I mmunotherapy has transformed the treatment of metastatic non-small cell lung cancer (NSCLC) in recent years, but few trials have explored the impact of immunotherapy in the neoadjuvant setting. The final analysis of 3-year overall survival (OS) from the NADIM study found that adding nivolumab to familiar paclitaxel plus carboplatin neoadjuvant therapy produced an OS rate of 81.9% at 36 months in an intention-to-treat (ITT) analysis. Historical 3-year OS rates are approximately 30%. “Survival time in the NADIM trial was almost three times that reported in historical series,” said Mariano Provencio, MD, PhD, Head of Medical Oncology at Puerta de Hierro University Hospital and Professor of Medicine at the Autonomous University of Madrid, Spain. “The addition of neoadjuvant nivolumab to chemotherapy did not worsen the safety profile.” Dr. Provencio revealed the results of NADIM during OA20: Exploring Treatment Modalities and Tools in Locally Advanced NSCLC on Monday. The trial also found that ctDNA levels following neoadjuvant therapy and before surgery may be a useful prognostic marker of longer-term treatment success. Primary results of the phase II trial CONQUERING THORACIC CANCERS WORLDWIDETUESDAY, SEPTEMBER 14 INSIDE: PAGE 4 Liquid biopsy testing keeps progressing PAGE 6 Update from the CHRYSALIS study PAGE 11 Retreatment with SABR PAGE 3 NSCLC biomarker guideline challenges PAGE 12 Social vulnerability and surgical outcomes UKLS DATA SUPPORT LOW-DOSE CHEST CT FOR SCREENING T he United Kingdom Lung Screening (UKLS) trial results have confirmed a lung cancer mortality reduction by low-dose computed tomography (LDCT) screening, according to results presented by John Field, PhD, FRCPath, of The University of Liverpool, Great Britain, at WCLC 2021. Dr. Field said that although the follow-up outcome data showed a difference in lung cancer mortality that was not statistically significant, it was consistent with the findings from other trials of a substantial reduction in lung cancer mortality. Dr. Field presented results from the UKLS trial and results from a random-effects meta-analysis including UKLS, the National Lung Screening Trial, the NELSON LDCT screening trial, and others during OA19: Screening and Early Detection: State of the Art. The meta- analysis showed a significant 16% reduction in lung cancer mortality when compared against a non-LDCT control arm (relative risk [RR] = 0.84; 95% CI: 0.76-0.92). The UKLS trial included 4,055 participants from October 2011 to February 2013 who had received a single invitation to LDCT screening or no screening (usual care) using the LLP version 2 lung cancer risk prediction model to select high-risk participants. The primary outcome was mortality due to lung cancer. “The uniqueness of the UKLS is that it is the only lung cancer [randomized clinical trial] to use a risk prediction model to select high-risk participants,” Dr. Field said. There were 76 lung cancer deaths: 30 in the screening arm and 46 in the control arm. There was not a statistically significant difference between these two arms. However, there was a benefit in terms of lung cancer mortality, Dr. Field said, with a difference emerging most strongly in years 3 to 6 after random assignment and continuing for the 7-year follow-up period. There were no differences in lung cancer mortality in the male (RR = 0.63; 95% CI: 0.37-1.08) or female (RR = 0.69; 95% CI: 0.28- 1.69) subgroups. There was a nonsignificant increase in incidence of lung cancer for men and women. The benefit of early detection was maintained beyond 5 years after Mariano Provencio, MD, PhD ... see SCREENING on page 15 NADIM: ADDING NIVOLUMAB TO NEOADJUVANT CHEMOTHERAPY MORE THAN DOUBLES 3-YEAR SURVIVAL FOR PATIENTS WITH STAGE III NSCLC AND NODAL INVOLVEMENT ... see NADIM on page 14 OUR COMMITMENT TO ONCOLOGY TODAY’S CLINICAL RESEARCH DEVELOPS HOPE FOR TOMORROW VV-OTHR-US-DEL-0521 04/2021 © Lilly USA, LLC 2021. All rights reserved. John Field, PhD, FRCPathLOCATION STUDY TREATMENTS KEY ELIGIBILITY CRITERIA ASIA, AUSTRALIA, NORTH AMERICA RANDOMIZED, PHASE 2, OPEN-LABEL •Zimberelimab (anti-PD-1 antibody) •Domvanalimab(anti-TIGIT antibody)+ Zimberelimab •Domvanalimab + Zimberelimab + Etrumadenant (dual adenosine A 2a /A 2b receptor antagonist) NSCLC: •Histologically confirmed squamous or nonsquamous •PD-L1 positive •Metastatic •No EGFR or ALK mutations These molecules and their uses are investigational, have not been proven to be safe and effective, and have not been approved by any health authority. ASIA, EUROPE, LATIN AMERICA RANDOMIZED, PHASE 3, OPEN-LABEL •Zimberelimab •Chemotherapy •Domvanalimab + Zimberelimab NSCLC: •Histologically confirmed squamous or nonsquamous •Treatment-naive •PD-L1 positive •Locally advanced or metastatic •No EGFR or ALK mutations Do you have patients with NSCLC who could benefit from participating in an EXPLORE THE STUDIES AT