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R. Herbst

Moderator of

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    SC05 - Novel Drugs in Thoracic Cancers (ID 329)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 4
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      SC05.01 - Immunotherapy in Malignant Pleural Mesothelioma (ID 6617)

      11:00 - 11:20  |  Author(s): R. Hassan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      SC05.02 - Novel Cytotoxic Drugs in Lung Cancer (ID 6618)

      11:20 - 11:40  |  Author(s): J. Soria

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Even in the era of precision medicine and immunotherapy, cytotoxic chemotherapies remain an essential component of lung cancer treatment, both in resectable disease as well as in advanced/metastatic lung cancer. We have chosen to focus on 2 new cytotoxic compounds, which are likely to emerge as new players in the field of lung cancer management. One (named PM1183) has activity in small-cell lung cancer (SCLC), the other TAS-114 has activity in non-small cell lung cancer (NSCLC). PM1183 is a DNA-binding chemotherapy with a new mechanism of action. PM1183 acts as an inhibitor of transcription. Binding of PM1183 to CG-rich motifs, triggers sequential phosphorylation of Pol II and stalling of elongating Pol II. This leads to recruitment of the ubiquitin-proteasome machinery, RNA Pol II degradation, and recruitment of XPF, generation of DNA breaks and induction of apoptosis. PM1183 has been tested in a phase IB trial in combination with doxorubicine. In the dose-finding part: recommended dose (RD) was defined at PM1183 4.0 mg flat dose (FD) or 2.0 mg/m2 + DOX 50 mg/m2 both on day (D)1 every three weeks (q3w). Myelosuppression was dose-limiting (DLT). Compelling activity was observed during escalation phase. It was especially remarkable as 2nd line in SCLC patients: 5 of 7 evaluable pts (71%) had objective partial response (PR) as per RECIST v.1.1. In an expansion cohort of 20 patients, PM1183 and DOX showed outstanding clinical activity: 67% response rate, including 10% of CRs, as 2nd line treatment in SCLC patients. A randomized phase III trial testing PM1183 + DOX is planned and will compare this combination with topotecan or CAV. TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor that acts as a modulator of the pyrimidine nucleotide metabolic pathway by blocking the conversion of 2’‑deoxyuridine-5’-triphosphate (dUTP; FdUTP) into 2’-deoxyuridine-5’-monophophate (dUMP; FdUMP) through reversible inhibition of dUTPase (gatekeeper protein), resulting in the enhanced incorporation of both uracil and fluorouracil into DNA. The activity of TAS-114, administered in combination with thymidine synthase (TS) inhibitors, 5-FU, S-1 or capecitabine, has been studied pre-clinically in various cancer cell lines and animal models. TAS-114 selectively inhibited dUTPase and showed a higher affinity than the substrates of dUTPase, dUTP and FdUTP, inhibition constant values of TAS-114 were 0.13 μM and 0.10 μM, respectively. The antitumor effect of TAS-114 combined with S-1 as compared to that of S-1 alone was investigated in vivo using a xenograft mouse model with NCI-H2228 (human NSCLC). Both regimens were administered orally (TAS-114: 600 mg/kg/day and S-1: 8.3 mg/kg/day vs S-1: 8.3 mg/kg/day through day 1 to 28) and resulted in relative tumor volumes of 1.61% vs 3.04%, p<0.01, inhibition rates of 52.7% vs 10.8%, and body weight changes of 6.8% vs 3.3%, respectively. A phase 1 clinical study of TAS-114 and S-1 combination treatment is currently ongoing to investigate the safety and to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in patients (pts) with advanced refractory solid tumors. TAS-114 and S-1 are administrated orally twice a day for 14 days followed by 7 days resting period for a 21-days cycle at the starting dosage of 5 mg/m² with the fixed dosage of 25 mg/m², respectively. To date, a total of 96 pts were enrolled with 37 pts in the dose escalation and 59 pts in the MTD expansion stages. TAS-114 and S-1 were escalated up to 240 mg/m² and 36 mg/m², respectively, with 2 DLTs observed at the highest dose level (1 patient with G3 rash and 1 patient with G2 rash/G2 HFS), therefore TAS-114 at 240 mg/m² and S-1 at 30 mg/m² was determined to be the MTD and RD. The most common treatment related adverse events were anemia and rash. There were 4 confirmed partial responses observed in 2 non-small cell lung (NSCLC) pts, 1 pancreas pt and 1 colorectal cancer patient to date. Amongst 6 evaluable NSCLC pts to date, there was an overall response rate of 33% (2/6) with 2 confirmed PR and a disease control rate of 100% (6/6). Pharmacodynamics analysis performed on patient tumor specimens treated at MTD indicated TAS-114 target engagement by reductions in the amount of intra-tumoral dUMP, a “surrogate” metabolite indicative of dUTPase inhibition, following TAS-114/S-1 combination as compared to S-1 alone administration. When TAS-114 is administered in combination with S-1, an additional cytocidal antitumor effect to TTP depletion by TS inhibition is expected as TAS-114 inhibits a gatekeeper protein, thereby allowing increased DNA incorporation of both uracil and 5-FU resulting in DNA damage.

