease progression (n = 14, 35%), CRT toxicity (n = 7, 18%), comorbidity or decline unrelated to CRT (n = 7, 18%), provider choice (n = 6, 15%) due to EGFR mutation (n = 5) or atypical histology (n = 1), pt refusal (n = 3, 8%), and death without progression (n = 3, 8%). The ICI group had better performance status (ECOG 0/1/2, 46%/49%/5% ICI vs 25%/48%/28% no ICI, p < 0.001) lower Charlson Comorbidity Index (median, 5 [IQR 4-6] ICI vs 6 [IQR 5-8] no ICI, p = 0.02), and lower rates of active autoimmune disease or immunosuppression (5% ICI vs 15% no ICI, p = 0.03). There were no differences between groups in age (median, 68 yrs [IQR 63-73] ICI vs 71 yrs [IQR 65-73] no ICI, p = 0.25), sex (female, 60% ICI vs 50% no ICI, p = 0.27), race (Black, 19% ICI vs 20% no ICI, p = 0.82), stage (IIIA/B/C, 42%/48%/11% ICI vs 40%/50%/10% no ICI, p = 0.96), and PD-L1 expression ( < 1%/1-50%/ > 50%/unknown, 36%/25%/29%/10% ICI vs 40%/25%/28%/8% no ICI, p = 0.97). 1- and 2-yr OS were 83% and 61% in the ICI group versus 52% and 34% in the no ICI group, respectively (p < 0.001). Within the no ICI group, OS was worse among those with versus those without disease progression (PD) post-CRT (1-yr OS 24% vs 74%, p = 0.03). Conclusions: In this retrospective study within a large academic health system, we found that over one-quarter of pts who completed chemoradiation for stage III NSCLC did not receive consolidation ICI, most commonly due to disease progression, CRT toxicity, or comorbidity. Survival amongst these pts is particularly poor, especially for those who experience PD shortly after CRT.

Acute splenic sequestration crisis (ASSC) is a life-threatening complication of sickle cell disease characterized by acute splenic enlargement and a rapid drop in hemoglobin (Hb) levels. Although ASSC is predominantly a disease of childhood, rare cases of ASSC have been reported in adults, frequently in association with heterozygous sickle cell disease. We describe a case of ASSC in a 29-year-old woman with homozygous Hb S (HBB: c.20A>T) disease and suspected hereditary persistence of fetal Hb (HPFH), which was accompanied by marked leukocytosis.

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: 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.

29 Background: Hospice has been associated with improved quality of life for patients, cost savings, and reduction in caregiver-grief-related depression. While cancer patients make up a plurality of hospice utilizers nationally, many patients are only on hospice for a limited period (in Medicare patients, a median of 18 days). Studies suggest engaging cancer patients to discuss goals and priorities using the Serious Illness Conversation (SIC) Guide has a positive impact on prognostic understanding and end-of-life planning. More frequent utilization of SICs may prompt earlier enrollment of oncology patients in hospice when appropriate. Methods: We identified cancer patients enrolled in hospice at the Abramson Cancer Center at Penn Presbyterian Medical Center from 2019-2020 after all providers received SIC training. Patient demographics, cancer diagnosis, type of hospice (home versus inpatient), SIC usage, palliative care referral patterns and time on hospice were abstracted. Results: 104 patients were enrolled in hospice during the study period. The majority of patients were female (51%). 45% were Caucasian, and 31% were African American. The most common cancer diagnoses were thoracic (52%) and gastrointestinal (32%) malignancies. 85 patients (82%) were enrolled on home hospice and 19 patients (18%) inpatient hospice. Palliative care usage included 50 inpatient and 24 outpatient consultations; 30 patients (29%) in the cohort never utilized palliative care. 52 (50%) of patients did not have a SIC. 47% (40 patients) enrolled in home hospice had an SIC while 63% (12 patients) on inpatient hospice had an SIC. The median time interval between a patient’s SIC conversation and hospice enrollment was longer in home hospice patients (74 days) compared to inpatient hospice (33 days). Patients on home hospice spent an average of 44 days on hospice versus 2 days in the inpatient setting. Conclusions: Half of the patients at Penn Presbyterian Medical Center enrolled in hospice during the study period did not have an SIC, and 29% did not see palliative care prior to starting hospice. The median time from SIC initiation to hospice enrollment was significantly longer for patients on home hospice compared to inpatient hospice suggesting a need for earlier SIC interventions. Patients enrolled in inpatient hospice spent a considerably shorter period of time on hospice also underscoring the importance of earlier end of life planning. Our findings indicate a need for additional interventions to facilitate earlier SIC conversations in the outpatient setting and a demand for increased palliative care access.

