Plunging Into the PACIFIC: Outcomes of Patients With Unresectable KRAS-Mutated Non-Small Cell Lung Cancer Following Definitive Chemoradiation and Durvalumab Consolidation.

BACKGROUND: Immune checkpoint inhibitor (ICI) consolidation following concurrent chemoradiotherapy (CRT) substantially improved progression free survival (PFS) and overall survival (OS) in the PACIFIC trial becoming the standard of care in locally-advanced, unresectable NSCLC. KRAS mutation may influence response to ICI. METHODS: In this single-institution, retrospective analysis, we compared treatment outcomes for patients with unresectable KRAS mutated (KRAS-mt) and wild-type (KRAS-wt) NSCLC treated with CRT between October 2017 and December 2021. Kaplan-Meier analysis was conducted comparing median progression free survival and median overall survival from completion of radiotherapy in all KRAS-mt patients and KRAS-G12C-mutated patients. Outcomes were also compared with and without ICI consolidation. RESULTS: Of 156 patients, 42 (26.9%) were KRAS-mt and 114 (73.1%) were KRAS-wt. Baseline characteristics differed only in histology; KRAS-mt NSCLC more likely to be adenocarcinoma. KRAS-mt patients had worse PFS (median 6.3 vs. 10.7 months, P = .041) but similar OS (median 23.1 vs. 27.3 months, P = .237). KRAS-mt patients were more likely to not receive ICI due to rapid disease progression post-CRT (23.8% vs. 4.4%, P = .007). Among patients who received ICI (n = 114), KRAS-mt was not associated with inferior PFS (8.1 vs. 11.9 months, P = .355) or OS (30.5 vs. 31.7 months, P = .692). KRAS-G12C patients (n = 22) had similar PFS and OS to other KRAS-mt. CONCLUSION: In one of the largest post-CRT KRAS-mt cohort published, KRAS-mt was associated with inferior PFS, largely due to rapid progression prior to ICI consolidation, but did not affect OS. Among those who received ICI consolidation, outcomes were comparable regardless of KRAS-mt status.

Acute hospitalizations after proton therapy versus intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in the durvalumab era.

INTRODUCTION: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity-modulated radiotherapy (IMRT). METHODS: Patients with locally advanced non-small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90-day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan-Meier method was used for progression-free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. RESULTS: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p < .001) and had higher Charlson Comorbidity Index scores (p = .02). The PBT group received a lower mean heart dose (p < .0001), left anterior descending artery V15 Gy (p = .001), mean lung dose (p = .008), and effective dose to immune circulating cells (p < .001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38-0.81; p = .002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37-0.81; p = .003). There was no difference in other G3+ toxicities, progression-free survival, or overall survival. CONCLUSIONS: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed.

Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation.

PURPOSE: We assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. METHODS AND MATERIALS: This single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). RESULTS: Median age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0-22) and median heart mean dose was 8.7 Gy (IQR 4.6-14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. CONCLUSIONS: With modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation.

PURPOSE: We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. METHODS AND MATERIALS: This single institution, multisite retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011-September 2017]; N = 448) or afterward (ICI era cohort [October 2017-December 2021]; N = 335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per Common Terminology Criteria for Adverse Events v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. RESULTS: G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs 20.1%; P < .001; IPTW-adjusted multivariable subdistribution hazard ratio, 2.03; 95% confidence interval, 1.53-2.70; P < .001). There was no significant interaction between ICI era treatment and either lung volume receiving ≥20 Gy (V20) or mean lung dose in Fine-Gray regression for G2P; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and mean lung dose (≥14 Gy). Cut-point analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs 19.8% below; P < .001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs 6.0%; P = .39; IPTW-adjusted multivariable subdistribution hazard ratio, 1.12; 95% confidence interval, 0.63-2.01; P = .70). CONCLUSIONS: In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in G2P but not G3P. With ICI consolidation, stricter lung dose constraints may be warranted.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer.

PURPOSE: Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. METHODS AND MATERIALS: This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. RESULTS: Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. CONCLUSIONS: In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.

Patterns of Failure, Low-Volume Relapse, and Subsequent Ablative Management in Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation and Consolidation Immune Checkpoint Inhibitors.

