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M. Hellmann, L. Paz-Ares, R. Caro, B. Żurawski, Sang-We Kim, E. Costa, Keunchil Park, A. Alexandru, L. Lupinacci, E. Jimenez, H. Sakai, I. Albert, A. Vergnenègre, S. Peters, K. Syrigos, F. Barlesi, M. Reck, H. Borghaei, J. Brahmer, K. O'Byrne, W. Geese, P. Bhagavatheeswaran, S. Rabindran, R. Kasinathan, F. Nathan, S. Ramalingam (2019)
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Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations
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short review memo https://doi.org/10.1007/s12254-020-00589-x Lena Horvath · Andreas Pircher Received: 22 January 2020 / Accepted: 25 February 2020 © The Author(s) 2020 Summary This article intends to summarize personal translational aspect focused on the identification of non-small cell lung cancer (NSCLC) highlights of the biomarkers for immunotherapy use and the charac- ESMO 2019 meeting. Again, immunotherapy in the terization as well as treatment of druggable genetic al- first-line setting of wildtype NSCLC was a major as- terations. It is becoming apparent that primary or sec- pect and the search of the optimal biomarker for ther- ondary resistance mechanism against immunother- apy stratification continues. Moreover, important data apy as well as targeted therapies can be most likely on the use of osimertinib, a third-generation epider- overcome via rationale combinational therapies. mal growth factor receptor (EGFR) inhibitor in the Due to better treatment options and the plethora first-line setting of EGFR-mutated NSCLC were pre- of highly effective drugs, the discussion on the right sented, emerging as the preferred therapeutic strat- treatment sequence becomes overt and increasingly egy in these patients. The ideal treatment sequence, important to further improve patient care. however, remains discussed controversially. The treat- ment of rare genetic alterations was another impor- Advanced stage non-small cell lung cancer tant topic, covering updated data on effective NTRK and ROS1 inhibition. In conclusion, ESMO 2019 fu- Immunotherapy first line without driver alterations eled the lung cancer community with inspiring new data, contributing to a more individualized, hopefully Two interesting studies (update on CheckMate 227 improved lung cancer treatment and continuing to and IMpower110) were presented, using PD-L1 ex- decrease lung cancer mortality. pression as a biomarker to guide immunotherapy in the first-line setting [1, 2]. Keywords EGFR · Osimertinib · NTRK · Ipilimumab · Nivolumab · Atezolizumab · NSCLC CheckMate 227 Cohorts of the CheckMate 227 have already been presented at earlier meetings [3, 4]and this presentation focused on the analysis of another Introduction co-primary endpoint. In general, the CheckMate 227 ESMO 2019 took place in Barcelona from 27 Septem- is an open-label first-line trial with six cohorts of ber to 1 October 2019 and again, treatment of non- nivolumab-based regimens compared with standard small cell lung cancer (NSCLC) was a major aspect chemotherapy in patients with stage IV or recurrent of the meeting. The congress was held under the NSCLC. The study design is complex and therefore tagline “Translating science into better cancer patient we refer to the main publications for further de- care” and intended to bridge basic research and clin- tails [3–5]. Part 1 of the trial comprises 2 cohorts ical–oncological therapy. With regard to NSCLC, the stratified by PD-L1 expression: patients with PD-L1 expression ≥1% (part 1a) and PD-L1 expression <1% (part 1b). In part 1a, 1189 patients were randomized Dr. L.Horvath ·PD Dr. A. Pircher () 1:1:1 to receive either histology-based chemotherapy Department of Hematology and Oncology, Internal (n = 397), nivolumab alone (n = 396) or nivolumab Medicine V, Medical University of Innsbruck, plus low-dose ipilimumab (n = 396). In part 1b, Anichstraße 35, 6020 Innsbruck, Austria andreas.pircher@i-med.ac.at 550 patients were randomized to nivolumab/low- K ESMO update 2019: lung cancer short review dose ipilimumab (n = 