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      SC05.03 - Novel Tyrosine Kinase Inhibitors in Lung Cancer (ID 6619)

      11:40 - 12:00  |  Author(s): C. Zhou

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The invited talk will firstly talk about the recent advances in novel TKIs overcoming resistance during EGFR-TKI and ALK-TKI treatment. Afterwards, several novel TKIs with CNS penetration that may substantially change the prognosis and treatment strategy of patients with brain metastases will be discussed. Finally, we will take an overview about targeted therapy against rare and novel, potentially druggable oncogenic drivers either in preclinical settings or early-stage clinical trials. As we know, the presence of EGFR activating mutations and ALK chromosomic rearrangements with corresponding tyrosine kinase inhibitors (TKIs) has revolutionized the treatment strategies of patients with non-small cell lung cancer (NSCLC) [1, 2]. Although tremendously initial response and manageable toxicity profiles, however, acquired resistance inevitably develops after approximately 1 year treatment with EGFR-TKIs (erlotinib and gefitinib) and ALK inhibitor (crizotinib). Encouragingly, third-generation EGFR-TKIs including AZD9291, CO1686 and HM61713 have showed striking efficacy overcoming acquired resisitance driven by T790M secondary mutations [3, 4]. In patients who get acquired resistance to first-generation EGFR-TKIs with T790M mutations, the objective response rate (ORR) of AZD9291 was 61% and median progression-free survival (PFS) was 9.7 months [4]. Other novel third-generation EGFR-TKIs such as ASP8274, EGF816, PF-06747775 and avitinib are also being investigated in early-stage clinical trials and the survival and safety data will be released in the near future. Another promising novel EGFR-TKI, namely AZD3759 has showed promising response in patients with brain metastases and leptomeningeal disease, a major case leading to treatment failure. In BLOOM study, 11 out of 21 patients with measurable brain metastases and heavily pre-treated progressed both extracranially and intracranially had tumor shrinkage in the brain at dose ≥50mg BID. Recently, EAI045, an EGFR allosteric inhibitor, in combination with cetuxmab exhibit antitumor activity in mouse models of lung cancer driven by L858R/T790M/C797S, a common resistant mechanism of AZD9291 [5]. Meanwhile, second-generation ALK inhibitors (ceritinib, alectinib and brigatinib) have entered clinical applications for NSCLC patients with ALK rearrangements after failure of crizotinib and third-generation ALK inhibitors (lorlatinib and ASP3026) are also being evaluated in clinical trials overcoming known ALK resistant mutations[6, 7]. In patients who progress on crizotinib, the ORR and PFS of brigatinib at 180mg was 54% and 12.9 months. Lorlatinib, a third-generation ALK inhibitor, also demonstrated robust clinical activity in ALK-rearrangement patients with NSCLC. The ORR was 57% in patients who received 1 prior ALK-TKI and 42% in patients who received ≥2 prior ALK-TKIs. On the other hand, with the development of high-throughput sequencing, called next-generation sequencing (NGS) and genomic technologies, more novel molecular targets such as MET 14 exon skipping splicing mutations[8]have been identified as potential therapeutic targets and simultaneously analyzing hundreds of molecular alterations have turned out reality with limited tumor tissues. In the recent years, the emergence of numbers of oncogenic drivers other than EGFR mutations and ALK rearrangements has divided NSCLC into multiple distinct subtypes amenable to corresponding targeted therapy, including ROS1 rearrangement, RET arrangement, BRAF-V600E mutations, HER2 mutations and MET 14 exon skipping mutations et al. For instance, dabrafenib either as monotherapy or in combination with MEK inhibitor (trametinib) has displayed promising antitumor activity and manageable safety profile in patients with BRAF V600E mutations [9, 10]. In 57 previously treated metastatic NSCLC patients with BRAF-V600E mutations, 63.2% patients (36/57) achieved an overall response [9]. Other novel molecular targets maybe serving as oncogenic drivers including mutations in HER2 (neratinib and pyrotinib) and PI3KCA (BKM120 and GDC0941), ROS1 (entrectinib, foretinib and lorlatinib), RET (XL184) and NTRK (entrectinib) rearrangements and FGFR1 gene amplification (AZD4547, Lenvatinib and FP-1039) are being evaluated either in preclinical settings or early-stage clinical trials. Reference: 1. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361: 947-957. 2. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371: 2167-2177. 3. Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015;372: 1700-1709. 4. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372: 1689-1699. 5. Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016;534: 129-132. 6. Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol 2016;34: 661-668. 7. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370: 1189-1197. 8. Paik PK, Drilon A, Fan PD, Yu H, Rekhtman N, Ginsberg MS, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5: 842-849. 9. Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016;17: 984-993. 10. Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17: 642-650.