PURPOSE: The objective of this study was to describe the patterns of failure, frequency of low-volume relapse (LVR), and candidacy for ablative therapy at time of disease progression (PD) after chemoradiation and consolidative immunotherapy (CRT + ICI) in patients with stage III non-small cell lung cancer. METHODS AND MATERIALS: We identified 229 consecutive patients with stage III non-small cell lung cancer treated with CRT + ICI between October 2017 and December 2021 at a single institution. PD was classified as isolated locoregional failure (LRF), isolated distant failure (DF), or synchronous LRF + DF. Any LRF was subclassified as in-field failure, marginal failure, or out-of-field failure. LVR was defined as 3 or fewer sites of PD in any number of organs. Ablative candidates were defined as having 5 or fewer sites of PD radiographically amenable to high-dose radiation or surgery. Time-to-event data were calculated using cumulative incidence analysis and Kaplan-Meier methods. Multivariable Cox modeling was used to examine the correlations between characteristics of relapse and postprogression survival. RESULTS: Of the 229 patients, 119 (52%) had PD. Of these 119 patients, 20 (21%) had isolated LRF, 28 (24%) had synchronous LRF + DF, and 71 (60%) had isolated DF. Of the 48 patients with any LRF, 28 (58%) had in-field failure, 10 (21%) marginal failure, and 10 (21%) out-of-field failure. The cumulative incidence of LRF and DF was 13% (95% CI, 9.2%-18%) and 32% (95% CI, 26%-38%) at 1 year and 19% (95% CI, 14%-24%) and 39% (95% CI, 33%-46%) at 2 years, respectively. Overall, 64 patients (54%) were considered to have LVR. At time of PD, 60 patients (50%) were eligible for ablative therapy. Patients with LVR had longer median survival versus with high-volume relapse (37.4 vs 15.2 months, P < .001). On multivariable analysis, LVR (hazard ratio, 0.32; 95% CI, 0.18-0.56; P < .001) was associated with improved postprogression survival. CONCLUSIONS: After CRT + ICI, approximately half of patients experience LVR at time of PD and are candidates for ablative therapies. Prospective trials are needed to validate the optimal treatment strategy for LVR.

The effective radiation dose to immune cells predicts lymphopenia and inferior cancer control in locally advanced NSCLC.

PURPOSE: To explore the association of the effective dose to immune cells (EDIC) with disease control, lymphopenia, and toxicity in patients with non-small cell lung cancer (NSCLC) and identify methods to reduce EDIC. METHODS: We abstracted data from all patients with locally advanced NSCLC treated with chemoradiation with or without consolidative immunotherapy over a ten-year period. Associations between EDIC and progression-free survival (PFS) and overall survival (OS) were modeled with Cox proportional hazards and Kaplan-Meier method. Logistic regression was used to model predictors of lymphopenia and higher EDIC. Analyses were performed with EDIC as a continuous and categorical variable. Lymphopenia was graded per CTCAE v5.0. RESULTS: Overall, 786 patients were included (228 of which received consolidative immunotherapy); median EDIC was 4.7 Gy. Patients with EDIC < 4.7 Gy had a longer median PFS (15.3 vs. 9.0 months; p < 0.001) and OS (34.2 vs. 22.4 months; p < 0.001). On multivariable modeling, EDIC correlated with inferior PFS (HR 1.08, 95 % CI 1.01-1.14, p = 0.014) and OS (HR 1.10, 95 % CI 1.04-1.18, p = 0.002). EDIC was predictive of grade 4 lymphopenia (OR 1.16, 95 % CI 1.02-1.33, p = 0.026). EDIC ≥ 4.7 Gy was associated with increased grade 2 + pneumonitis (6-month incidence: 26 % vs 20 %, p = 0.04) and unplanned hospitalizations (90-day incidence: 40 % vs 30 %, p = 0.002). Compared to protons, photon therapy was associated with EDIC ≥ 4.7 Gy (OR 5.26, 95 % CI 3.71-7.69, p < 0.001) in multivariable modeling. CONCLUSIONS: EDIC is associated with inferior disease outcomes, treatment-related toxicity, and the development of severe lymphopenia. Proton therapy is associated with lower EDIC. Further investigations to limit radiation dose to the immune system appear warranted.

Patterns of Failure in Metastatic NSCLC Treated With First Line Pembrolizumab and Use of Local Therapy in Patients With Oligoprogression.

