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This Viewpoint describes the use of broad molecular marker testing in patients with early-stage non–small cell lung cancer

Anatomic surgical resection followed by cisplatin-based platinum-doublet adjuvant chemotherapy has been a long-standing standard of care for patients with early-stage, resectable non–small-cell lung cancer (NSCLC). More recently, incorporating of immunotherapy and targeted therapy in the perioperative setting has demonstrated improved disease-free or event-free survival in biomarker-defined subsets of patients. This article summarizes the results of major trials that led to approvals beyond chemotherapy in the perioperative setting. Alongside adjuvant osimertinib as a favored strategy for patients with EGFR mutation–positive NSCLC, there are competing potential standards of care for integrating immunotherapy in the neoadjuvant versus adjuvant setting, with advantages and disadvantages for each strategy. Emerging data in the coming years will provide further insight that may potentially lead to a combination of neoadjuvant and adjuvant treatment for many patients. Future trials should focus on clarifying the benefit of each component of treatment, defining an optimal treatment duration, and incorporating minimal residual disease to optimize treatment decisions.

This JAMA Oncology Patient Page describes genetic testing, fertility concerns, adverse treatment effects, and psychosocial challenges among adolescents and young adults with cancer.

ImportanceAlthough cancer-related mortality continues to decline, lung cancer remains the No. 1 cause of cancer deaths in the US. Almost half of the patients with non–small cell lung cancer (NSCLC) are diagnosed with early-stage, local or regional disease and are at high risk of recurrence within 5 years of diagnosis.ObservationsImmune checkpoint inhibitors (ICIs) have improved outcomes for patients with metastatic NSCLC and have recently been tested in multiple clinical trials to determine their efficacy in the neoadjuvant or adjuvant setting for patients with local or regional disease. The landscape for perioperative ICIs in lung cancer is evolving rapidly, with recently reported and soon to mature clinical trials; however, the recent data highlight the potential of ICIs to increase response rates and decrease rates of relapse in early stages of lung cancer. Concurrently, novel applications of cell-free DNA may guide perioperative management strategies.Conclusions and RelevanceThis article reviews the various approaches of incorporating perioperative use of immunotherapeutic agents for the treatment of early stages of NSCLC.

Background The selection of later-line treatment for older patients with AJCC (version 7) stage IV non-small cell lung cancer (NSCLC) remains controversial. Nanoparticle albumin-bound (nab)-paclitaxel is approved with carboplatin for the first-line treatment of patients with NSCLC and subgroup analysis of phase 3 data has suggested superior survival in older patients. Methods The authors conducted a phase 2 study of nab-paclitaxel in 42 patients aged ≥70 years who had been treated previously with a platinum doublet regimen; patients also could have received a PD-1 inhibitor. The primary endpoint of the current study was grade 3 to 5 toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). In addition to response rate, progression-free survival (PFS), and overall survival (OS), geriatric assessments also were performed before and during treatment, associations between baseline sarcopenia and outcomes were explored, and changes in T lymphocyte p16 before and during treatment were measured. The authors also performed a retrospective subgroup analysis of 19 older patients who were treated with nab-paclitaxel as part of a larger, randomized, phase 2 study; data were not combined. Results The rate of grade 3 to 5 toxicities was 33.7%. The most common grade 3 to 5 toxicities were decreased white blood cell count (11.9%), neutropenia (9.5%), and fatigue (11.9%). The response rate was 34.2% (2.6% complete response rate and 31.6% partial response rate). The median PFS was 5.2 months and the median OS was 9.3 months. Adverse prognostic factors were common: 42% of patients were frail and 39% of patients were prefrail, whereas 21% had an Eastern Cooperative Oncology Group performance status of 2 and 27% were sarcopenic. Only frailty was found to be predictive of inferior survival. A subgroup analysis of 19 older patients treated with nab-paclitaxel alone in a prior trial demonstrated a response rate of 15.8%, a PFS of 4.2 months, and an OS of 13.6 months. Conclusions Fit and prefrail older patients with stage IV NSCLC should be considered for treatment with nab-paclitaxel after disease progression with doublet chemotherapy.