arcusbio.com/clinical-trials/lung-cancer HAVE A PATIENT TO REFER? email us at clinicaltrials@arcusbio.com today! Arcus Biosciences, a company focused on precision combinations for cancer, is currently enrolling: ALK= anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; NSCLC=non-small cell lung cancer; PD-1=programmed death protein 1; PD-L1=programmed death ligand 1; TIGIT=T cell immunoreceptor with immunoglobulin and ITIM domain. © 2021 Arcus Biosciences, Inc. All rights reserved. Approved July 2021. ANTI-TIGIT CLINICAL TRIAL?TUESDAY, SEPTEMBER 14, 2021 | WORLDWIDE VIRTUAL EVENT3 O nly 40% of clinicians who specialize in non-small cell lung cancer (NSCLC) are very familiar or extremely familiar with the 2018 Molecular Testing Guideline for lung cancer from the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP). And clinicians are least confident in coordinating care across the multidisciplinary team and when to order testing. These findings are part of a 2020 survey of U.S. oncology clinicians developed for the Association of Community Cancer Centers (ACCC) by an expert panel. Survey invitations were emailed to a random sample of ACCC member oncology clinicians caring for patients with NSCLC who were insured by Medicaid or uninsured. Results were validated by focus groups with community- based and academic clinicians. “This study identified key areas of ongoing clinician need related to biomarker testing,” said Leigh Boehmer, PharmD, BCOP, ACCC chief medical officer. “Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions compared to 73% of academic clinicians. That finding was statistically significant.” Dr. Boehmer presented the results of the survey during OA10: Improving Care for People with Lung Cancer on Thursday. A total of 99 NSCLC clinicians responded to the survey, 68% from community settings and 32% from academic centers. Just 53% of community clinicians and 64% of academic clinicians cited clinical practice guidelines as a reason to order or recommend biomarker testing. Only 9% of community clinicians 12% of academic clinicians cited patient expectations for molecular testing. “Recent advances in cancer genomics and targeted therapies have substantially changed the management of lung cancer,” Dr. Boehmer noted. “However, we have an epidemic of imprecise access to precision medicine. Many things contribute to disparities in biomarker testing, not the least of which is the degree to which patients and clinicians comprehend the importance of biomarker testing.” Clinicians remain reluctant to share decision making with patients. Most respondents, 52%, said they prefer to make the final biomarker testing decision themselves, while 41% prefer to share responsibility. The other 6% prefer to leave the decision to patients. Focus group participants said that patients lack both comprehension and interest in what biomarker testing entails and what results mean for treatment options. Clinicians believe patients need more educational material about lung cancer and treatment and are most likely to provide printed (65%) or online (56%) education materials. Nearly one-fourth of respondents, 22%, said patients needed improved financial assistance, but only 44% of those respondents provided financial counseling. Similarly, 23% of respondents said patients needed more information regarding psychosocial support services, but only 27% of them actually provide wraparound services to support their patients. “We need better tools for improving patient and clinician discussions about biomarker testing,” said discussant Joshua K. Sabari, MD, assistant professor of medicine, NYU Langone Health Perlmutter Cancer Center, New York. MINORITY OF CLINICIANS UNDERSTAND, USE BIOMARKER GUIDELINES IN NSCLC TREATMENT OR PATIENT DISCUSSIONS PROTON THERAPY REDUCED NORMAL TISSUE EXPOSURE, DEATH FROM INTERCURRENT DISEASE IN LOCALLY ADVANCED NSCLC P roton beam therapy (PBT) resulted in reduced normal tissue exposure and reduced risk of death from intercurrent disease (DID) compared with photon therapy in patients with locally advanced non- small cell lung cancer (NSCLC). Nikhil Yegya-Raman, MD, of University of Pennsylvania, presented results from a retrospective study comparing the two approaches at WCLC 2021 during MA06: Differentiating Outcomes and Impact in Unresectable NSCLC on Thursday. “Patients with locally advanced NSCLC often harbor preexisting cardiopulmonary comorbidities and may receive significant radiation exposure to central structures,” Dr. Yegya-Raman explained. “Proton therapy has the ability to reduce normal tissue exposure, however, the clinical benefit of proton therapy in this setting remains unsettled.” The study included 187 patients with locally advanced disease that received definitive chemoradiotherapy with either PBT (98 patients) or photo therapy (89 patients). The study abstract noted that no patient received