187), chemotherapy (n = 186) high group is limited as pembrolizumab monother- or nivolumab/chemotherapy (n = 177). Nivolumab apy is an already well-established therapy option with was administered at 3 mg/kg every 2 weeks. In the more favorable toxicity profile compared to the ICI combination arm ipilimumab was given at 1 mg/kg combo. Although not evaluated as a study endpoint, every 6 weeks. The independent co-primary end- the advantage of ICI combination in a PD-L1 negative points of the study focused on comparing nivolumab setting is worth being discussed as a good treatment plus ipilimumab versus chemotherapy and comprised alternative for patients who do not want to be treated progression-free survival (PFS) in a high tumor mu- with chemotherapy. tational burden (TMB) population (i.e., >10 mut/Mb) and overall survival (OS) in the PD-L1 ≥1% popu- IMpower110 A second interesting presentation was lation. Secondary endpoints included PFS and OS the IMpower110 phase III study evaluating ate- with nivolumab/chemotherapy versus chemotherapy zolizumab as first-line treatment in PD-L1 selected in the PD-L1 <1% subgroup, and OS with nivolumab patients with advanced NSCLC, independent of tu- versus chemotherapy in patients with PD-L1 expres- mor histology. The study enrolled 572 patients with sion ≥50%. Data on the co-primary endpoint PFS chemotherapy-naïve stage IV NSCLC with PD-L1 ex- had already been published before ESMO 2019 and pression ≥1% on tumor cells (TC) or immune cells showed a significant PFS benefit for nivolumab plus (IC). Patients were randomized 1:1 to receive either ipilimumab in patients with a high TMB compared to atezolizumab 1200 mg every 3 weeks (arm A) or 4 or chemotherapy. However, this observation could not 6 cycles of platinum-based chemotherapy (arm B). be transferred to final OS data in which PD-L1-high Primary endpoint of the study was OS by hierarchi- and TMB-high patients showed similar OS results as cal clustering, with the analysis of the TC3 or IC3 PD-L1-low and TMB-low patients. subgroup preceding evaluation of the TC2/3 or IC2/3 At the current ESMO meeting, Peters et al. [1] group, which again preceded the TC1/2/3 or IC1/2/3 presented the OS data of the PD-L1 ≥1% population group. The TC3 or IC3 population was defined as PD- and the study met its primary endpoint. Median L1 expression ≥50% on tumor cells (TC3) or ≥10% on OS was 17.1 versus 14.9 months in the nivolumab/ tumor-infiltrating immune cells (IC3). ipilimumab arm compared to chemotherapy alone At ESMO 2019 D. Spigel [2]presented an interimOS (HR for nivolumab/ipilimumab vs. chemotherapy, analysis of the TC3 and IC3 subgroup, showing an im- 0.79; 97.72% CI, 0.65–0.96). Moreover, median OS proved OS for atezolizumab monotherapy compared was 17.1 months with the combination therapy and to platinum-based chemotherapy as a first-line treat- 13.9 months with chemotherapy in patients regard- ment in patients with wild-type NSCLC. At a median less of PD-L1 expression status (HR, 0.73; 95% CI, follow-up of 15.7 months (range, 0–35 months), me- 0.64–0.84). Results also showed that in patients with dian OS was 20.2 months (95% CI, 16.5–not evaluable) PD-L1 expression ≥1%, the 1- and 2-year OS rates for the atezolizumab arm, compared to 13.1 months were 63 and 40% with nivolumab/ipilimumab and (95% CI, 7.4–16.5) in the chemotherapy arm (HR, 0.59; 56 and 33% with chemotherapy, respectively. The 95% CI, 0.40–0.89; P = 0.0106). The OS testing bound- median duration of response (DOR) by blinded inde- ary was not crossed in the TC2/3 or IC2/3 wild-type pendent central review was 23.2 and 6.2 months for population; therefore, OS was not formally tested in nivolumab/ipilimumab and chemotherapy, respec- this population as well as in the TC1/2/3 and IC1/2/3 tively. populations. Median PFS was 8.1 months (95% CI, In part 1b, patients with PD-L1-negative NSCLC 6.8–11.0) in the atezolizumab arm versus 5.0 months also had a numeric advantage of the immune check- (95% CI, 4.2–5.7) in the chemotherapy arm (HR, 0.63; point inhibitor (ICI) combination, showing a median 95% CI, 