PURPOSE: AccessHope is a program developed initially by City of Hope to provide remote subspecialist input on cancer care for patients as a supplemental benefit for specific payers or employers. The leading platform for this work has been an asynchronous model of review of medical records followed by a detailed assessment of past and current management along with discussion of potential future options in a report sent to the local oncologist. This summary describes an early period of development and growth of this service, focusing on cases of lung cancer, particularly during the COVID-19 pandemic. METHODS: Cases were primarily identified by a trigger list of cancer diagnoses that included non–small-cell lung cancer and small-cell lung cancer. After medical records were obtained, a summary narrative was provided to a thoracic oncology specialist who wrote a case review sent to the local physician, followed by a direct discussion with the recipient. We focused on feasibility as measured by case volumes, the rates of concordance between the subspecialist reviewer with the local team, and cost savings from recommended changes, using descriptive statistics. RESULTS: From April 2019 to November 2020, 110 cases were reviewed: 55% male, median age 62.5 years (range, 33-92 years); 82% non–small-cell lung cancer (12% stage I or II, 16% stage III, and 57% stage IV), and 17% small-cell lung cancer (4% limited and 14% extensive). Median turnaround time for report send-out was 5.0 days. The review agreed with local management in 79 (72%) cases and disagreed in 31 (28%) cases; notably, specific additional recommendations were associated with evidence-based anticipated improvements in efficacy in 76 cases (69%) and improvement in potential for cure in 14 cases (13%). Recommendations leading to cost savings were identified in 14 cases (13%), translating to a projected cost savings of $19,062 (USD) per patient for the entire cohort of patient cases reviewed. CONCLUSION: We demonstrate the feasibility of completing a rapid turnaround of cases of lung cancer either patient-initiated for review or prospectively triggered by diagnosis and stage. This program of asynchronous second opinions identified evidence-based management changes affecting current treatment in 28% and potential improvements to improve care in 92% of patients, along with cost savings realized by eliminating low-value interventions.

125 Background: The advent of immunotherapy (IO) has led to significant improvement in outcomes for patients (pts) with advanced non-small cell lung cancer (adv NSCLC). The rate of crossovers and receipt of post-protocol IO in pivotal trials leading to FDA approvals of IO in NSCLC has not been systematically evaluated. Here, we evaluate crossover rates and post protocol therapies for pts with adv NSCLC across multiple first-line (1L) IO monotherapy and chemotherapy/IO (chemo/IO) combination trials. Methods: We utilized the publicly available data from pivotal clinical trials leading to approvals of IO or chemo/IO regimens in 1L treatment of adv NSCLC. We extracted data on outcomes, rate of crossover from control arm to IO, proportion of pts in control arm receiving IO and the start dates of these clinical trials. The primary outcomes were the rates of crossover and the proportion of patients in control arms who received post-control IO. Results: The study included 4 trials with IO monotherapy and 12 trials with chemo/IO combinations in 1L adv NSCLC. The primary endpoints for these trials were PFS (25%), OS (19%), and both PFS and OS (56%). The crossover rate from control arm to experimental arm (with IO) ranged from 0-74% in IO monotherapy trials and 0-49% in chemo/IO trials. Two IO monotherapy trials and five chemo/IO trials did not allow crossover; among them, 3 trials had a PFS/OS co-primary endpoint, while others had OS as primary endpoint. Ten of 16 trials provided explicit information on use of subsequent post-protocol therapies in their publications. Among the two IO monotherapy trials which did not allow crossover, post-protocol IO was administered in only 20-30% of patients. Among the six chemo/IO trials with information on post-protocol therapies, 30%-59% patients on the control arm subsequently received some form of IO on progression. Nine of 12 trials started accrual after 10/2015, when nivolumab was approved in the United States as second-line (2L) therapy for adv NSCLC regardless of tumor PD-L1 expression. Conclusions: Despite the highly significant OS benefit from 2L IO, which was the standard of care (SOC) in the United States, the rates of crossover and post-protocol IO administration was distressingly low in 1L IO monotherapy and chemo/IO trials for 1L adv NSCLC. This low rate of 2L treatment with IO may have been due to limited global availability prior to widespread regulatory approval during the conduct of these trials. There is an increased need for consistency in reporting of crossover treatment and post-protocol treatments to allow adequate assessment of the true 1L benefit with IO. Control arms in pivotal trials require scrutiny to ensure confirmation with SOC to provide access to optimal treatments for patients and prevent magnification of observed benefits in experimental arms. The difficulty lies in the global conduct of large randomized clinical trials with differing regulatory approvals.

The efficacy of atezolizumab (A) and/or bevacizumab (B) with carboplatin/paclitaxel (CP) chemotherapy was explored in the phase III, randomized IMpower150 study in patients with non-squamous non-small cell lung cancer (NSCLC) according toMutation status was determined by circulating tumor DNA next-generation sequencing. Overall survival (OS) and progression-free survival (PFS) were analyzed in a mutation-evaluable intention-to-treat population (MEP; n=920) and SP263 (programmed cell death ligand 1 (PD-L1)) biomarker-evaluable population (n=774).Within the mThese analyses support previous findings of mutation of

This JAMA Oncology Patient Page describes the use of systemic therapy in addition to surgery in the treatment of early-stage lung cancer.