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.

Objectives The management of recurrent NSCLC in the setting of prior radiation therapy is challenging. Proton radiotherapy (PRT) is ideally suited to minimize toxicity to previously irradiated organs. We report the safety/feasibility of PRT for NSCLC reirradiation in a prospective multi-institutional study. Materials and Methods Between October 2010 and December 2015, 57 patients with recurrent NSCLC in or near their prior radiation field were treated at three proton centers. Patients were classified by tumor volume, location, and clinical characteristics. Toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Survival outcomes were estimated by using Kaplan-Meier analysis. Results Fifty-two patients (93%) completed the reirradiation course. Their median age was 65 years (41–86). Patients with high tumor volume (clinical target volume–to–internal target volume ratio ≥250 cm 3 ) were closed to enrollment owing to infeasibility in August 2012. Concurrent systemic therapy was delivered to 67% of patients. Fourteen patients (25%) had evidence of local (n = 9) or regional (n = 5) recurrence. Distant metastases after reirradiation developed in six patients (11%). The 1-year rates of overall and progression-free survival were 59% and 58%, respectively. In total, grade 3 or higher acute and/or late toxicity developed in 24 patients (42%), acute toxicity developed in 22 (39%), and late toxicity developed in seven (12%). Six grade 5 toxicities were observed. Increased overlap with the central airway region, mean esophagus and heart doses, and concurrent chemotherapy were associated with significantly higher rates of grade 3 or higher toxicity. Decreased overall survival was seen with increased mean esophagus dose ( p = 0.007). Conclusions In this prospective study, PRT for recurrent NSCLC is feasible but can be associated with significant toxicity. Providers should remain cautious in reirradiating NSCLC, paying close consideration to tumor volume, location, and relevant dosimetric parameters. Further research is needed for optimal patient selection to improve overall outcomes.

Purpose: The role of plasma-based tumor mutation burden (pTMB) in predicting response to pembrolizumab-based first-line standard-of-care therapy for metastatic non–small cell lung cancer (mNSCLC) has not been explored. Experimental Design: A 500-gene next-generation sequencing panel was used to assess pTMB. Sixty-six patients with newly diagnosed mNSCLC starting first-line pembrolizumab-based therapy, either alone or in combination with chemotherapy, were enrolled (Clinicaltrial.gov identifier: NCT03047616). Response was assessed using RECIST 1.1. Associations were made for patient characteristics, 6-month durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS). Results: Of 66 patients, 52 (78.8%) were pTMB-evaluable. Median pTMB was 16.8 mutations per megabase (mut/Mb; range, 1.9–52.5) and was significantly higher for patients achieving DCB compared with no durable benefit (21.3 mut/Mb vs. 12.4 mut/Mb, P = 0.003). For patients with pTMB ≥ 16 mut/Mb, median PFS was 14.1 versus 4.7 months for patients with pTMB < 16 mut/Mb [HR, 0.30 (0.16–0.60); P < 0.001]. Median OS for patients with pTMB ≥ 16 was not reached versus 8.8 months for patients with pTMB < 16 mut/Mb [HR, 0.48 (0.22–1.03); P = 0.061]. Mutations in ERBB2 exon 20, STK11, KEAP1, or PTEN were more common in patients with no DCB. A combination of pTMB ≥ 16 and absence of negative predictor mutations was associated with PFS [HR, 0.24 (0.11–0.49); P < 0.001] and OS [HR, 0.31 (0.13–0.74); P = 0.009]. Conclusions: pTMB ≥ 16 mut/Mb is associated with improved PFS after first-line standard-of-care pembrolizumab-based therapy in mNSCLC. STK11/KEAP1/PTEN and ERBB2 mutations may help identify pTMB-high patients unlikely to respond. These results should be validated in larger prospective studies.

