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Carlos Carracedo Gonzales

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    PC04 - Is Chemotherapy Necessary for Advanced NSCLC Patients With PD-L1 50% or More? (ID 86)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
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      PC04.01 - Pro: Chemotherapy Is Necessary (Now Available) (ID 3571)

      11:30 - 13:00  |  Presenting Author(s): Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Abstract

      As first-line therapy single agent pembrolizumab showed better outcomes than chemotherapy (CT) in patients with NSCLC and PD-L1 expression ≥50% [1]. Recently has been published another phase 3 trial in which patients with aNSCLC with an expression of PD-L1 ≥1%, treated with pembrolizumab as single agent, results in better overall survival (OS) than CT in first-line, mainly in subgroup with PD-L1 ≥50% [2].

      After the approval and subsequent use of pembrolizumab as single agent in first-line in NSCLC with PD-L1 ≥50%, in 2018 several phase III trials explored the combination of immunotherapy agents (pembrolizumab and atezolizumab), with no regards of PD-L1 status, in association with standard CT, gaining better outcomes than CT alone in first-line NSCLC [3-8].

      A matter of debate is what we have to do in patients with PD-L1 ≥50% due to the absent comparison between combination therapy and ICI as single agent and similar results in 1-year OS among these treatments [1,3-4].

      So, why should we suggest the use of combination over ICIs as single agent in patients with PD-L1 ≥50% in first-line?

      First of all, we can see that trials of combination therapy report benefit with CT plus ICI across all PD-L1 subgroups, with a greater magnitude of benefit in patients with PD-L1 ≥50% with no regards of kind of drugs used (either CT and ICI) and histology (squamous or non-squamous) [3-8]. This magnitude of benefit is supported from an higher objective-response rate (ORR) in patients treated with combination therapy over ICI as single agent in subgroups of patients with PD-L1 ≥50% [1-4], suggesting combination therapy as best choice even in patients with highly symptomatic disease with the purpose of obtaining a fast shrinkage of tumor.

      Analyzing Kaplan-Meyer curves of single agent trials [1,2], you can observe that there is a violation of proportional hazard assumptions. We can see a crossing of the curves within first 3-6 months suggesting us that there’s a subgroup of patients who have a worse prognosis when treated with single agent immunotherapy over CT. This worse prognosis could be possibly partially due to a phenomenon called hyperprogressive disease [9], a quicken tumor growth during treatment with ICIs in NSCLC irrespectively of the line of therapy. If we look at Kaplan-Meyer curves of all combination studies, we can see that the combination of CT plus ICI abrogates the crossing curves [3,4,6,8], probably overcoming hyperprogessive disease with the addiction of CT by modulating tumor microenvironment.

      In subgroups of patients with liver and/or brain metastases, generally considered at worse prognosis, combination therapy demonstrates a benefit. In a retrospective analysis of KEYNOTE189 [10] were evaluated outcomes of patients with brain and/or liver metastases. In this analysis the addiction of pembrolizumab to CT grants a benefit over CT alone either in progression-free survival, OS and ORR in patients with liver and/or brain metastases. Another evidence of benefit in patients with liver metastases in combination therapy was seen in IMpower150, in which the addiction of atezolizumab to bevacizumab plus CT seemed to add something even though there’s a bias due to the use of bevacizumab [5].

      In advanced NSCLC treated with ICI as single agent [1,2] we see a lower benefit in non-smoker than in current or former smoker patients, whilst in combination studies this difference isn’t seen regardless kind of drug and histology [3,6-8].

      Even gender may be a possible reason to choose combination instead of ICI as single agent. As we previously do for smoking habit, we indirectly compare trials with single agent and with combination. We can see that in KEYNOTE024 there’s a stronger benefit using pembrolizumab in males over females. This reported benefit for male patients is lost in combination treatment, with slight better outcomes in women instead, with no regards of drugs used and histology [3,4,6-8].

      Finally, basing on preclinical evidences, we know that the combination between CT and ICIs may enhance the immune system activity due to immunological effect of cytotoxic agents through the expression of PD-L1 on the surface of tumor cells, the depletion of myeloid-derived suppressor cells and T-regulatory cells and the augmentation of the presentation of antigens by cancer cells [10].

      At the state of the art the aim of our discussion remains an unanswered question but based on what we previously said, at least in patients with high tumor burden, in never smokers, we suggest CT plus ICI as first-line in aNSCLC with PD-L1 ≥50%.This could allow us not to lose patients in the first six months of treatment.