Summary Background Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer. Methods IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m2 intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFRwt and ALKwt) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781. Findings Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2–23·6] in the atezolizumab plus chemotherapy group and 19·2 months [15·4–23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0–21·2] in the atezolizumab plus chemotherapy group and 13·9 months [12·0–18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64–0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2–7·3] in the atezolizumab plus chemotherapy group and 5·5 months [4·4–5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54–0·77]; p Interpretation IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer. Funding F. Hoffmann-La Roche.

Over the last decade, the treatment of patients with advanced non–small cell lung cancer (NSCLC) has become reliant on tissue and/or blood biomarkers to help guide treatment decisions. There are now multiple biomarker-defined patient subgroups, with evidence showing that treatment with targeted therapies has superior clinical outcomes when compared with traditional cytotoxic chemotherapy. However, rapid change in the field of precision oncology brings with it the challenge of translating recommendations into clinical practice. In this review, we discuss the major guidelines recommending biomarker testing in NSCLC, as well the logistical challenges to applying these guidelines to patients with NSCLC both in the United States and worldwide. The techniques commonly used for biomarker testing will be discussed, both for tissue- and blood-based biomarkers. Finally, we discuss the challenge of interpreting the results of biomarker testing and using these results to guide treatment decisions.

Aim: Evaluate real-world patient preferences, experiences and outcomes (health-related quality of life [HRQoL]) from patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) utilizing the ALKConnect Patient Insight Network. Patients & methods: Demographics, disease history/status/treatment, patient preferences and HRQoL (MD Anderson Symptom Inventory lung cancer module, reported as symptom severity and interference) were evaluated for US adults with ALK+ NSCLC. Results: Among 104 patients (median age: 53.0 years, 67.3% female, 40.0% employed), HRQoL and 3-month delay in disease progression were important treatment attributes. Burdensome symptoms included fatigue and disturbed sleep. Symptoms interfered most with work and day-to-day activity. Higher HRQoL was associated with ALK tyrosine kinase inhibitor (TKI) treatment and employment. Conclusion: ALKConnect demonstrated that disease progression, HRQoL, fatigue/sleep, ALK TKIs and employment matter in ALK+ NSCLC.

BackgroundThe efficacy of atezolizumab (A) and/or bevacizumab (B) with carboplatin/paclitaxel (CP) chemotherapy was explored in the phase III, randomized IMpower150 study in patients with non-squamous non-small cell lung cancer (NSCLC) according to KRAS mutations (mKRAS) and co-occurring STK11, KEAP1, or TP53 mutations.MethodsMutation status was determined by circulating tumor DNA next-generation sequencing. Overall survival (OS) and progression-free survival (PFS) were analyzed in a mutation-evaluable intention-to-treat population (MEP; n=920) and SP263 (programmed cell death ligand 1 (PD-L1)) biomarker-evaluable population (n=774).ResultsWithin the mKRAS population (24.5% of MEP), ABCP showed numerical improvements vs BCP in median OS (19.8 vs 9.9 months; HR 0.50; 95% CI 0.34 to 0.72) and PFS (8.1 vs 5.8 months; HR 0.42; 95% CI 0.29 to 0.61)—greater than with ACP (OS: 11.7 vs 9.9 months; HR 0.63; 95% CI 0.43 to 0.91; PFS: 4.8 vs 5.8 months; HR 0.80; 95% CI 0.56 to 1.13) vs BCP. Across PD-L1 subgroups in mKRAS patients, OS and PFS were longer with ABCP vs BCP, but OS with ACP was similar to BCP in PD-L1-low and PD-L1-negative subgroups. Conversely, in KRAS-WT patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups. KRAS was frequently comutated with STK11, KEAP1, and TP53; these subgroups conferred different prognostic outcomes. Within the mKRAS population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-WT and/or KEAP1-WT. In mKRAS patients with co-occurring mSTK11 and/or mKEAP1 (44.9%) or mTP53 (49.3%), survival was longer with ABCP than with ACP or BCP.ConclusionsThese analyses support previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. While clinical efficacy favored ABCP and ACP vs BCP in these mutational subgroups, survival benefits were greater in the mKRAS and KEAP1-WT and STK11-WT population vs mKRAS and mKEAP1 and mSTK11 population, suggesting both prognostic and predictive effects. Overall, these results suggest that atezolizumab combined with bevacizumab and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with mKRAS and co-occurring STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

We report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC.Chemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS).The intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49-0.72, p0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64-1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71-1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively.IMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified.