consolidation immunotherapy as this cohort predated results of the PACIFIC trial that showed the benefit of that approach. The primary endpoint was DID, defined as death in the absence of disease progression. Dr. Yegya-Raman noted that at his institution PBT was introduced in 2011 and given typically to patients with Medicare. As a result, patients in the PBT group were older with a median age of 69 years compared with 62 years and were treated more recently. This group also had a greater burden of cardiovascular comorbidity. The 3-year cumulative incidence of DID had a trend favoring the PBT arm (7.1% vs 14.6%; P = 0.098). There was no difference in overall survival (OS) and disease progression between groups. The 3-year cumulative incidence of disease progression was 68.4% compared with 67.4% (P = 0.9). The median OS was about 29 months in both groups. A univariate analysis showed that age, ECOG performance status, and higher mean heart and esophageal dose were all associated with increased risk for DID. The multivariable analysis controlled for age and ECOG status. Here, PBT was associated with a reduced risk for DID (sHR = 0.25; 95% CI: 0.1- 0.65; P = 0.004) and mean heart and esophageal dose retained their association with increased risk for DID. Additionally, higher mean heart dose was associated with an increased risk for death (HR = 1.03; 95% CI: 1.01-1.04; P = 0.013). Median overall survival for patients with a higher compared with lower mean heart dose was 23 months compared with 34 months (P < 0.001). “This endpoint may become more clinically relevant as the risk of disease progression decreases with immunotherapy,” Dr. Yegya-Raman said. “Given the retrospective nature of study and the small number of events, our findings are hypothesis generating and could be studied in ongoing or future proton trials.” Discussant Megan E. Daly, MD, of University of California Davis Comprehensive Cancer Center, said that proton radiation for locally advanced NSCLC “shows promise dosimetrically” and results are awaited from a randomized phase III trial of the approach. Nikhil Yegya- Raman, MD Leigh Boehmer, PharmD, BCOP4IASLC WORLD CONFERENCE ON LUNG CANCER | #WCLC21 A s regulatory bodies approve more targeted therapies with high response rates, the need for molecular testing is growing. Current guidelines recommend broad molecular profiling for all newly diagnosed patients with nonsquamous NSCLC to evaluate all patients for actionable mutations. “We know testing for actionable mutations and treating with the appropriate targeted therapy is associated with improved overall survival (OS) in our patients,” said Jeffrey C. Thompson, MD, assistant professor of Medicine at the University of Pennsylvania Abramson Cancer Center, Philadelphia. “However, the majority of patients do not receive guideline- recommended tumor genotyping. Only 37% of patients in a recent study underwent tissue next- generation sequencing (NGS) prior to receiving first-line therapy. There is significant progress to be made in biomarker testing for our patients.” One problem is time. When advanced NSCLC is suspected and identified, usually via imaging, a tissue biopsy is taken. If NSCLC is confirmed, all patients at Abramson receive PD-L1 testing and tissue NGS. Sequencing typically takes 14 to 28 days, Dr. Thompson noted. Patients typically have their initial medical oncology visit while genotyping results are still pending. Without molecular testing results, clinicians cannot discuss specific targeted therapy. Many clinicians order plasma genotypic during that first visit to help expedite treatment decisions. “We were curious whether performing plasma genotyping earlier in the diagnostic journey would expedite molecular testing results and lead to earlier treatment,” he said. “So we designed a study.” Dr. Thompson described the study during OA16: Clinical Impact of Liquid Biopsy for Patients with NSCLC. Patients with suspected stage IIIB/IV NSCLC based on imaging were evaluated for biopsy. If a diagnostic biopsy was indicated, a plasma sample was obtained and submitted for genotyping using a commercially available 74-gene panel. Results typically take 7 to 10 days and were available at the initial medical oncology visit. A cohort of 55 patients with advanced NSCLC were enrolled for liquid biopsy. The control group was a retrospective cohort of 55 consecutive, newly diagnosed patients with advanced NSCLC who underwent reflex tissue NGS per the institutional pathway. The two cohorts were well matched, Dr. Thompson said, and the number of oncogenic driver mutations was similar: 62% from plasma NGS vs 64% for tissue NGS (P = 0.84). A therapeutically informative driver mutation was detected in a majority of patients in both cohorts. Median time to first medical oncology visit was similar, but median turnaround time for plasma NGS was 8 days vs 22 days for tissue NGS (P < 0.0001). Most patients, 85%, in the plasma NGS cohort had results available at the first medical oncology visit vs 9% in the tissue NGS cohort (P < 0.0001), driven largely by the earlier plasma NGS results. Most patients who underwent plasma NGS, 74%, had treatment initiated at the first oncology visit vs 46% of those who underwent tissue NGS (P = 0.005). Time to first-line therapy was significantly shorter with plasma NGS at 12 days, vs 30 days for tissue NGS (P = 0.003). Time to treatment was even shorter in patients with an identified oncogenic drive mutation—10 days vs 18 days (P = 0.001). “This provides proof of concept to implementing plasma genotyping earlier in the diagnostic evaluation of patients with suspected NSCLC to facilitate the timely deliver of guideline-concordant care,” Dr. Thompson said. It is not clear if these results are generalizable to practices that do not routinely use tumor genotyping, said discussant Lecia V. Sequist, MD, MPH, director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital. “The availability of the NGS results at the first oncology appointment was much improved when it was sent [early],” she said. It was the same for time-to-treatment initiation and treatment being initiated at that first oncology appointment. “We have to work on the systems where we are to optimize the work flow.” COST AS A DRIVER One problem in optimizing workflow is the lack of routine plasma NGS. “The leading barrier is cost,” said Doreen A. Ezeife, MD, MSc, clinical assistant professor at the University of Calgary and Staff Oncologist at Tom Baker Cancer Center, Canada. “We designed a study to assess the cost-effectiveness of adding liquid biopsy to standard tissue profiling in [patients with] newly-diagnosed NSCLC from the perspective of the Canadian public healthcare system.” The prospective VALUE trial enrolled 292 treatment-naïve patients with stage IV NSCLC at six Canadian cancer centers. All patients had standard-of-care tissue profiling, and 146 patients in the treatment group also had plasma DNA profiling. All patients with an actionable oncogenic driver mutation received the appropriate targeted therapy. If no targeted therapies were available in Canada, patients received chemoimmunotherapy. The trial model compared overall survival (OS) and progression- free survival (PFS) for targeted vs nontargeted therapy and the combined costs of first-line therapies, disease management, treatment-related costs, terminal care costs, and direct testing costs between tissue-only and tissue plus plasma profiling. The study population was largely female (64%), with an average age of 64 years old, and 80% had chosen to never smoke. Serum- plus-tissue profiling identified 100 patients (68%) with actionable mutations vs 77 patients (53%) by tissue profiling alone. Median PFS in the non-targeted therapy group was targeted therapy group was 9.8 months vs 11.4 months in the targeted therapy group. The median OS for non-targeted therapy was 19.5 months while the targeted therapy group has not yet reached median OS. The cost of treatment for the plasma plus tissue profiling group was Canadian $1,305,527 per patient. Per patient cost for tissue profiling alone was C$1,342,740, an increase of C$37,216 per patient. “Sensitivity analysis showed that the model was most sensitive to drug acquisition costs and the prevalence of actionable mutations,” Dr. Ezeife said. “As the cost of chemoimmunotherapy increases, the liquid biopsy strategy becomes more favorable. Routine use of liquid biopsy in this lung cancer population should be used to improve patient outcomes and reduce system costs.” Dr. Sequist noted that plasma NGS testing clearly led to cost savings and more personalized, optimal care. “There is a growing body of evidence that early plasma DNA analysis can be helpful for patients having a quicker diagnosis and getting on the more appropriate treatment,” Dr. Sequist said. LIQUID BIOPSY SHOWS CLINICAL VALUE AS TESTING PROGRESSES Jeffrey C. Thompson, MD Doreen A. Ezeife, MD, MSc Stage IV NSCLCTargeted therapy (n=82)Non-targeted therapy (n=48) Median PFS, months (95%CI)11.4 (8.3 - not reached) 9.8 (4.4 – 19.5) Median OS, months (95% CI)Not reached19.5 (10.2 – 19.5) TestingstrategyCost (CAD$)QALY Incremental cost (CAD$) Liquidbiopsy + Tumourtissue biopsy1,305,5247.17Reference Tumourtissue biopsy alone1,342,7407.1037,216 RESULTSDo you have a plan to test for RET ? Ensure your testing methods include RET Consider NGS for your patients Retevmo ® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates. Other product/company names mentioned herein are the trademarks of their respective owners. PP-SE-US-0786 08/2021 © Lilly USA, LLC 2021. All rights reserved. NGS=next-generation sequencing; RET=rearranged during transfection. VISIT RETEVMO.COM/TEST TO LEARN MORE ABOUT TESTING METHODS FOR THIS ACTIONABLE BIOMARKERCHRYSALIS: AMIVANTAMAB ACTIVE IN MET EXON 14 SKIPPING NSCLC T he EGFR-MET bispecific antibody amivantamab had antitumor activity in patients with non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METex14) mutation, results of the CHRYSALIS study showed. Alexander Spira, MD, PhD, FACP, of Virginia Cancer Specialists and US Oncology Research, Fairfax, VA, presented early results from the phase I study during OA15: Upcoming Molecular Targeted Agents for EGFR exon 20 Insertion and MET Skipping on Sunday at WCLC 2021. The study has two key objectives: dose escalation to establish the recommended phase II dose and expansion to establish safety and efficacy at that dose. For this cohort, included patients had metastatic or unresectable NSCLC with measurable disease and the METex14 skipping mutation. Disease progression must have occurred after receipt or decline of standard of care. Patients in the dose-escalation cohorts received amivantamab at doses from 140 mg to 1,750 mg. The recommended phase II dose was 1,050 mg for patients receiving less than 80 kg and 1,400 mg for patients who were receiving 80 kg or more. Dosing was weekly for Cycle 1 and every-other week beyond that cycle. The expansion cohort has accrued 19 patients with METex14 skipping mutations, with up to 100 patients planned. In the METex14 cohort, safety was consistent with what had bene observed previously, Dr. Spira said. Treatment-related grade 3 or greater adverse events occurred in 16% of patients: one patient had dyspnea, one had hypoalbuminemia, and one had rash. Five percent of patients had treatment- related discontinuations, 11% underwent dose reductions, and 32% had dose interruptions. Of the 14 response-evaluable patients, nine had partial response (64%); five of these are confirmed, and four are pending confirmation. Activity was observed in both treatment-naïve and previously treated patients, including four partial responses in seven patients previously treated with MET TKIs. The median time to first confirmed response was 4.1 months. Responses were durable, Dr. Spira said. No patient demonstrated an increase in tumor assessment as defined by change in size of target lesions. The median treatment duration was 6.5 months, with a median duration of response not reached. Eight of nine patients who demonstrated treatment response had ongoing responses at data cutoff. “This first report of amivantamab activity in METex14 NSCLC confirms the bispecific targeting action of amivantamab, with monotherapy activity now demonstrated in both EGFR-driven (Exon20ins) and MET-driven NSCLC,” Dr. Spira concluded. T elisotuzumab vedotin at a dose of 1.9 mg/kg was tolerable, and a promising overall response rate was seen for patients with nonsquamous EGFR wild- type advanced non-small cell lung cancer (NSCLC), according to results presented during OA15: Upcoming Molecular Targeted Agents for EGFR exon 20 Insertion and MET Skipping Mutation by D. Ross Camidge, MD, PhD, University of Colorado Cancer Center, Aurora, CO. The overall response rate was highest for the cohort of patients with high c-Met expression but was also clinically meaningful in the c-Met–intermediate group, Dr. Camidge noted. “Telisotuzumab vedotin is a first- in-class MET-directed antibody–drug conjugate (ADC) driving internalization and degradation of the Met protein and facilitating delivery of a cytotoxic payload,” Dr. Camidge said. A phase Ib study established a dose of 1.9 mg/kg once every 2 weeks. Patients had nonsquamous NSCLC with known EGFR status or squamous cell NSCLC. Those with nonsquamous disease were further classified by intermediate or high c-Met expression levels. Patients could be pre-screened for c-Met status. As of December 2020, 841 patients were screened with evaluable c-Met data. Among the patients with nonsquamous disease, 25% of patients with wild-type EGFR and 37% of those with mutations were c-Met positive. Among the patients with EGFR wild type, 12% were classified as c-Met high and 13% were classified as c-Met intermediate; in the EGFR mutant group, 22% were c-Met high and 15% were c-Met intermediate. Thirty-nine percent of the squamous cohort had c-Met positive tumors. “Approximately 50% to 60% of Met-positive [patients] within the nonsquamous groups had Met protein levels of the high as opposed to intermediate levels,” Dr. Camidge noted. The squamous cohort had a 14% overall response rate and did not meet criteria for further exploration. In the EGFR-mutant group the response rate was 18.2% for the group with high c-Met expression and 0% for the intermediate cohort. However, in the wild-type group, the response rate was 25% for the intermediate group and 53.8% in the high group. The median duration of responses by independent clinician review was 6.9 months. Almost all patients experienced at least one treatment-related adverse event. Forty-four percent of patients had a grade 