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      SC05.04 - Lung Cancer Vaccines: An Update (ID 6620)

      12:00 - 12:20  |  Author(s): E. Quoix

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Treatment of small-cell lung cancer (SCLC) has not been modified since decades : and consists in a chemotherapy (CT) with platin+etoposide+/-concurrent radiotherapy (RT) and prophylactic cranial irradiation in case of a (near)complete response to therapy. Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers and around 50% are metastatic at presentation. Systemic treatment (platin-based doublets) has been implemented for stage IV NSCLC but also for locally advanced and early stages as a (neo)adjuvant therapy to surgery or RT. By the end of the XXth century, a plateau has been reached with CT in stage IV disease with similar results whatever the drug used in conjunction with platin-salt. Since the beginning of the XXIst century there have been tremendous innovations in the systemic treatment of NSCLC. First, adjunction of bevacizumab to CT for stage IV non-squamous cell carcinoma and the use of maintenance therapy have led to an improvement in median survival time (MST) exceeding now one year. Second, targeted therapies proved to be of major interest for patients with EGFR activating mutations leading to a MST>2 years. Other targets of interest have been found such as ALK and ROS1 translocations, V600EBRAF mutations leading to prolonged survival with appropriate treatments. Third, immunotherapy represents now an exciting approach especially for those patients without targetable mutations/translocations. Lung cancer has long been considered as a poor candidate for immunotherapy because of low content of tumor-infiltrating lymphocytes (TIL) compared to other tumors. On the other hand, in case of the presence of TIL the prognosis is better (1). The fact that incidence of lung cancer is especially high in patients who were transplanted (2)or in patients with HIV infection (3)is against the assumption of lung cancer being non immunogenic. There are two types of immunotherapy : the immune checkpoint blockers which aim at enhancing a T-cell response directed against tumoral cells and abrogate the immune tolerance and the therapeutic vaccines designed to induce or amplify an immune response directed against tumor-associated antigens (TAA). The immune checkpoint blockers in current development are anti CTLA4 monoclonal antibodies (ipilimumab), first used in the treatment of melanoma and now investigated in NSCLC and SCLC, anti PD1 (nivolumab, pembrolizumab) or anti PDL1 (avelumab, atezolizumab). All these molecules are now either at an advanced stage of development or already authorized (4). Therapeutic vaccines have already a long story beginning with Coley toxins at the end of the nineteenth century (5). The Coley's toxins, (cultures of streptococci) were infused in patients with bone and soft tissue sarcomas and some impressive regressions were observed. The hypothesis was that the immune reaction provoked by the infusion of the "toxins" present in the infectious material was able to destroy the tumoral cells. However, due to the reluctance of doctors to administer dangerous bacterial culture and the appearance of novel treatments of cancer (CT and RT), the Coley's toxin approach has been