Telemedicine has historically been underutilized in medicine broadly, and specifically in oncology, despite the general availability of the needed infrastructure to offer it as a platform for remote care. The COVID-19 pandemic posed new risks of infection exposure and potentially life-threatening complications, particularly in patients with cancer, created a new setting for cancer care ideally suited for the rapid roll-out of telemedicine for patients with cancer who need regular follow up but in whom live visits may not be critical. In the months since the upheaval of our health care system and wider society in the United States, as well as other countries, our early experience with telemedicine has demonstrated the feasibility of telemedicine for a subset of patients with cancer, facilitated by a removal of regulatory hurdles and payment parity, at least temporarily. At the same time, however, many patients still need to return to the clinic for routine infusions of anti-cancer therapy that obviate much of the value of remote clinic visits, and many patients remain limited by access to hardware, fast and reliable internet, and technical expertise. While we need to address these shortcomings and ensure training of health care professionals in "webside manner" with patients, as well as to work to develop ways to incorporate remote care in the conduct of clinical trials, telemedicine is poised to emerge not merely as an interim solution to a transient challenge but as a valuable tool ideally suited to deliver cancer care efficiently for a subset of patients well suited to adopt this platform.

Non-small cell lung cancer with very limited extent of metastatic spread commonly is termed, oligometastatic disease (OMD), and typically described as no more than 3 to 5 lesions. Definitive local therapy potentially leads to significant improvement in progression-free survival and overall survival. OMD may occur de novo prior to initiation of systemic therapy or as an induced state after initiation of systemic therapy. Although prospective data are limited to small trials, they have consistently supported local therapy as an appropriate consideration if not a clear standard of care for well-selected patients. Several trials in OMD are ongoing.

Introduction: AccessHope (AH) is a program developed initially by City of Hope to provide remote subspecialist input on cancer care for patients as a supplemental benefit for specific payers and employers. While offering several platforms, the leading one has been an asynchronous model of review of medical records followed by a detailed assessment of past and current management along with discussion of potential future options in a report sent to the local oncologist. The intent of this program is that the patient can continue to have most or all management in their home environment, with the input and support of a subspecialist in that tumor type available “on demand”. This summary describes an early period of development and growth of this service, focusing in cases of lung cancer, particularly relevant during the COVID-19 pandemic. Methods: Appropriate cases for the eligible “at risk” population were identified by a trigger list of cancer diagnoses associated with a significant degree of risk of poor outcomes that included non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Medical records were solicited from the local medical team, from which a summary narrative and chronology was developed by a team of nurses at AH. This was shared with a physician specialist in thoracic oncology from AH who wrote a summary report within several days that was sent to the local physician, followed by a direct discussion with the recipient. Using descriptive statistics, case metrics focusing on concordance with the current or proposed management plan were tracked, along with recommended changes and clinical trial options, as well as potential cost savings from suggested changes. Results: Over a 19-month period from 4/19 through 11/20, 110 cases were reviewed: 55% male, median age 62.5 yrs (range 33-92);82% NSCLC (12% stage I/II, 16% stage III, 57% stage IV) and 17% SCLC (4% limited, 14% extensive). Median turnaround time for send out of report of 5.0 days. The AccessHope review agreed with the proposed or ongoing treatment in 79 (72%) cases and disagreed in 31 (28%) cases. Even with general agreement in the treatment approach, specific additional recommendations were associated with evidence-based anticipated improvements in efficacy in 76 cases (65%) and improvement in potential for cure in 14 cases (12%, only feasible in patients with curable disease). Specific recommendations associated with cost savings were identified in 14 cases (12%), associated with a total cost savings of $2,096,859. Molecular testing was ordered rarely for SCLC;for NSCLC, NGS was strongly favored and more commonly associated with more advanced stage and non-squamous histology. Conclusion: We have implemented a novel program of asynchronous reviews of cases of patients with lung cancer by thoracic oncology subspecialists and have demonstrated the feasibility of completing reports for a growing volume over the course of the pandemic without requiring travel and enabling patients to receive their care close to home. More than a quarter of these case reviews include recommendations associated with evidence to support improved clinical outcomes, as well as potentially significant cost savings from low value practices unsupported by evidence. Keywords: remote care, pandemic, expert review