TheWe conducted a retrospective review of patients with metastatic NSCLC andFrom February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored anAmong patients with advanced NSCLC and

There are no established imaging biomarkers that predict response during chemoradiation for patients with locally advanced non-small cell lung carcinoma. At our institution, proton therapy (PT) patients undergo repeat computed tomography (CT) simulations twice during radiation. We hypothesized that tumor regression measured on these scans would separate early and late responders and that early response would translate into better outcomes.Patients underwent CT simulations before starting PT (CT0) and between weeks 1 to 3 (CT1) and weeks 4 to 7 (CT2) of PT. Primary tumor volume (TVR) and nodal volume (NVR) reduction were calculated at CT1 and CT2. Based on recursive partitioning analysis, early response at CT1 and CT2 was defined as ≥20% and ≥40%, respectively. Locoregional and overall progression-free survival (PFS), distant metastasis-free survival, and overall survival by response status were measured using Kaplan-Meier analysis.Ninety-seven patients with locally advanced non-small cell lung carcinoma underwent definitive PT to a median dose of 66.6 Gy with concurrent chemotherapy. Median TVR and NVR at CT1 were 19% (0-79%) and 19% (0-75%), respectively. At CT2, they were 33% (2-98%) and 35% (0-89%), respectively. With a median follow-up of 25 months, the median overall survival and PFS for the entire cohort was 24.9 and 13.2 months, respectively. Compared with patients with TVR and NVR20% at T1 and40% at T2, patients with TVR and NVR ≥20% at CT1 and ≥40% at CT2 had improved median locoregional PFS (27.15 vs 12.97 months for TVR ≥40% vs40%, P.01, and 25.67 vs 12.09 months for NVR ≥40% vs40%, P.01) and median PFS (22.7 vs 9.2 months, P.01, and 20.3 vs 7.9 months, P.01), confirmed on multivariate Cox regression analysis.Significantly improved outcomes in patients with early responses to therapy, as measured by TVR and NVR, were seen. Further study is warranted to determine whether treatment intensification will improve outcomes in slow-responding patients.

We performed an analysis of patients with stage IVWe identified 131 consecutive patients withThe presence of

Background Patients with metastatic non–small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited. Patients and Methods We conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation. Results Between Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P = .671), PFS (mPFS 9.2 vs. 7.7 months; P = .609), or OS (mOS 18.0 vs. 18.7 months; P = .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy. Conclusions Patients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy.

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.

9599 Background: Patients (pts) with mNSCLC with active brain metastases (BM) are often excluded from clinical trials; data on efficacy and safety of immunotherapy in this population are limited. We compared outcomes of pts with mNSCLC with and without BM who received pembrolizumab-based therapy. Methods: We conducted a retrospective single-center study of pts with mNSCLC treated with pembrolizumab (P) with or without chemotherapy. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier methodology and compared using multivariable Cox regression and log rank testing. Results: We identified 587 consecutive pts with mNSCLC who began P-based therapy between 8/2013 and 12/2018: 306 (52%) female, median age 67 years (range 32-98), 437 (74%) adenocarcinoma, and 508 (87%) former/current smokers. 388 (66%) patients received P in first line therapy, and 334 (57%) received single-agent P. 131 pts (22%) had detectable BM at baseline (start of P-based therapy). Pts with BM were younger (median 65 y vs 68 y, p < 0.01) and more likely to have adenocarcinoma (86% vs. 71%, p < 0.01) and baseline steroid use (22% vs 1%, p < 0.01). Presence of BM did not differ by race, sex, line of therapy, treatment regimen, or PD-L1 status. Of the 131 patients with detectable BM on pre-treatment brain MRI, 55 (42%) had stable BM as a result of prior local therapy, while 76 (58%) had active (new or growing) BM on pre-treatment imaging. Most patients with active BM underwent radiation therapy (RT) in either the 30 days before (n = 46) or 30 days after (n = 17) P start; of the remaining 13 treated with P-based therapy alone, intracranial responses included 2 CR, 2 PR, 3 SD, and 4 PD. As of 1/1/2020, with 15-month median follow up, there was no difference in mPFS (9.2 vs 7.3 months, p = 0.41) or mOS (18.3 vs 18.0 mo, p = 0.67) between pts with and without BM in our P-treated cohort. On multivariable analysis, female sex, ECOG 0-1, adenocarcinoma histology, and P as first line therapy were associated with improved PFS and OS. Presence of BM, baseline steroid use, and timing of local RT (before vs. after P) were not associated with inferior survival. Conclusions: In our single-center experience of pts with mNSCLC treated with P, pts with and without BM had similar PFS and OS. We observed several intracranial responses to P-based therapy alone, but most pts with active BM underwent local RT. mNSCLC pts with BM should be considered for P-based therapy; BM may be treated with RT immediately before or even after P with similar survival outcomes.