INTRODUCTION: The patterns of failure (POF) for metastatic non-small-cell lung cancer (mNSCLC) treated with immunotherapy are not well established. METHODS: We conducted a retrospective cohort study of mNSCLC that received first-line pembrolizumab with or without chemotherapy at a single academic center from 2015 to 2021. We defined POF with 2 classifications: 1) local, regional, or distant failure, or 2) failure in existing lesions, new lesions, or a combination. Oligoprogression was defined as disease progression (PD) in ≤3 sites of failure. Overall survival (OS) was measured via Kaplan-Meier and modelled with Cox regression. RESULTS: Of 298 patients identified, 198 had PD. Using POF classification 1, most failures were distant (43.9%) or a combination of locoregional and distant (34.4%). For POF classification 2, failures occurred in a combination of new and existing lesions (45.0%), existing lesions alone (33.3%), or in new lesions only (21.7%). Oligoprogression occurred in 39.9% (n = 79) cases. Median OS was higher in the following: PD in existing lesions vs. new or new + existing lesions (28.7 vs. 20.2 vs. 13.9 months, P < .001) and oligoprogression vs. polyprogression (35.1 vs. 12.2 months, P < .001). In oligoprogression, median OS was better for those who received radiation to all sites of PD (62.2 months) than for those who changed systemic therapy (22.9 months, P = .007). On multivariable analysis, radiation for oligoprogression (HR 0.35, 95% CI: 0.20-0.62, P < .001) was associated with improved OS. CONCLUSIONS: In mNSCLC treated with pembrolizumab, oligoprogression is relatively common. Randomized data are needed to define the benefits of radiation in oligoprogressive mNSCLC.

Brief Report: Second-line treatment outcomes in patients with advanced NSCLC previously treated with first-line immunotherapy regimens.

CLINICAL PRACTICE POINTS: In the United States of America, nearly all patients with advanced NSCLC, absent oncogenic drivers, receive some form of immunotherapy (IO) as part of initial treatment. Current national guidelines currently recommend against IO re-challenge if there is disease progression on IO in the first line, but re-treatment with IO is attractive given its favorable toxicity profile and descriptions of durable clinical benefit in a subset of patients treated beyond disease progression on initial IO (Gandara, J Thorac Oncol, 2018). Data in the non-clinical trial setting on the efficacy of IO in sequential lines of treatment after initial IO are lacking. In our large cohort study of patients with advanced NSCLC treated with immunotherapy regimens in the first-line setting, we find that outcomes after second-line treatment did not differ statistically by type of treatment used in the second line. While current prospective clinical trials are investigating several aspects of the utility of continuing immunotherapy and adding novel agents, our study offers data outside of a clinical trial. In addition, with the increased prevalence of adjuvant immunotherapy we urgently need to wrestle with whether to continue immunotherapy in the first-line metastatic setting if a patient experiences disease progression on adjuvant immunotherapy. While this analysis does not directly investigate that question, it does provide hypothesis-generating evidence for further evaluations.

Association Between Availability of Molecular Genotyping Results and Overall Survival in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

PURPOSE: Current guidelines recommend molecular genotyping for patients newly diagnosed with metastatic nonsquamous (mNSq) non-small-cell lung cancer (NSCLC). The association between availability of molecular genotyping before first line (1L) therapy and overall survival (OS) is not known. METHODS: We conducted a real-world cohort study using electronic health records in patients newly diagnosed with mNSq NSCLC. Cox proportional-hazards multivariable regression models were constructed to examine the association between OS and test result availability before 1L therapy, adjusting for covariates. Additional analyses were conducted to assess the consistency and strength of the relationship. Multivariable logistic regression models were used to examine the association between concurrent tissue and plasma testing (v tissue alone) and result availability. RESULTS: Three hundred twenty-six patients were included, 80% (261/326) with results available before 1L (available testing group), and 20% (65/326) without results available (unavailable testing group). With 14.2-month median follow-up, patients in the available testing group had significantly longer OS relative to the unavailable testing group (adjusted hazard ratio, 0.43; 95% CI, 0.30 to 0.62; P < .0001). The adjusted odds of availability of results before 1L therapy was higher with concurrent tissue and plasma testing (v tissue testing alone; adjusted odds ratio, 2.06; 95% CI, 1.09 to 3.90; P = .026). CONCLUSION: Among patients with mNSq NSCLC in a real-world cohort, availability of molecular genotyping results before 1L therapy was associated with significantly better OS. Concurrent tissue and plasma testing was associated with a higher odds of availability of results before 1L therapy. These findings warrant renewed attention to the completion of molecular genotyping before 1L therapy.