3 or greater treatment-related adverse event. The most frequent was malignant neoplasm progression, occurring in 6% of patients. Three deaths, possibly attributed to the drug, were reported. TELISOTUZUMAB VEDOTIN YIELDED PROMISING RESPONSES IN NON- SQUAMOUS EGFR WILD-TYPE NSCLC SCIENCE TO WATCH Alexander Spira, MD, PhD, FACP NEOADJUVANT CHEMOTHERAPY SAFER THAN NEOADJUVANT CHEMORADIATION SEFORE SLEEVE LUNG RESECTION THE LARGEST-EVER RETROSPECTIVE study of neoadjuvant treatment before sleeve lung resection for patients with locally advanced, resectable non- small cell lung cancer (NSCLC) found a 5-fold increase in 90-day mortality for chemoradiation versus chemotherapy alone. There was no difference in long- term survival. “We found that there is no national consensus on the choice of neoadjuvant modalities prior to sleeve resection,” said Mark Jaradeh, BS, third-year medical student at Loyola University Chicago Stritch School of Medicine. “The mortality associated with neoadjuvant chemoradiation is not justified by any meaningful difference in overall survival. Neoadjuvant chemotherapy alone in patients requiring a sleeve lung resection may be a safer alternative and does not jeopardize long-term outcomes.” Trimodal therapy, neoadjuvant chemotherapy plus radiation, followed by surgery, is often used for patients with locally advanced disease, Mr. Jaradeh said during OA20: Exploring Treatment Modalities and Tools in Locally Advanced NSCLC. But few patients undergoing sleeve resections have been included in randomized controlled trials. Several small studies have suggested the potential for increased morbidity and mortality follows neoadjuvant radiation before sleeve resection. Researchers queried the National Cancer Database (NCDB) for patients with locally advanced lung cancer treated with neoadjuvant therapy followed by sleeve lung resection between 2006 and 2017. A total of 176 patients were stratified by neoadjuvant therapy alone (47.7%) or neoadjuvant chemoradiation (52.3%). The two groups were similar in age, sex, race, comorbidities, histology, tumor size, tumor location, and other potential confounders. “There is a marked increase at 12% in 90-day mortality with neoadjuvant chemoradiation compared to 2.2% with neoadjuvant chemotherapy alone,” Mr. Jaradeh reported. “The rates of margin- negative resection were similar between the two groups, at 80%.” There was a trend toward higher rates of pathologically complete resection with neoadjuvant chemoradiation, he added, but the difference was not statistically significant. “Most importantly, there was no difference in overall survival,” he said. The study was observational, he noted, subject to both selection bias and unmeasured confounding factors. The balance between the two groups at baseline is an important strength and suggests the lack of clinical consensus on the management of this challenging patient population. D. Ross Camidge, MD, PhD Mark Jaradeh, BS 6TUESDAY, SEPTEMBER 14, 2021 | WORLDWIDE VIRTUAL EVENT7 DZD9008 HAD A FAVORABLE safety profile and promising anti- tumor efficacy in patients with pre-treated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions and other EGFR or HER2 mutations, according to data presented at WCLC 2021. The only approved therapy for EGFR exon 20 insertion is amivantamab; no tyrosine kinase inhibitors (TKIs) have been approved. DZD9008 is a selective, irreversible EGFR inhibitor being developed in NSCLC with EGFR or HER2 mutations. Pasi Jänne, MD, PhD, Dana Farber Cancer Institute, presented data on DZD9008 from two ongoing phase I studies: WU-KONG1 (United States, Australia, South Korea, Taiwan) and WU-KONG2 (China) during OA15: Upcoming Molecular Targeted Agents for EGFR exon 20 Insertion and MET Skipping Mutation. “DZD9008 demonstrated encouraging antitumor activities in heavily, previously pre-treated [patients with] advanced NSCLC with different subtypes of EGFR exon 20 insertion mutations,” Dr. Jänne said. Both studies had similar trial designs. The studies included a dose-escalation portion, which included EGFR or HER2 mutations, and dose-expansion cohorts, which included EGFR or HER2 exon 20 insertion. Patients with stable brain metastases were allowed. Drug-related adverse events of grade 3 or higher occurred in approximately 33.3% of patients. These events increased dose proportionally. Discontinuation due to drug-related adverse events occurred in 5.9% of patients, with a higher percentage in the 400- mg group. Dose interruptions and dose reductions were also highest in the 400-mg group. The efficacy analysis included 56 patients with EGFR exon 20 insertions treated with DZD9008 at doses ranging from 50 mg to 400 mg once daily, with at least one post-treatment RECIST assessment. The confirmed overall response rate was 37.5%. Unconfirmed partial responses occurred in 41.1% of patients, and confirmed partial responses in 