e21093 Background: Malignant peritoneal mesothelioma (MPM) is a rare variant of malignant mesothelioma, representing < 30% of cases. Standard of care is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) when feasible. The benefit of systemic chemotherapy (chemo) (Neoadjuvant- N, Adjuvant- A, or 1st-line metastatic –M) is not well established and some retrospective studies report worse outcomes with N chemo. However, our institution has favored use of N chemo prior to surgery for symptom relief and surgical optimization. We conducted a single-center retrospective cohort study of MPM patients treated at our institution to evaluate the effect of N vs. A chemo on outcomes. Methods: We identified non-papillary MPM patients via ICD9/10 codes seen at our institution between 1/1/2009 and 9/1/2019. Pts were followed until 1/1/2020. Patients without pathologic diagnosis were excluded. We explored the effect of receipt of CRS, type of systemic therapy, and histology on overall survival. Median overall survival (mOS) from diagnosis was estimated from Kaplan-Meier curves. A Cox proportional hazard model computed hazard ratios (HR) to assess the effect of the exposure on OS. Results: We identified 47 patients with non-papillary MPM: median age 62 years, 77% epithelioid histology, 74.5% white, 55.3% known asbestos exposure. CRS was performed in 24 (51%) and 18/24 (75%) received HIPEC. The majority received systemic therapy (34/47 (72%)). Among those that received chemo and surgery, N chemo was more common than A chemo (N:12 (all platinum/pemetrexed), A:7). Median OS was 52.7 months (mo) overall and 77.2 mo with surgery vs 20.2 mo without (log rank p = 0.006). Toxicity from N chemo did not prevent surgery with 8/12 successfully receiving surgery (1 surgery scheduled, 2 lost to follow up). Of the 10 pts with evaluable scans: 5 had radiographic reduction of disease (2 complete responses by RECIST 1.1), 4 stable disease and 1 with disease growth. N chemo reduced ascites in 3 out of 4 pts with baseline ascites. N chemo was not associated with worse mOS compared to A chemo (HR 0.64, 95% CI 0.1-3.0, p = 0.62). Non-epithelioid histology was not associated with a worse OS compared to epithelioid (HR 1.5, 95% CI 0.6-4.1, p = 0.4). Conclusions: N chemo was not associated with worse outcomes compared to A chemo and toxicity from N chemo did not preclude surgery. In addition, N chemo resulted in reduction of disease burden and ascites in pts with MPM.

e21620 Background: In patients (pts) with advanced non-small cell lung cancer (NSCLC), national guidelines recommend against retrial of immunotherapy (IO) if there is disease progression on IO in the 1st-line (1L). However, optimal 2nd-line (2L) therapy after 1L IO remains unclear and there is significant practice variation. We compared outcomes of 2L approaches after 1L IO or chemoimmunotherapy (chemoIO). Methods: This retrospective cohort study utilized the Flatiron Health EHR-derived de-identified advanced NSCLC database. The study population included pts with disease progression on 1L IO or chemoIO and who subsequently received 2L therapy. Pts with targetable alterations were excluded. We defined the exposure by type of 2L therapy (IO, chemoIO, chemo). Multivariate covariates included age, sex, race, 1L progression-free survival (PFS) and PDL1 level. Median overall survival (mOS) and median real-world PFS (mPFS, based upon abstraction of clinician documentation) times were estimated from Kaplan-Meier curves. A multivariate Cox proportional hazard model computed hazard ratios (HRs) to assess the effectiveness of 2L treatment. Results: 532 NSCLC pts received 1L IO and a 2L therapy, of which 393 (74%) received 1L IO and 139 (26%) received 1L chemoIO. Among 1L IO patients, 2L therapies included chemo (315 (80%)), IO (39(10%), 18/39 (46%) switched IO), and chemoIO (39(10%)). Among 1L chemoIO patients, 2L therapies included: chemo (121 (87%)), IO (8(6%), 6/8 switched IO) and ChemoIO (10 (7%), 8/10 changed chemo used). All pts who received 2L ChemoIO continued the same IO agent. Demographics were well balanced between 2L groups except for higher PDL1 level in the IO-based groups and older age in the IO alone group. There was no statistically significant difference in mPFS or mOS between 2L IO and non-IO containing regimens (Table), nor were there differences among patients switching IO agents in the 2L (multivariate p interaction = 0.2 (PFS), 0.06 (OS)) (Table). Conclusions: Despite national guidelines against this practice, a small proportion of pts in routine care receive 2L IO-based therapies after disease progression on 1L IO or chemoIO. We found similar outcomes between IO and non-IO based 2L therapies after progression on 1L IO or chemoIO. [Table: see text]