Association Between Duration of Immunotherapy and Overall Survival in Advanced Non-Small Cell Lung Cancer.

Importance: For patients with advanced non-small cell lung cancer (NSCLC) treated with frontline immunotherapy-based treatment, the optimal duration of immune checkpoint inhibitor (ICI) treatment is unknown. Objective: To assess practice patterns surrounding ICI treatment discontinuation at 2 years and to evaluate the association of duration of therapy with overall survival in patients who received fixed-duration ICI therapy for 2 years vs those who continued therapy beyond 2 years. Design, Setting, and Participants: This retrospective, population-based cohort study included adult patients in a clinical database diagnosed with advanced NSCLC from 2016 to 2020, who received frontline immunotherapy-based treatment. The data cutoff was August 31, 2022; data analysis was conducted from October 2022 to January 2023. Exposures: Treatment discontinuation at 2 years (between 700 and 760 days, fixed duration) vs continued treatment beyond 2 years (greater than 760 days, indefinite duration). Main Outcomes and Measures: Overall survival from 760 days was analyzed using Kaplan-Meier methods. Multivariable Cox regression that adjusted for patient-specific and cancer-specific factors was used to compare survival beyond 760 days between the fixed-duration group and the indefinite-duration group. Results: Of 1091 patients in the analytic cohort who were still on ICI treatment at 2 years after exclusion criteria for death and progression were applied, 113 patients (median [IQR] age, 69 [62-75] years; 62 [54.9%] female; 86 [76.1%] White) were in the fixed-duration group, and 593 patients (median [IQR] age, 69 [62-76] years; 282 [47.6%] female; 414 [69.8%] White) were in the indefinite-duration group. Patients in the fixed-duration group were more likely to have a history of smoking (99% vs 93%; P = .01) and be treated at an academic center (22% vs 11%; P = .001). Two-year overall survival from 760 days was 79% (95% CI, 66%-87%) in the fixed-duration group and 81% (95% CI, 77%-85%) in the indefinite-duration group. There was no statistically significant difference in overall survival between patients in the fixed-duration and indefinite-duration groups, either on univariate (hazard ratio [HR] 1.26; 95% CI, 0.77-2.08; P = .36) or multivariable (HR 1.33; 95% CI, 0.78-2.25; P = .29) Cox regression. Approximately 1 in 5 patients discontinued immunotherapy at 2 years in the absence of progression. Conclusions and Relevance: In a retrospective clinical cohort of patients with advanced NSCLC who were treated with immunotherapy and were progression-free at 2 years, approximately only 1 in 5 discontinued treatment. The lack of statistically significant overall survival advantage for the indefinite-duration cohort on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years.

A Phase II Open-Label Trial of Binimetinib and Hydroxychloroquine in Patients With Advanced KRAS-Mutant Non-Small Cell Lung Cancer.

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 ß 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).

Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer.

PURPOSE: To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. PATIENTS AND METHODS: In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. RESULTS: Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. CONCLUSION: Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Utilization and Factors Precluding Receipt of Checkpoint Inhibitor Consolidation for Stage III NSCLC in a Large US Academic Health System.

OBJECTIVES: We sought to determine the proportion of patients with stage III non-small cell lung cancer (NSCLC) who initiate consolidation durvalumab or other immune checkpoint inhibitors (ICIs) after concurrent chemoradiotherapy (cCRT), as well as reasons for nonreceipt and prognostic implications. MATERIALS AND METHODS: We retrospectively identified consecutive patients with unresectable stage III NSCLC treated with definitive cCRT between October 2017 and December 2021 within a large US academic health system. Patients either received consolidation ICIs (ICI group) or did not (no-ICI group). Baseline characteristics and overall survival (OS) of the groups were assessed. Factors predictive of ICI nonreceipt were evaluated using logistic regression. RESULTS: Of 333 patients who completed cCRT, 229 (69%) initiated consolidation ICIs; 104 (31%) did not. Reasons for ICI nonreceipt included progressive disease post-cCRT (N = 31, 9%), comorbidity or intercurrent illness (N = 25, 8%), cCRT toxicity (N = 23, 7%; 19/23 pneumonitis), and EGFR/ALK alteration (N = 14, 4%). The no-ICI group had worse performance status and a higher rate of baseline pulmonary comorbidity. Larger planning target volume was associated with post-cCRT progressive disease, and higher lung radiation dose with cCRT toxicity. Median OS was 16 months in the no-ICI group and 34.4 months in the ICI group. In the no-ICI group, OS was superior among those with EGFR/ALK alterations (median 44.5 months) and worst among those with progressive disease (median 5.9 months, P < 0.001). CONCLUSION: 31% of patients who completed cCRT for stage III NSCLC did not receive consolidation ICIs. Survival amongst these patients is poor, especially for those with progressive disease post-cCRT.