37.5% of patients. The overall disease control rate was 85.7%. Antitumor efficacy was observed at doses of 100 mg or greater and across different EGFR exon 20 insertion subtypes, Dr. Jänne noted. Tumor response was also observed in patients with baseline brain metastases. Across all dose levels, the longest treatment duration was 17 months. In 23 patients that achieved partial response, 15 are still on treatment and responding and six had progression of disease. The longest duration of response was longer than 8 months. The median duration of response was longer than 3.5 months and has not been reached. Additionally, median progression-free survival was longer than 4 months and has not been reached, Dr. Jänne said. MOBOCERTINIB PROVIDED CLINICALLY MEANINGFUL BENEFIT IN EGFR EXON 20 INSERTION-POSITIVE NSCLC TREATMENT WITH MOBOCERTINIB resulted in clinical benefit for patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer (NSCLC) who had disease control on prior EGFR-targeted therapy, according to results presented by Alexander Spira, MD, PhD, FACP, Virginia Cancer Specialists and US Oncology Research, during OA15: Upcoming Molecular Targeted Agents for EGFR exon 20 Insertion and MET Skipping Mutation. EGFR exon 20 insertions occur in approximately 4% to 10% of EGFR mutations in NSCLC and account for approximately 2% of all NSCLC cases, Dr. Spira said. Real-world data have shown a low median overall survival (OS) in patients with EGFR exon 20 insertions, with a median OS ranging from 7.1 months to 13.6 months in the second-line setting. Based on preliminary phase I/II results, mobocertinib was granted Breakthrough Therapy designation for patients with EGFR exon 20 insertion-positive NSCLC who previously progressed on platinum- chemotherapy in the United States or who had prior chemotherapy in China. Dr. Spira presented efficacy and safety data from an expansion cohort (Cohort 5) of patients who experienced disease progression after objective response or stable disease for 6 or more months on any prior EGFR-targeted tyrosine kinase inhibitor (TKI) in the phase I/ II study. More than one-half (55%) of patients received EGFR TKIs as the most recent prior therapy. At data cutoff, 35% of patients who received prior TKIs remained on mobocertinib. With a median follow-up of 14.2 months, the overall response rate was 40%. “Confirmed objective response were observed regardless of prior TKI therapy,” Dr. Spira noted. The confirmed disease control rate was 90%. Median duration of response of 13 months. The 6-month OS rate was 94.7%, with the median OS not reached. Median progression-free survival (PFS) per IRC assessment was 7.3 months. Ninety-five percent of patients had a reduction from baseline in the sum of target lesion diameter per IRC assessment. Clinical activity was observed in patients with various EGFR exon 20 mutation types, Dr. Spira said. The safety profile in this cohort was manageable and generally consistent with other TKIs, Dr. Spira said. Adverse events led to dosage reduction in 20% of patients and to treatment discontinuation in 10% of patients. Federico Cappuzzo, MD, PhD, Istituto Nazionale Tumori Regina Elena, Rome, Italy, said that these data are incredibly similar to previous data published in early 2021 from Cohort 1 of the study which included pretreated patients. The logical question when looking at all the data available for EGFR exon 20 insertions is, “What is the best agent?” Dr. Cappuzzo said. Available agents include amivantamab, mobocertinib, and DZD9008, and in an indirect comparison, response rates, duration of response, and PFS rates, are quite similar among them. The most important difference may be in terms of safety, with a more favorable profile for amivantamab, particularly for gastrointestinal toxicity, Dr. Cappuzzo said. At data cutoff (November 1, 2020), 7 patients (35%) who received prior TKIs remained on mobocertinib, with a median time on treatment of 7.8 months (range, 2−21) Median follow-up was 14.2 months (range, 5.2–21.2) Mobocertinib Clinical Activity Confirmed ORR, n (%; 95% CI) PR, n(%) SD,n (%) Confirmed ORRa on mobocertinib by prior TKI, n/N (%) Poziotinib Osimertinib Afatinib Erlotinib Investigational TKI IRC Assessment N=20 8 (40%; 19.1%−63.9%) 8 (40) 10(50) 4/13 (31) 2/4 (50) 1/4 (25) 1/2 (50) 1/1 (100) Data cutoff date: November 1, 2020. IRC, independent review committee; NA, not available; ORR, objective response rate; PR, partial response; SD, stable disease; TK I, tyrosine kinase inhibitor. a Confirmed ORR defined as the proportion of the patients who are confirmed to have achieved complete or partial response after the initiation of study treatment; confirmed responses are those that persist on repeat imaging 4 weeks (allowing a minus 3-day window) or more after initial response. • ORR by RECIST v1.1 per investigator (primary endpoint) is 20% (95% CI, 5.7%−43.7%) • • DZD9008 