e21094 Background: Clinical trials evaluating pembrolizumab (P) in malignant mesothelioma (MM) have included small numbers of peritoneal MM (MPM) patients (pts), but the efficacy of P in the MPM subpopulation remains unclear. We evaluated the efficacy of P in a cohort of MPM pts treated at our institution. Methods: This retrospective cohort study identified MPM pts via ICD9/10 codes seen at our institution between 1/1/2009 and 9/1/2019. Pts were included if they received P as treatment for MPM. Median progression free survival (PFS) and median overall survival (mOS) were estimated from Kaplan-Meier curves. PFS was defined as the start of P until radiologic or clinical progression. Best overall response rate (BOR) and disease control rate (DCR) were determined retrospectively using RECIST 1.1 criteria. Results: We identified 13 non-papillary MPM pts who received P. All pts had received prior chemotherapy (12 platinum/pemetrexed, 1 pemetrexed). Median age at diagnosis was 65.6 years; 77% were white; 46% never smokers; 62% with known asbestos exposure; 70% epithelioid/15% biphasic/ 7.7% sarcomatoid/ 7.7% desmoplastic. BOR to P was 18% (Partial response (PR): 2, Progressive disease (PD): 2, Stable disease (SD): 7, Lost to follow up: 2). DCR was 81% and mPFS 5.7mo. From the start of P mOS was 20.9 mo. Only 3 pts had known PDL1 positivity (1%, 2%, 80%), 4 were negative, 6 untested. Median PFS was not statistically different between PDL1 positive and negative pts (mPFS 5.1mo vs. 5.7 mo, log rank p = 0.73, respectively). Three pts experienced a PFS of > 2 years (PDL1/BOR/% tumor change: Unknown/SD/19%, Negative/SD/-21%, 80%/PR/-70%). The patient with PDL1 80%, biphasic histology and a PR experienced skin toxicity requiring a treatment break. Outcomes for epithelioid histology vs non-epithelioid after P did not differ statistically (mPFS 5 mo vs 39 mo, log rank p = 0.14; mOS 17.5 mo vs NA, log rank p = 0.31). Conclusions: In a real world setting, P has clinically meaningful activity in a PDL1 unselected cohort of MPM pts and should be considered a treatment option for this subpopulation of MM. We did not detect a difference in outcomes based on PDL1 level or histology.