      [1] Reck M et al.Pembrolizumab versus chemotherapy for PD-L1 positive non-small cell lung cancer. NEJM 2016; 375: 1822-1833

      [2] Mok TSK et al. Pembrolizumab versus chemotherapy for previously untreated , PD-L1 expressing, locally advanced or metastatic non-small cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019; 393: 1819-1830

      [3] Gandhi L et al. Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer. NEJM 2018; 378: 2078-2092

      [4] Paz-Ares L et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. NEJM 2018; 379: 2040-2051

      [5] Socinski MA et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. NEJM 2018; 378(24): 2288-2301

      [6] Cappuzzo F et al. IMpower130: efficacy and safety from a randomise phase 3 study of carboplatin and nab-paclitaxel with or without atezolizumab in 1L advanced non-squamous NSCLC. Presented at ESMO 2018

      [7] Jotte R et al. IMpower131: primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. Presented at ASCO 2018

      [8] Papadimitrakopoulou VA et al. IMpower132: PFS and safety results with 1L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. Presented at WCLC 2019

      [9] Proto C et al. Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out. Cancer Treat Rev 2019; 75:39-51

      [10] Garassino MC et al. Outcomes among patients with metastatic nonsquamous NSCLC with liver metastases or brain metastases treated with pembrolizumab plus pemetrexed-platinum: results from the KEYNOTE-189 study. Presented at AACR 2019

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      PC04.02 - CON: ICI Is Enough (Now Available) (ID 3572)

      11:30 - 13:00  |  Presenting Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Abstract

      The implementation of anti PD-1 / anti PD-L1 checkpoint inhibitors has completely changed management of patients with advanced non-small-cell lung cancer (NSCLC). On the way to an individualized use of these agents a correlation between the PD-L1 expression on tumor cells and immune cells and efficacy of immunotherapies could be demonstrated across different agents and treatment lines.

      In particular a clear correlation between survival and PD-L1 expression on tumor cells (TPS-score) has prospectively been evaluated and validated for the anti-PD1 antibody pembrolizumab defining a TPS score of =/> 50% as a predictor for enhanced outcome by pembrolizumab and showing impressive 4 and 5 year overall survival rates for untreated patients with a TPS-Score of =/> 50% of 48% and 29.6% respectively (1,2).

      Two prospectively randomized phase III trials confirmed the superior efficacy of pembrolizumab monotherapy with a significant prolongation of overall survival compared to platinum based chemotherapy in untreated patients with a TPS-score of =/> 50% (3,4).

      Recently the concept of combining immunotherapies with chemotherapies has demonstrated superior efficacy compared to chemotherapy patients with advanced NSCLC independent from the PD-L1 expression and the question appears, whether such a combination would also be the preferred treatment for the selected group of patients with a TPS-score of =/>50%.

      Analysing this question a couple of points need to be addressed:

      First of all this important question has never been addressed appropriately in a prospective trial and in none of the combination trials a immunotherapy monotherapy arm was part of investigated schedule. Therefore all assumptions remain subjective and exploratory.

      Second: We have seen a dramatic improvement of survival expectation together with a relevant prolongation of treatment duration by the adaption of immunotherapies in management of advanced NSCLC. Therefore tolerability, symptom control and quality of life become essential parameters for feasibility of treatment. Across all chemo-immunotherapy combination trials the frequency of CTC grade 3-5 treatment related adverse events (TRAEs) was substantially higher compared to the pembrolizumab monotherapy arms. In particular in an updated report of the Keynote 189 trial the frequency of TRAEs grade 3-5 was 71.9% for the combination of pembrolizumab and chemotherapy compared to 17.8% in the Keynote 42 trial and 31.2% in the Keynote 24 trial leading to a treatment discontinuation rate of 33.6% compared to 9% and 13.6% in the Keynote 42 and 24 trial (4,5,6).

      Considering the symptomatic efficacy ICI monotherapy has shown a clinical relevant improvement of symptoms during treatment compared to chemotherapy assessed by the QLA-C30 GHS/QOL score together with a substantial prolongation of time to symptom deterioration in the Keynote-24 (7). This unique pattern of symptomatic efficacy, which clearly reflects the patient related impact of anti tumor therapy has so far not been to that extent for the combination trials.

      Third: Besides the impressive activity demonstrated by the use of first line chemo-immunotherapy combinations we are confronted with the rapidly emerging clinical problem, that we suffering effective and tolerable post progression treatment opportunities. So far no specific treatment approaches are available and mostly we are ending up with the use of limited effective docetaxel +/- an antiangiogenic agent. In contrast a first line ICI monotherapy offers the opportunity of a post progression full dosed platinum based combination treatment with clearly higher efficacy compared to docetaxel alone.

