Virtual Library

Start Your Search

Alejandro Navarro

Moderator of

  • +

    MS09 - Immunotherapy in Small Cell Lung Cancer (ID 72)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 3
    • Now Available
    • +

      MS09.01 - Immune Checkpoint Blockade for SCLC: State of the Art (Now Available) (ID 3487)

      14:00 - 15:30  |  Presenting Author(s): Scott J. Antonia

      • Abstract
      • Presentation
      • Slides

      Abstract

      It is clear that small cell lung cancer can be an immunotherapeuticly responsive disease. Single agent anti-PD1 and anti-PD-L1 can produce tumor regressions. Anti-PD-L1 given in combination with chemotherapy produces a survival benefit when given as first-line therapy for extensive stage disease. Anti-PD1 is also an option in third line. Although responses are produced in the second line setting neither anti-PD1 nor anti-PD-L1 has proven to produce a survival benefit in unselected patients. The proper application of relevant biomarkers such as TMB has the potential to identify patients who are likely to benefit. Given the fact that small cell lung cancer tumors have a paucity of tumor infiltrating lymphocytes, it is not surprising that immunotherapeutics solely directed at the immune suppressed tumor microenvironment have limited clinical activity. It is likely that combination immunotherapy, with a component of the combination influencing the lymphoid compartment to increase the number of tumor reactive T cells will be necessary to significantly increase the clinical activity of immune-based therapies. There are several potential ways that this could be accomplished. Anti-CTLA.4 can have an impact on regulatory T cells in the tumor microenvironment, however at least in melanoma it has been shown to be operational within the lymphoid compartment as well to increase circulating tumor reactive T cells. Anti-CTLA.4 has been combined with both anti-PD1 and anti-PD-L1. Response rates of the combination have been higher than what can be produced with anti-PD 1 monotherapy. The combination has not yet been shown to produce a survival advantage. Another approach to increasing tumor reactive T cells is to utilize radiation which can release tumor antigens and immunogenic fashion. Trials are ongoing combining radiation with anti-PD1 and anti-CTLA.4. Vaccines offer another potential means to accomplish expansion of tumor reactive T cells. An autologous dendritic cell based vaccine with p53 as the tumor antigen has been shown to produce clinical responses in small cell lung cancer as monotherapy, and is now being combined with anti-PD1 and anti-CTLA.4. An alternative approach is to redirect peripheral T cells through ex vivo transduction with tumor protein-specific antigen binding molecules. An example of this is a chimeric antigen receptor specific for DLL 3. These sorts of combinations have the potential to advance the efficacy of immunotherapy for small cell lung cancer.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MS09.02 - Clincal and Molecular Biomarkers for Selection of Sclc Patients Candidate to Immunecheckpoint Blockade (Now Available) (ID 3489)

      14:00 - 15:30  |  Presenting Author(s): Lauren Averett Byers

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immunotherapy has dramatically altered the treatment options available to patients with lung cancer. In the past year, small cell lung cancer (SCLC) fully joined the immunotherapy era with approvals by the US Federal Drug Administration (FDA) for three separate immune checkpoint inhibitors – atezolizumab for frontline therapy in patients with extensive stage SCLC (ES-SCLC) (in combination with platinum-etoposide chemotherapy) and nivolumab and pembrolizumab (each as monotherapy) for relapsed SCLC. The combination of nivolumab plus ipilimumab also demonstrated durable activity in a subset of patients treated on the Phase 1/2 CheckMate032 trial, with an overall response rate of 22% and a 2 year overall survival rate of 26%.1 The addition of atezolizumab to carboplatin and etoposide as a new standard of care was based on results from the Phase 3 IMpower133 trial.2 In that randomized trial, the addition of atezolizumab to carboplatin-etoposide, followed by atezolizumab maintenance, led to improvements in both progression free survival (PFS) (4.3 months in the placebo control arm versus 5.2 months in patients receiving atezolizumab) and overall survival (OS) (10.3 months with placebo versus 12.3 months with atezolizumab). Additional randomized trials testing other immune checkpoint inhibitors in combination with standard platinum-etoposide chemotherapy are ongoing, with clinical findings expected in the next several months. This includes the phase 3 trial of durvalumab plus platinum-etoposide (CASPIAN), which has now been reported to show improved overall survival (OS) with the addition of durvalumab at a planned interim analysis (press release).