0.45–0.88; P = 0.007) in the TC3/IC3 wild-type OS of 17.2 months for nivolumab/ipilimumab versus population; the confirmed ORR was 38.3% vs. 28.6%, 12.2 months with chemotherapy (HR for nivolumab/ respectively; the median DOR was not reached versus ipilimumab vs chemotherapy, 0.62; 95% CI, 0.48–0.78; 6.7 months, respectively. HR for nivolumab/chemotherapy vs chemotherapy, The authors of the study concluded that ate- 0.78; 95% CI, 0.60–1.02). zolizumab represents a promising first-line treatment In regards of tolerability, no new safety findings for option in NSCLC patients with high PD-L1 expression. the combination were reported within longer follow- Interestingly, this study showed for the first time that up. Grade 3/4 treatment-related adverse events were PD-L1 expression on immune cells plays an impor- reported in 33 and 36% of patients in the nivolumab/ tant role in therapy stratification and can also be used ipilimumab versus chemotherapy arms, respectively. as predictive biomarker. However, we have to await In conclusion, this study could show an OS ben- how these data will be integrated into our common efit for the ICI combination therapy compared to treatment approach of PD-L1 high patients. Lastly, chemotherapy, independent of PD-L1 expression. IMpower 110 could show the applicability of the less Clinically meaningful benefits were documented in commonly used PD-L1 score TC3/IC3 (IHC antibody the two subgroups of PD-L1 high (>50%) and PD-L1 Ventana SP142) in this patient setting. Due to the widespread use of the PD-L1 TPS score (IHC antibody negative NSCLC. However, clinical utility in the PD-L1 ESMO update 2019: lung cancer K short review Dako 22C3) it would be beneficial for clinical practice Take-home messages to validate the study results with the latter biomarker. Nivolumab/Ipilimumab combination improves OS compared to chemotherapy independent of PD-L1 Targeted therapies in genetically driven NSCLC status and presents a potential chemotherapy-free Frontline EGFR inhibition represents the gold stan- option as r fi st-line treatment of selected NSCLC IV dard therapy in EGFR-mutated NSCLC and up to now patients. three different generations of EGFR inhibitors have Atezolizumab improves OS in PD-L1 high wild- been approved. type NSCLC in the r fi st-line setting compared to The FLAURA study is a landmark study [6], which chemotherapy. proved that the third generation irreversible EGFR-ty- Osimertinib prolongs OS in EGFR-mutated NSCLC IV rosine kinase inhibitor (TKI) osimertinib significantly and evolves as new r fi st-line treatment standard. prolonged PFS compared to first generation EGFR-TKI Entrectinib shows high efcacy fi in NTRK and ROS1- erlotinib or gefitinib (18.9 months versus 10.2 months; mutated NSCLC. Mutational screening should be HR 0.42). At the first FLAURA presentation 2018, OS warranted. data were not yet mature and at ESMO 2019 S. Ra- Funding The review was supported by the “Verein für Tu- malingam presented the final OS results [7]. FLAURA morfoschung”, Anichstraße 35, Innsbruck, Austria. could translate the PFS benefit into a significant OS benefit (38.6 months versus 31.8 months; HR 0.79), Funding Open access funding provided by University of Inns- proving clinically meaningful OS benefit for the first bruck and Medical University of Innsbruck. time in this setting. As OS was a secondary endpoint Conflict of interest L. Horvath has no conflicts of interest to of the study it was not powered for all subgroups. declare. A. Pircher has received speaker’s fees and honoraria However, most subgroups gained OS benefit from os- for advisory boards from Astra Zeneca, BMS, Roche, Pfizer, imertinib compared to erlotinib and gefitinib. Takeda and MSD. Regarding subsequent therapies after disease pro- Open Access This article is licensed under a Creative Com- gression, around 30% of patients did not receive a sec- mons Attribution 4.0 International License, which permits ond-line therapy in either arm. The predominant sec- use, sharing, adaptation, distribution and reproduction in ond-line therapy was osimertinib (47%) in the