      Fourth: Currently the most appropriate endpoint to assess efficacy of immunotherapies remains to be determined and we have seen in various trials that response and PFS might not be the optimal endpoints. In contrast it is general accepted the survival represents the most eminent and meaningful endpoint. Looking on the survival results of the different trials the differences in follow up periods need to be taken into account leading potential differences in the assessment of survival times. However respecting the lack of prospective randomised trials it appears that no benefit in survival in particular long term survival could be generated by the addition of chemotherapy to immunotherapy in the group of patients with a TPS-score =/> 50%. In an exploratory analysis of the Keynote 189 trial the 2 year OS rate for patients with a TPS-score =/> 50% was 51.9% for the combination of chemotherapy and pembrolizumab compared to 51.5% and 44.7% for pembrolizumab monotherapy in the Keynote-24 and -42 trial. Furthermore also the Hazard ratios were comparable across the trials (HR 0.59 for Keynote-189 compared to HR 0.63 and 0.69 in Keynote-24 and -42).

      In summary ICI monotherapy represents the preferred new highly effective and well tolerable first-line treatment opportunity in untreated patients with a TPS-score of =/> 50%. Addition of chemotherapy is associated with poorer tolerability and in particular long-term tolerability.

      Ongoing research might define the few patients, where tumor control cannot be achieved by ICI monotherapy.

      1. Garon EB, Rizvi NA, Rui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372 (2015): 2018-2018

      2. Garon EB, Hellmann MD, Rizvi NA et al: Five-Year Overall Survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I Keynote-001 studay. J Clin Oncol (2019): e-published June 2, 2019-06-01

      3. Reck M, Rodriguez-Abreu D, Robinson AG et al: Pembrolizumab versus chemotherapy for PD-L1 positive non-small-cell lung cancer. N Engl J Med (2016): 1823-1833.

      4. Mok TSK, Wu Y-L, Kudaba I et al: Pembrolizumab versus chemotherapy for previously untreated PD-L1-expressing locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet (2019): 1819-1830.

      5. Gadgeel S, Garrassino MC, Esteban E, et al: Keynote-189: Updated overall survival and progression after the next line of therapy with pembrolizumab plus chemotherapy with pemetrexed and platinum vs placebo plus chemotherapy for metastatic nonsquamous NSCLC: ASCO 2019, abstract 9013

      6. Reck M, Rodriguez-Abreu D, Robinson AC et al: Updated analysis of Keynote-024: Pembrolizumab vers platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 Tumor Poportion Score of 50% or greater: J Clin Oncol 37 (2019): 537-546

      7- Brahmer J, Radriguez-Abreu D, Robinson AG et al: Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (Keynote-024): a multicentre, intenational, randomised, open-label phase 3 trial. Lancet Oncology 18 (2017): 1600-1609.

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    EP1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 206)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.16-11 - Immunotherapy in NSCLC: Real World Experience in a Peruvian Population (Now Available) (ID 1035)

      08:00 - 18:00  |  Presenting Author(s): Carlos Carracedo Gonzales

      • Abstract
      • Slides

      Background

      Checkpoint inhibitors drugs, have achieved positive results above chemotherapy in 2nd line and 1st line for specific populations with lung cancer. Nowadays, investigations continue studying biomarkers which could be useful as predictive factors of response as if inflammatory markers might have some role.

      Method

      The study design included patients with non-small cell lung cancer (NSCLC) that receivedimmunotherapy with “Pembrolizumab” or “Nivolumab” in two private cancer centers of reference since January 2015 until January 2018. The adverse effects were evaluated by medical oncologists and classified by CTCAE v 4.0. The response were assessed by RECIST criteria. Furthermore, inflammatory markers results were obtained from blood work performed before immunotherapy started. All patients that received at least one dose of immunotherapy were taken into analysis.

      Result

      A total of 158 patients with lung cancer were diagnosed in that period, only 18 patients were assessed, the mean age was 62, and the vast majority had adenocarcinoma. The mean number of cycles was 27 (2-52). The ORR was of 28% , 80% had partial response (PR) and 20% had complete response (CR). Thirty-nine percen had stable disease (SD) while 33% had progressive disease (PD). The median of time to achieve a response was of 11.5 weeks. The response according to the PD-L1 expression was stratified, founding clinical benefit in all the groups. The time to progression since immunotherapy was 15weeks. One case was reported as unconfirmed progressive disease by week 10.

      Markers of inflammation analyzed showed Neutrophil-lymphocyte rate (NLR) and Platelet-lymphocyte rate (PLR) means were 4.37 (1.42 – 21.6) and 270.19 (93.1-650.7)respectively. The values obtained according to response found that the group that progressed to therapy had 4.23 NLR and 343.9 PLR. The group who had clinical benefit, had 4.39 NLR and 229.9 PLR. 33% of the population present toxicity, from which 83% was graded G1-2 and 17% G3-4.

      Conclusion

      A high PLR might be associated with an unfavorable prognosis although more studies are needed. This is the first study in Peruvian population that shows results of immunotherapy in lung cancer.

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