Importance The clinical implications of adding plasma-based circulating tumor DNA next-generation sequencing (NGS) to tissue NGS for targetable mutation detection in non–small cell lung cancer (NSCLC) have not been formally assessed. Objective To determine whether plasma NGS testing was associated with improved mutation detection and enhanced delivery of personalized therapy in a real-world clinical setting. Design, Setting, and Participants This prospective cohort study enrolled 323 patients with metastatic NSCLC who had plasma testing ordered as part of routine clinical management. Plasma NGS was performed using a 73-gene commercial platform. Patients were enrolled at the Hospital of the University of Pennsylvania from April 1, 2016, through January 2, 2018. The database was locked for follow-up and analyses on January 2, 2018, with a median follow-up of 7 months (range, 1-21 months). Main Outcomes and Measures The number of patients with targetable alterations detected with plasma and tissue NGS; the association between the allele fractions (AFs) of mutations detected in tissue and plasma; and the association of response rate with the plasma AF of the targeted mutations. Results Among the 323 patients with NSCLC (60.1% female; median age, 65 years [range, 33-93 years]), therapeutically targetable mutations were detected inEGFR,ALK,MET,BRCA1,ROS1, RET, ERBB2,orBRAFfor 113 (35.0%) overall. Ninety-four patients (29.1%) had plasma testing only at the discretion of the treating physician or patient preference. Among the 94 patients with plasma testing alone, 31 (33.0%) had a therapeutically targetable mutation detected, thus obviating the need for an invasive biopsy. Among the remaining 229 patients who had concurrent plasma and tissue NGS or were unable to have tissue NGS, a therapeutically targetable mutation was detected in tissue alone for 47 patients (20.5%), whereas the addition of plasma testing increased this number to 82 (35.8%). Thirty-six of 42 patients (85.7%) who received a targeted therapy based on the plasma result achieved a complete or a partial response or stable disease. The plasma-based targeted mutation AF had no correlation with depth of Response Evaluation Criteria in Solid Tumors response (r = −0.121;P = .45). Conclusions and Relevance Integration of plasma NGS testing into the routine management of stage IV NSCLC demonstrates a marked increase of the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy.

3040 Background: Circulating tumor DNA next generation sequencing (ctDNA NGS) is increasingly being used to detect mutations (MT) in patients (pts) with metastatic (m) NSCLC. Limited data exist on the correlation of baseline ctDNA NGS profile and serial ctDNA NGS monitoring to response to immunotherapy. Methods: We conducted a prospective study in pts with mNSCLC receiving pembrolizumab monotherapy. Plasma was collected at weeks 0 (T0), 9 (T1), and 18 (T2). ctDNA NGS was performed using a 73 gene panel. Number of MTs and variant allelic fraction (VAF) were determined at baseline, and serially; change in mean VAF was calculated between T1-T0, and T2-T0. Response rate (RR) was assessed using RECIST 1.1. Correlations were made for pt characteristics, RR, progression free survival (PFS), and overall survival (OS). Results: We analyzed 95 samples from 33 pts, 21 female, median age 69 (range 51-89 years), smokers (n = 29), adenocarcinoma (n = 23), 25 pts enrolled at initial diagnosis, majority had high PD-L1 ≥50% (n = 29, 88%). At T0, 32 pts had detectable MT, median number of MTs was 4 (range 0-21), (non-synonymous MT = 3), most common MT was TP53 (n = 21). Confirmed PR was 27% (n = 9), clinical benefit rate (SD+PR) was 64% (n = 21), and 2 pts were not evaluable for response. Smokers were more likely to have higher number of MT at T0 (4 vs. 1 p = 0.003); there was no correlation with smoking and overall RR (p = 0.17). RR was not related to number of MT at T0, p = 0.37. A decrease in ctDNA VAF was seen in 6/9 pts with PR (mean VAF change range -0.11 to -0.001); 2/5 pts with PD showed an increase in mean VAF while 3 showed decrease. At median follow up of 9.26 months (mos), median PFS and OS were 7.4 and 10.5 mos, respectively. Median PFS was longer for pts with a decrease in ctDNA VAF at both T1-T0 (8.9 vs. 5 mos, p = 0.02) and T2-T0 (9.1 vs. 5.5 mos, p = 0.006). OS and additional biomarker analyses including correlation of response to a 2mb ctDNA plasma-based NGS panel will be reported at the meeting. Conclusions: Our results demonstrate that it is feasible to serially monitor plasma NGS, decline in mean ctDNA VAF correlates with radiographic response and PFS on immunotherapy with pembrolizumab.