      Despite these landmark approvals for immune checkpoint inhibitors in ES-SCLC, a large number of patients with SCLC do not appear to receive clinic benefit with the currently available inhibitors of PD-1/PD-L1 and/or CTLA-4. Furthermore, there are not yet established biomarkers for identifying those patients with SCLC who are likely to respond. As with non-small cell lung cancer, immunohistochemistry (IHC) for PD-L1 levels and tumor mutation burden (TMB) are both candidate biomarkers.3,4 However, neither of these have been prospectively validated to date in SCLC and there may be important differences in their performance depending on how testing is done (e.g., variation between antibodies, scoring methods/cutoffs, or technical differences between molecular platforms).

      Recently, new combinations of targeted therapies together with immune checkpoint inhibitors (such as inhibitors of DNA damage response (DDR) such as PARP1 or Chk1 to enhance STING pathway activation) have demonstrated promise in preclinical studies of SCLC and are being translated into the clinic for further investigation.5 In addition, other new immunotherapeutic approaches are being tested in ongoing trials. Examples of these include studies of chimeric antigen receptor T-cells (CAR-T) and bi-specific T-cell engagers (BiTE molecules) targeting the notch inhibitor ligand DLL3 for patients with relapsed SCLC. In this context, additional biomarkers related to specific combinations of targeted and immune-therapies and/or new classes of immunotherapy (e.g., SLFN11 levels for PARP inhibitors; cMyc status for Chk1 inhibitors; markers of STING pathway activation; or DLL3 expression levels) may emerge as additional biomarkers relevant to immune responses. Finally, a better understanding of tumor and immune environment heterogeneity between patients – as well as intra-tumoral heterogeneity – will lead to more effective strategies for matching patients to specific immunotherapies and overcoming immunotherapy resistance.

      REFERENCES

      1. Della Corte CM, Gay CM, Byers LA. Beyond chemotherapy: Emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era. Cancer 2019;125:496-8.

      2. Horn L, Mansfield AS, Szczesna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 2018;379:2220-9.

      3. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883-95.

      4. Hellmann MD, Callahan MK, Awad MM, et al. Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell 2018;33:853-61 e4.

      5. Sen T, Rodriguez BL, Chen L, et al. Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer. Cancer Discov 2019;9:646-61.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MS09.03 - Small Cell Lung Cancer: The Immune Microenvironment (Now Available) (ID 3490)

      14:00 - 15:30  |  Presenting Author(s): Stephen V. Liu

      • Abstract
      • Presentation
      • Slides

      Abstract

      Based in part on the relatively high tumor mutational burden (TMB) and the strong link to tobacco use, there was a relative optimism regarding the prospects of success with immunotherapy in small cell lung cancer (SCLC). Over the past few years, while we have seen promising activity with checkpoint inhibitors in SCLC, the gains have been somewhat modest. As in other immune-responsive tumors, durable responses and long-term survival are possible. Nivolumab and pembrolizumab monotherapy have both demonstrated impressive durations of response, circling 18 months in the third line setting (Ready, JTO 2018; Chung, AACR 2019). Landmark survival rates far exceed historic controls in this setting. Meaningful benefit, though, is limited to a subset of patients, with response rates of only 12-19%. Both agents received accelerated approval by the FDA as third-line therapy for SCLC, but given the high attrition rate in SCLC, the impact of these approvals will be limited. Second-line and maintenance trials have failed to improve upon historic standards (Reck, ESMO 2018; Owonikoko, ELCC 2019). Fortunately, the addition of the PD-L1 inhibitor atezolizumab to first line carboplatin and etoposide improved both progression-free survival and overall survival (Horn, NEJM 2018). While the long-overdue improvement in survival was important and led to the FDA approval of atezolizumab in March 2019, there is significant room for improvement.

      The current use of checkpoint inhibitors in SCLC is empiric, though it is glaringly obvious that the true, durable benefit is limited to a subset of patients. Biomarkers are needed to identify those patients – to ensure they receive the appropriate therapy but also to help direct other patients to novel strategies. Predictive biomarkers can also provide valuable insight into the underlying biology of immune responses. Biomarker studies are challenging in SCLC; tissue samples are often scant, and the aggressive nature of the disease often precludes in depth study. Early data, though, speak to particular importance of the immune microenvironment in SCLC.