Clinical Outcomes Associated With Pembrolizumab Monotherapy Among Adults With Diffuse Malignant Peritoneal Mesothelioma.

Importance: Diffuse malignant peritoneal mesothelioma (DMPM) represents a rare and clinically distinct entity among malignant mesotheliomas. Pembrolizumab has activity in diffuse pleural mesothelioma but limited data are available for DMPM; thus, DMPM-specific outcome data are needed. Objective: To evaluate outcomes after the initiation of pembrolizumab monotherapy in the treatment of adults with DMPM. Design, Setting, and Participants: This retrospective cohort study was conducted in 2 tertiary care academic cancer centers (University of Pennsylvania Hospital Abramson Cancer Center and Memorial Sloan Kettering Cancer Center). All patients with DMPM treated between January 1, 2015, and September 1, 2019, were retrospectively identified and followed until January 1, 2021. Statistical analysis was performed between September 2021 and February 2022. Exposures: Pembrolizumab (200 mg or 2 mg/kg every 21 days). Main Outcomes and Measures: Median progression-free survival (PFS) and median overall survival (OS) were assessed using Kaplan-Meier estimates. The best overall response was determined using RECIST (Response Evaluation Criteria in Solid Tumors) criteria, version 1.1. The association of disease characteristics with partial response was evaluated using the Fisher exact test. Results: This study included 24 patients with DMPM who received pembrolizumab monotherapy. Patients had a median age of 62 years (IQR, 52.4-70.6 years); 14 (58.3%) were women, 18 (75.0%) had epithelioid histology, and most (19 [79.2%]) were White. A total of 23 patients (95.8%) received systemic chemotherapy prior to pembrolizumab, and the median number of lines of prior therapy was 2 (range, 0-6 lines). Of the 17 patients who underwent programmed death ligand 1 (PD-L1) testing, 6 (35.3%) had positive tumor PD-L1 expression (range, 1.0%-80.0%). Of the 19 evaluable patients, 4 (21.0%) had a partial response (overall response rate, 21.1% [95% CI, 6.1%-46.6%]), 10 (52.6%) had stable disease, and 5 (26.3%) had progressive disease (5 of 24 patients [20.8%] were lost to follow-up). There was no association between a partial response and the presence of a BAP1 alteration, PD-L1 positivity, or nonepithelioid histology. With a median follow-up of 29.2 (95% CI, 19.3 to not available [NA]) months, the median PFS was 4.9 (95% CI, 2.8-13.3) months and the median OS was 20.9 (95% CI, 10.0 to NA) months from pembrolizumab initiation. Three patients (12.5%) experienced PFS of more than 2 years. Among patients with nonepithelioid vs epithelioid histology, there was a numeric advantage in median PFS (11.5 [95% CI, 2.8 to NA] vs 4.0 [95% CI, 2.8-8.8] months) and median OS (31.8 [95% CI, 8.3 to NA] vs 17.5 [95% CI, 10.0 to NA] months); however, this did not reach statistical significance. Conclusions and Relevance: The results of this retrospective dual-center cohort study of patients with DMPM suggest that pembrolizumab had clinical activity regardless of PD-L1 status or histology, although patients with nonepithelioid histology may have experienced additional clinical benefit. The partial response rate of 21.0% and median OS of 20.9 months in this cohort with 75.0% epithelioid histology warrants further investigation to identify those most likely to respond to immunotherapy.

Death without progression as an endpoint to describe cardiac radiation effects in locally advanced non-small cell lung cancer.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2; n = 66), CCI intermediate (3-4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs < 10 Gy, DWP was higher (5-year rate, 16.9 % vs 6.7 %, p = 0.04) and OS worse (median, 22.9 vs 34.1 months, p < 0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose ≥ 5.5 Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP. Conclusion: Cardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.

Long-Term Efficacy and Safety of Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Final Results of the Phase 1/2 and Randomized Phase 2 (ALTA) Trials.