* Authors E. M. B. and M. E. M. contributed equally Introduction: LKB1/STK11 is a tumor suppressor and a negative regulator of mTOR signaling. NSCLC patients with STK11 mutations (MT) commonly also have other co-mutations. We evaluated the impact of STK11 MT on outcomes following chemotherapy for metastatic NSCLC, and the role of common co-existing MTs in KRAS and TP53. Methods: We conducted a retrospective review of patients (pts) with NSCLC and STK11 MT treated at the University of Pennsylvania. STK11 MT was identified through next generation sequencing (NGS) in tissue or using the Guardant 360TM platform for plasma. Four treatment groups were analyzed: STK11 alone (A), and 3 co-MT groups: STK11/KRAS (B), STK11/TP53 (C), and STK11/KRAS/TP53 (D). Chi-square analysis was used to assess differences in baseline characteristics between the MT groups. Cox proportional hazard models (HR) were used to determine the relationship of STK11 co-MT to survival. Kaplan-Meier analysis was used to estimate overall survival (OS) and progression-free survival (PFS). Results: Between 2/14/13 and 12/1/16, 77 pts with STK11 MT who received systemic therapy were identified (56 tissue, 21 plasma): median age at diagnosis 66 yrs, 51.5% male, 85% ECOG PS of 0 or 1, 94% of pts received 1st-line chemotherapy. There were no significant differences in baseline characteristics among mutation groups. Pts with STK11/KRAS had a worse median PFS and OS vs. pts with STK11 alone (Table 1). Pts with STK11/TP53 had a significantly better OS compared to STK11/KRAS patients. Conclusion: Among STK11 mutant NSCLC pts treated with chemotherapy, co-MT with KRAS was associated with a significantly worse PFS and OS compared to patients with STK11 alone. By contrast, co-MT with TP53 conferred a better prognosis. These results warrant further validation in a larger study. Table 1: Outcomes by mutation statusA:STK11alone n=16 (24.2%)B:STK11/KRAS n=21 (31.8%)C:STK11/TP53 n=18 (27.3%)D:STK11/KRAS/TP53 n=11 (16.7%)Median PFS5.3 mo2.4 mo*9.9mo4.9 moMedian OS13.1 mo6.9 mo**22.2 mo***13.9 mo*compared to A, HR 2.8, 95% CI 1.1 to 6.9, p = 0.026**compared to A, HR 6.4, 95% CI 2.4 to 17.3, p Citation Format: Erin M. Bange, Melina E. Marmarelis, Wei-Ting Hwang, Yu-Xiao Yang, Jeffrey C. Thompson, Joshua Bauml, Christine A. Ciunci, Evan W. Alley, Tracey L. Evans, Jennifer J. Morrissette, Roger B. Cohen, Corey J. Langer, Erica L. Carpenter, Charu Aggarwal. Impact of KRAS and TP53 co-mutations on outcomes following 1st-line therapy among patients with LKB1/STK11 mutated stage IV NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 783.

Immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC). However, thus far, its use has only been established in patients with advanced disease either as first-line therapy in selected patients or following chemotherapy. What is not yet known is how best to incorporate radiation with immunotherapy agents. Many patients with advanced disease can benefit from palliative radiation, but the combination of radiation with immunotherapy has the potential to increase the toxicity of both modalities. Intriguingly, the combination also has the potential to enhance the efficacy of both modalities. For this reason, combining immunotherapy and radiation may help salvage patients with recurrent localized disease who are candidates for re-irradiation. We review the current data evaluating immunotherapy with both palliative radiation as well as definitive re-irradiation in NSCLC.

Surveillance PET after curative-intent treatment of non-small-cell lung cancer (NSCLC) or colorectal cancer (CRC) is not clearly supported by available evidence or the Choosing Wisely campaign. However, the frequency of PET imaging during the surveillance period is relatively unknown.Using Surveillance, Epidemiology, and End Results-Medicare data, 65,748 patients aged 66 years or older who were diagnosed with stage I to IIIA NSCLC or stage I to III CRC from 2001 through 2009 and who underwent surgical resection were identified. Trends in "any PET" or "PET-only" use 6 to 18 months postoperatively were assessed.Any PET use more than doubled over the study period. Eleven percent of patients with NSCLC and 4% of those with CRC diagnosed in 2001 received any PET, compared with 25% of patients with NSCLC and 13% of those with CRC in 2009 (P.001 for both). Higher stage disease was correlated with higher PET utilization and faster growth in use over the study period. PET-only use also increased over the study period, especially in higher stage disease. Fewer than 2% of patients diagnosed with stage IIIA NSCLC in 2001 received PET only, compared with 15% of patients diagnosed in 2009 (P = .014). Similarly, 1% of patients diagnosed with stage III CRC in 2001 received PET only, compared with 8% of patients diagnosed in 2009 (P.001).PET utilization during the surveillance period increased between 2001 and 2009. Further research is needed to determine the factors driving use of surveillance PET and to examine relationships between PET and patient outcomes.