      Expression of PD-L1 by immunohistochemistry holds predictive value in non-small cell lung cancer (NSCLC). Its role in SCLC is evolving. In the CheckMate-032 study, nivolumab alone or in combination with the anti-CTLA-4 antibody ipilimumab, was explored in patients with previously treated SCLC (Hellmann, ASCO 2017). Using the 28-8 PD-L1 clone and a cutoff of 1%, only 18% of evaluable samples expressed PD-L1. Surprisingly, responses were more frequent in the PD-L1 negative tumors. With nivolumab alone, the response rate was 9% in PD-L1 positive tumors compared to 14% in PD-L1 negative tumors. With the combination of nivolumab and ipilimumab, the difference was even greater with a 10% response rate in PD-L1 positive tumors compared to 32% in PD-L1 negative. Some parallels are seen with pembrolizumab, but our understanding of PD-L1 as a biomarker is evolving. In a single arm study of maintenance pembrolizumab for SCLC (Gadgeel, JTO 2018), only 3 out of 30 patients had tumors with PD-L1 expression using the 22C3 clone (tumor proportion score, TPS). While the median PFS for the entire population was only 1.4 months, the 3 patients with TPS PD-L1 positive tumors all had a PFS over 10 months. Expression of PD-L1 at the stromal interface was also explored (combined proportion score, CPS). More patients had PD-L1 positive tumors using the CPS approach (8/20, 40%) and outcomes were superior in the CPS PD-L1 positive population: response rate was 37.5% vs. 8.3%, median PFS was 6.5 months vs. 1.3 months, and median overall survival was 12.8 months compared to 7.6 months. Similar results were seen in the salvage setting. In KEYNOTE-158, patients with previously treated SCLC received pembrolizumab monotherapy (Chung, ASCO 2018). Using the CPS approach, 39% of patients were PD-L1 positive, 47% were negative and 14% were non-evaluable. Again, outcomes favored the CPS PD-L1 positive subset including response rate (35.7% vs. 6%) and overall survival (14.9 months vs. 5.9 months). A separate retrospective analysis of a 95-sample cohort noted tumor expression of PD-L1 in 18% of samples but PD-L1 expression on tumor infiltrating lymphocytes (TILs) was seen in 67% of samples (Rivalland, ASCO 2017). There was no difference in survival based on tumoral expression of PD-L1, but median survival was longer in patients with PD-L1 positive TILs compared to PD-L1 negative TILs (17.2 months vs. 7.9 months, HR 0.36; 95% CI 0.22-0.60). The importance of the immune microenvironment in facilitating an immune response is becoming increasingly clear but it extends beyond expression of PD-L1. The presence and the specific location of tumor-infiltrating T-cells also holds value. Specific immunophenotypes are present and have been described as immune-desert (with few or no CD8+ T cells), immune-excluded (with CD8+ T cells present but limited to the adjacent stroma), and immune-inflamed (with CD8+ T cells in contact with tumor cells). A study of olaparib and durvalumab examined these phenotypes in patients with advanced SCLC (Thomas, JTO 2019) and found 14% with an immune-desert phenotype, 64% of samples with an immune-excluded phenotype and 21% with an immune-inflamed phenotype. PD-L1 expression was noted in all patients who achieved a response but was also noted in non-responders. In contrast, all of the patients with an immune-inflamed phenotype achieved a response.

      Much more work is needed to fully understand how the immune microenvironment facilitates (or precludes) immune responses. It is not yet clear whether these characteristics can be used as a predictive marker for use of checkpoint inhibitors. It is also not clear whether strategies to alter the microenvironment (with radiation therapy or other immune modulators) will induce effective immune responses. What is clear is that empiric therapy can only take us so far in the management of this exceptionally lethal disease. The path forward will require insight into the complexities orchestrating immune responses and a personalization of therapy for specific subsets of SCLC, subsets that certainly exist but, to date, evade proper detection. We have made tremendous strides in recent years to improve outcomes in SCLC but there remains much work to do.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.



Author of

  • +

    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
    • +

      P1.16-05 - Incidence and Outcome of Multiple Primary Cancers (MPC) in a Series of Lung Cancer (LC) Patients (ID 1030)

      09:45 - 18:00  |  Author(s): Alejandro Navarro

      • Abstract
      • Slides

      Background

      The number of cancer survivors has increased as a result of significant progress in prevention, diagnosis and treatment of malignant tumors. The risk of developing a second neoplasm, after treatment of an initial primary cancer, is increasing and indeed lung cancer represents a commonly diagnosed second primary malignancy. This study investigates the co-occurrence of MPC among patients (p) diagnosed with lung cancer (LC).