PROMISING FOR ADVANCED NSCLC WITH EGFR EXON 20 INSERTIONS Pasi Jänne, MD, PhDReference: COSELA (trilaciclib). Prescribing Information. G1 Therapeutics, Inc; 02/2021. G1 Therapeutics™ and the G1 Therapeutics logo, COSELA™ and the COSELA logo are trademarks of G1 Therapeutics, Inc. ©2021 G1 Therapeutics, Inc. All rights reserved. US-2100258 07/2021 SPARE THE MARROW. COSELA HELPS PROTECT AGAINST MYELOSUPPRESSION, PROACTIVELY HELP PROTECT AGAINST MULTIPLE MYELOSUPPRESSIVE CONSEQUENCES WITH THE FIRST AND ONLY MYELOPROTECTION THERAPY The Pivotal Study (Study 1) compared an etoposide/carboplatin + atezolizumab (E/P/A) regimen with COSELA vs without COSELA* To decrease the incidence of chemotherapy-induced myelosuppressionin patients when administered prior to a platinum/ etoposide-containing regimen or topotecan-containing regimen FOR EXTENSIVE-STAGE SMALL CELL LUNG CANCER (ES-SCLC) COSELA™ (trilaciclib) helps protect hematopoietic stem and progenitor cells (HSPCs), the source of blood cell lineages INDICATION COSELA is indicated to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide-containing regimen or topotecan-containing regimen for extensive-stage small cell lung cancer (ES-SCLC). * COSELA was evaluated in 3 randomized, double-blind, placebo-controlled clinical studies. The Pivotal Study (Study 1) evaluated COSELA or placebo administered prior to treatment with E/P/A in 107 patients with newly diagnosed ES-SCLC not previously treated with chemotherapy. In this study, COSELA significantly reduced the primary endpoints of incidence (adjusted relative risk [aRR] 0.038 [95% CI, 0.008, 0.195], P<0.0001) and duration in Cycle 1 (mean difference -3.6 [95% CI, -4.9, -2.3], P<0.0001) of severe neutropenia and significantly decreased the rate of all-cause chemotherapy dose reductions (aRR 0.242 [95% CI, 0.079, 0.742]). The incidence of Grade 3/4 anemia was 19% and 28% (aRR 0.663 [95% CI, 0.336, 1.310]) and RBC transfusions on/after 5 weeks were 13% and 21% (aRR 0.642 [95% CI, 0.294, 1.404]) with and without COSELA, respectively. VISIT COSELA.COM FOR MORE DETAILSTo report suspected adverse reactions, contact G1 Therapeutics at 1-800-790-G1TX or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. This information is not comprehensive. Please see the Brief Summary of Prescribing Information on the adjacent page. SPEAR THE TUMOR. WHILE CHEMOTHERAPY TARGETS CANCER CELLS SELECT IMPORTANT SAFETY INFORMATION CONTRAINDICATION • COSELA is contraindicated in patients with a history of serious hypersensitivity reactions to trilaciclib. WARNINGS AND PRECAUTIONS Injection-Site Reactions, Including Phlebitis and Thrombophlebitis • COSELA administration can cause injection-site reactions, including phlebitis and thrombophlebitis, which occurred in 56 (21%) of 272 patients receiving COSELA in clinical trials, including Grade 2 (10%) and Grade 3 (0.4%) adverse reactions. Monitor patients for signs and symptoms of injection-site reactions, including infusion-site pain and erythema during infusion. For mild (Grade 1) to moderate (Grade 2) injection-site reactions, flush line/cannula with at least 20 mL of sterile 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after end of infusion. For severe (Grade 3) or life-threatening (Grade 4) injection-site reactions, stop infusion and permanently discontinue COSELA. Injection-site reactions led to discontinuation of treatment in 3 (1%) of the 272 patients. Acute Drug Hypersensitivity Reactions • COSELA administration can cause acute drug hypersensitivity reactions, which occurred in 16 (6%) of 272 patients receiving COSELA in clinical trials, including Grade 2 reactions (2%). Monitor patients for signs and symptoms of acute drug hypersensitivity reactions. For moderate (Grade 2) acute drug hypersensitivity reactions, stop infusion and hold COSELA until the adverse reaction recovers to Grade ≤1. For severe (Grade 3) or life-threatening (Grade 4) acute drug hypersensitivity reactions, stop infusion and permanently discontinue COSELA. Interstitial Lung Disease/Pneumonitis • Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with cyclin- dependent kinases (CDK)4/6 inhibitors, including COSELA, with which it occurred in 1 (0.4%) of 272 patients receiving COSELA in clinical trials. Monitor patients for pulmonary symptoms of ILD/pneumonitis. For recurrent moderate (Grade 2) ILD/ pneumonitis, and severe (Grade 3) or life-threatening (Grade 4)ILD/pneumonitis, permanently discontinue COSELA. Embryo-Fetal Toxicity • Based on its mechanism of action, COSELA can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should use an effective method of contraception during treatment with COSELA and for at least 3 weeks after the final dose. ADVERSE REACTIONS • The most common adverse reactions (≥10%) were fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia. 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