Introduction: We report brigatinib long-term efficacy and safety from phase 1/2 and phase 2 (ALTA) trials in ALK-rearrangement positive (ALK+) NSCLC. Methods: The phase 1/2 study evaluated brigatinib 30 to 300 mg/d in patients with advanced malignancies. ALTA randomized patients with crizotinib-refractory ALK+ NSCLC to brigatinib 90 mg once daily (arm A) or 180 mg once daily (7-d lead-in at 90 mg; arm B). Results: In the phase 1/2 study, 79 of 137 brigatinib-treated patients had ALK+ NSCLC; 71 were crizotinib pretreated. ALTA randomized 222 patients (n = 112 in arm A; n = 110 in arm B). Median follow-up at phase 1/2 study end (≈5.6 y after last patient enrolled) was 27.7 months; at ALTA study end (≈4.4 y after last patient enrolled), 19.6 months (A) and 28.3 months (B). Among patients with ALK+ NSCLC in the phase 1/2 study, median investigator-assessed progression-free survival (PFS) was 14.5 months (95% confidence interval [CI]: 10.8-21.2); median overall survival was 47.6 months (28.6-not reached). In ALTA, median investigator-assessed PFS was 9.2 months (7.4-11.1) in arm A and 15.6 months (11.1-18.5) in arm B; median independent review committee (IRC)-assessed PFS was 9.9 (7.4-12.8) and 16.7 (11.6-21.4) months, respectively; median overall survival was 25.9 (18.2-45.8) and 40.6 (32.5-not reached) months, respectively. Median intracranial PFS for patients with any brain metastases was 12.8 (9.2-18.4) months in arm A and 18.4 (12.6-23.9) months in arm B. No new safety signals were identified versus previous analyses. Conclusions: Brigatinib exhibited sustained long-term activity and PFS with manageable safety in patients with crizotinib-refractory ALK+ NSCLC.

A single-center retrospective cohort study of perioperative systemic chemotherapy in diffuse malignant peritoneal mesothelioma.

BACKGROUND: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare variant of malignant mesothelioma, representing 10-15% of malignant mesothelioma cases. The preferred therapeutic approach is cytoreductive surgery (CRS) accompanied by hyperthermic intraperitoneal chemotherapy (HIPEC); the role of systemic chemotherapy is not well established. While some limited retrospective studies report worse outcomes with neoadjuvant chemotherapy, our institution has favored the use of neoadjuvant chemotherapy for symptom relief and surgical optimization. The aim of our study was to assess the outcomes of patients receiving neoadjuvant chemotherapy, compared to those receiving adjuvant or no perioperative chemotherapy. PATIENTS AND METHODS: We conducted a single-center retrospective cohort study of treatment-naïve, non-papillary DMPM patients seen at our institution between 1/1/2009 and 9/1/2019. We explored the effect of type of systemic therapy on clinical outcomes and estimated median overall survival (mOS) using Kaplan-Meier curves. Hazard ratios (HR) calculated by Cox proportional hazard model were used to estimate effect of the exposures on overall survival. RESULTS: 47 patients were identified with DMPM (median age at diagnosis 61.2 years, 76.6% epithelioid histology, 74.5% white race, 55.3% known asbestos exposure). CRS was performed in 53.2% of patients (25/47); 76.0% of surgical patients received HIPEC (19/25). The majority received systemic chemotherapy (37/47, 78.7%); among patients receiving both CRS and chemotherapy, neoadjuvant chemotherapy was more common than adjuvant chemotherapy (12 neoadjuvant, 8 adjuvant). Overall mOS was 84.1 months. Among neoadjuvant patients, 10/12 underwent surgery, and 2 were lost to follow-up; the majority (9/10) had clinically stable or improved disease during the pre-operative period. There were numerical more issues with chemotherapy with the adjuvant patients (4/8: 2 switches in platinum agent, 2 patients stopped therapy) than with the neoadjuvant patients (2/10: 1 switch in platinum agent, 1 delay due to peri-procedural symptoms). Neoadjuvant chemotherapy was not associated with worse mOS compared to adjuvant chemotherapy (mOS NR vs 95.1 mo, HR 0.89, 95% CI 0.18-4.5, p = 0.89). CONCLUSIONS: When used preferentially, the use of neoadjuvant chemotherapy in DMPM patients was not associated with worse outcomes compared to adjuvant chemotherapy. It was well-tolerated and did not prevent surgical intervention.