control any medium or format, as long as you give appropriate credit arm and cytotoxic therapy (68%) in the osimertinib to the original author(s) and the source, provide a link to arm. The toxicity profile showed no new signs over the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article time and good tolerance. are included in the article’s Creative Commons licence, unless In conclusion, FLAURA shows that osimertinib is indicated otherwise in a credit line to the material. If material the preferred agent in the first-line setting of EGFR- is not included in the article’s Creative Commons licence and mutated NSCLC. Nevertheless, the optimal treatment your intended use is not permitted by statutory regulation or sequence and other questions, such as synergistic exceeds the permitted use, you will need to obtain permis- combinational partners, remain open and controver- sion directly from the copyright holder. To view a copy of this sially discussed. licence, visit http://creativecommons.org/licenses/by/4.0/. In the setting of rare mutations, updated data on the subgroups of NTRK-positive and ROS1-rearranged References NSCLC were presented [8]. 1. Peters S, Ramalingam SS, Paz-Ares L, et al. LBA4_PRNivolu- In NTRK-positive NSCLC (n = 10), entrectinib mab (NIVO) + low-dose ipilimumab (IPI) vs platinum- showed an ORR of 70% with a complete response doublet chemotherapy (chemo) as first-line (1L) treatment rate (CRR) of 10% and a partial response rate (PRR) (tx) for advanced non-small cell lung cancer (NSCLC): of 60%. In ROS1-positive NSCLC patients entrectinib CheckMate 227 part 1 final analysis. Ann Oncol. showed an ORR of 79.2% with an CRR of 9.4%. The 2019;30:v851–v934. https://doi.org/10.1093/annonc/ median DOR was 24.6 months (95% CI 12.6–34.8), mdz394 median PFS was 19.0 months (95% CI 12.2–29.6), 2. SpigelD,deMarinisF,GiacconeG,etal. LBA78IMpower110: Interim overall survival (OS) analysis of a phase III study and median OS was not estimable (95% CI 30.8–NE). of atezolizumab (atezo) vs platinum-based chemotherapy These results underline the high efficacy of entrec- (chemo) as first-line (1L) treatment (tx) in PD-L1–selected tinib in NTRK-positive and ROS1-rearranged NSCLC. NSCLC. Ann Oncol. 2019;30:v851–v934. https://doi.org/ Furthermore, these studies highlight the significance 10.1093/annonc/mdz394 of broad molecular testing in NSCLC patients and 3. Borghaei H, Hellmann MD, Paz-Ares LG, et al. Nivolumab that patients with molecular alterations should be (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non- treated with specific inhibitors as response rates are smallcelllungcancer (NSCLC) with 〈1% tumor PD-L1 high and long-lasting. Nevertheless, long-term effi- expression: Results from CheckMate 227. J Clin Oncol. cacy has to be proven and the optimal sequence has 2018;36:9001–9001. to be established. K ESMO update 2019: lung cancer short review 4. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab Ann Oncol. 2019;30:v602–v660. https://doi.org/10.1093/ plus Ipilimumab in lung cancer with a high tumor muta- annonc/mdz260 tional burden. N Engl J Med. 2018;378:2093–104. Publisher’s Note Springer Nature remains neutral with regard 5. HellmannMD,Paz-AresL,BernabeCaroR,etal. Nivolumab to jurisdictional claims in published maps and institutional plus ipilimumab in advanced non-small-cell lung cancer. affiliations. N Engl J Med. 2019;381:2020–31. 6. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113–25. 7. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall For latest news from interna- survival with osimertinib in untreated. N Engl J Med. tional oncology congresses see: 2020;382:41–50. http://www.springermedizin.at/ 8. de Braud F, Siena S, Barlesi F, et al. 64PEntrectinib in lo- memo-inoncology cally advanced/metastatic ROS1 and NTRK fusion-positive non-small cell lung cancer (NSCLC): Updated integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. ESMO update 2019: lung cancer K
memo - Magazine of European Medical Oncology – Springer Journals
Published: Mar 20, 2020
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