      Method

      Review of clinical data of all consecutive patients with histologically confirmed LC visited at our institution between October 2017 and August 2018

      Result

      Out of 1386 p with LC, two primary cancers occurred in 206 cases (15%), including 41 p (3%) with three primary cancers. Patients with MPC were predominantly males (67%), smokers (88%), statin users (40%) and 28% had known family history. Second cancer was detected in a routine follow-up in 62%, whereas 27% were symptomatic patients. Median age at the first tumor diagnosis was 61 years (27-85). LC occurred as first neoplasm in 34% of the cases, as subsequent neoplasm in 41% and as two consecutive primary neoplasm in 25%. The most common primary cancer was LC in 34%, followed by breast (16%), colorectal (15%), prostate (9%), bladder (8%) and head and neck (6%). Treatment received for the first cancer included surgery in 80%, chemotherapy in 47% and radiotherapy in 32%. As a second tumor LC represented 41%, followed by bladder (19%), colorectal (10%), prostate (9%) and breast (7%). Surgery was performed in 70% of the cases with a second cancer. Regarding only patients with LC as two primary tumours (first and second tumour), 25 pts (89%) were not metastatic at second tumour, surgery was performed in 82% and 7 pts (24%) developed a third tumour. Overall, median time of diagnosis between the first and the second neoplasm was 4.2 years (CI95% 3.2-5.2), without significant differences if primary tumor was LC or another neoplasm (p=0.82). Smoking was associated with a shorter time of the second neoplasm diagnosis (3.8 years vs 7.9 years for non-smokers, p=0.09), whereas taking statins exhibited longer time of diagnosis of the second neoplasm (5.1 vs 3.3 year, p=0.05). With a median follow up of 7.3 years after diagnosis of the first neoplasm, the 5-year survival rate was 97.2% (94.8-99.7%).

      Conclusion

      In our series, the frequency of the MPC co-occurrence among LC p is 15%, indicating that surveillance strategies are recommended. Many p are treated with curative intent. Moreover, smoking and taking statins influences the time interval between tumors

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.12 - Small Cell Lung Cancer/NET (ID 180)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
    • +

      P2.12-04 - CLEPSIDRA: A Phase II Trial Combining Iadademstat with Platinum-Etoposide in Platinum-Sensitive Relapsed SCLC Patients (ID 1243)

      10:15 - 18:15  |  Author(s): Alejandro Navarro

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, shows a dismal prognosis with the current pharmacopeia. Notch is a tumor suppressor repressed in SCLC. Iadademstat is the leading selective LSD1 inhibitor and has been shown to re-activate the NOTCH pathway in SCLC, resulting in the repression of ASCL1, a well-known non-druggable SCLC tumor driver, and to produce robust, and in some cases complete and durable, tumor regression in some chemoresistant PDX models. In a previous Phase I study in acute leukemia, iadademstat was safe and well tolerated, supporting it is a meaningful candidate for combination therapy with other agents. This is the first combo trial in SCLC with a LSD1 inhibitor and the current SoC.

      Method

      CLEPSIDRA (EudraCT nº 2018-000469-35) is a Phase II study of iadademstat as a second line treatment in combination with platinum plus etoposide re-challenge chemotherapy in patients with relapsed extensive stage SCLC, that includes biopsy biomarkers expression as inclusion criteria to increase likeliness of response to iadademstat treatment. CLEPSIDRA is an open label single-arm multicenter study to assess for the first time the safety, tolerability, dose finding and efficacy of iadademstat in combination with chemotherapy in SCLC patients. It is planned to enroll up to 36 patients. The study is composed of a dose/regime finding part aimed to establish the recommended dose and regime of the combination, and a second part to assess clinical activity by RECIST criteria.

      Result

      The design of the trial and the preliminary results in safety, tolerability and clinical activity as per August 2019 cut-off will be presented and discussed. Preliminary results of the first three subjects with RECIST data available as per April showed a 72% RECIST reduction (from 80 at screening to 43 on cycle 2 and 23 after 4 cycles of treatment) in one subject and stable disease at cycle 2 in the other two subjects.

      Conclusion

      Combination of multiple oncological drugs requires careful selection of doses and regimes as their toxicity is often accentuated by the addition of a new component. Neutropenia induced by the etoposide-platinum has to be managed when dosing iadademstat. Current data suggest that these toxicities may be managed in an acceptable manner. The initial clinical responses observed also suggest that the combination of iadademstat with SoC may be clinically effective in second line relapsed SCLC patients.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.