9071 Background: BRG is a kinase inhibitor approved for the treatment of patients (pts) with ALK+ metastatic NSCLC; specific details for BRG use vary by indication and country. We report long-term efficacy and safety results of the Phase 1/2 and Phase 2 (ALTA) trials of BRG. Methods: The Phase 1/2 study was a single-arm, open-label trial (NCT01449461) of BRG 30–300 mg/d in pts with advanced malignancies. ALTA (NCT02094573) randomized pts with CRZ-refractory ALK+ NSCLC to receive BRG at 90 mg qd (arm A) or 180 mg qd with 7-d lead-in at 90 mg (arm B). For the Phase 1/2 study, investigator assessments of confirmed objective response rate (cORR; RECIST v1.1), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety in pts with ALK+ NSCLC are reported. The primary endpoint of ALTA was cORR per investigator; secondary endpoints included cORR per independent review committee (IRC), DoR, PFS, and OS. Results: In the Phase 1/2 study, 137 pts received BRG; of these, 79 pts had ALK+ NSCLC (71/79 had prior CRZ; 28/79 received 180 mg qd [7-d lead-in at 90 mg]; 14/79 received 90 mg qd). In ALTA, 222 pts with CRZ-refractory ALK+ NSCLC were randomized (n = 112/110, arm A/B). At the end of the Phase 1/2 study (Feb 18, 2020), with median 27.7 mo follow-up (̃67 mo after last pt enrolled), 4 pts remained on BRG. At the end of ALTA (Feb 27, 2020), with median 19.6/28.3 mo follow-up in arm A/B (̃53 mo after last pt enrolled), 10/17 pts in arm A/B were still on treatment. Table shows efficacy results from final analyses with long-term follow-up. In ALTA, the IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B. With long-term follow-up, no new safety signals were identified. Treatment-emergent adverse events led to dose interruption (Phase 1/2: 59%; ALTA arm A/B: 49%/61%), dose reduction (13%; 8%/33%), or discontinuation (10%; 4%/13%). Conclusions: BRG showed sustained long-term activity, PFS, and manageable safety in pts with CRZ-refractory ALK+ NSCLC. The 180 mg/d dose after 7-d lead-in at 90 mg/d led to numerically higher median PFS and OS. Final results are similar to those reported for other approved ALK tyrosine kinase inhibitors in this setting. Clinical trial information: NCT01449461, NCT02094573. [Table: see text]

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 in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2, or BRAF for 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.

IMPORTANCE: Although treatment with first-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. OBJECTIVE: To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. INTERVENTIONS: The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. RESULTS: From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation. TRIAL REGISTRATION: UMIN Clinical Trials Registry Identifier: UMIN000023761

Background We evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non–small-cell lung cancer. Patients and Methods Patients with treatment-naive squamous non–small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m2 on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m2 (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS). Results Overall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator’s discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC). Conclusions The results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC.

Purpose The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) guideline on molecular testing for the selection of patients with lung cancer for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors was considered for endorsement. Methods American Society of Clinical Oncology (ASCO) staff reviewed the CAP/IASLC/AMP guideline for developmental rigor; an ASCO ad hoc review panel of experts reviewed the guideline content. Results The ASCO panel concurred that the recommendations are clear, thorough, and based on the most relevant scientific evidence in this content area and present options that will be acceptable to patients. The CAP/IASLC/AMP guideline comprises 37 recommendations (evidence grade A or B), expert consensus opinions, or suggestions that address the following five principal questions: (1) When should molecular testing be performed? (2) How should EGFR testing be performed? (3) How should ALK testing be performed? (4) Should other genes be routinely tested in lung adenocarcinoma? (5) How should molecular testing be implemented and operationalized? Conclusion The ASCO review panel endorses the CAP/IASLC/AMP guideline. This guideline represents an important advance toward standardization of EGFR and ALK testing practices and is of major clinical relevance in advancing the care of patients with lung cancer. In the Discussion section, the ASCO review panel highlights three evolving areas: advances in ALK testing methodology, considerations for selecting appropriate populations for molecular testing, and emergence of other targetable molecular alterations.

Purpose Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib. Methods This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR). Results Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3–16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3–27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa. Conclusions Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib. Electronic supplementary material The online version of this article (doi:10.1007/s00280-017-3283-z) contains supplementary material, which is available to authorized users.

This study assesses differences in survival according to the time interval between non–small-cell lung cancer resection and the initiation of postoperative chemotherapy to determine the association between adjuvant treatment timing and efficacy.