abandoned although numerous articles were devoted to this subject (6). Non specific vaccines using for example BCG to stimulate innate immunity have been disappointing as well in SCLC (7-8)and NSCLC (9). Specific immunotherapy aims at the stimulation of adaptive immunity against the vaccine components and thus induces or amplifies an immune response against TAA. These vaccines are either peptides (Tecemotide, MAGE-A3), cellular vaccines (Belagenpumatucel) or vaccines using viral vector (TG4010). Tecemotide and TG4010 are a MUC1 antigen-specific cancer immunotherapy. MUC1 is expressed at the apical surface of mucin-secreting normal epithelial cells of various tissues and can be overexpressed and aberrantly glycosylated in some tumors and thus is an attractive target for immunotherapy. Tecemotide is a liposomal vaccine. In a randomized phase II trial (10), 171 NSCLC patients who were not progressing after induction CT or CT-RT received subcutaneous tecemotide plus best supportive care (BSC) or BSC alone as maintenance therapy . Median survival time (MST) was longer in patients receiving tecemotide (17.2 vs. 13.0 months) but this did not reach statistical significance. As in a post hoc analysis the benefit appeared to be more important for patients with stage IIIB disease, it was decided to perform a phase III study in locally advanced NSCLC (11,12)comparing in non-progressing patients after CT with platin-based doublet and RT, tecemotide versus placebo. MST was 25.8 months with tecemotide versus 22.4 months with placebo (HR 0.89, 95%CI 0.77-1.03, p=0.111). In the concurrent CT-RT subgroup, there was a significant survival benefit in favor of tecemotide whereas in the sequential CT-RT subgroup, survival did not differ between the two arms. A similar study (13)was initiated in Asian people. This trial was prematurely terminated as the sponsor decided to discontinue program with tecemotide in NSCLC MAGE-A3 is an antigen expressed in 76% of melanoma and in 35% of NSCLC. It is absent from normal tissues except for testis and placenta. This vaccine, has been investigated in early stage of NSCLC as an adjuvant treatment. A randomized phase II study(14)compared the MAGE-3A vaccine to a placebo in 182 patients operated of a stage IB or II NSCLC with their tumor expressing MAGE-A3 antigen. The randomization was on a 2 :1 basis. The main objective was to compare the Disease Free Interval (DFI) defined as the time from resection to the date of recurrence (any type) or second primary lung neoplasm. Although there was a trend toward a numerically longer DFI in the MAGE-A3 vaccine group, the main objective was not met. Nevertheless, even if these trends were by far not significant, the results appear promising to the sponsors and a phase III trial was launched (MAGRIT trial) with the same scheme(15). Unfortunately, the biggest trial ever performed with the inclusion of 2312 NSCLC patients is negative regarding as well the primary objective: disease-free survival (DFS) but also the secondary objective, DFS in the group of patients not receiving adjuvant chemotherapy or other subgroups. Belagenpumatucel-L is a vaccine comprising 4 tranforming growth factor-β2-antisense gene-modified irradiated allogeneic NSCLC cell lines. A randomized phase III trial (16)comparing this vaccine to a placebo was performed after platinum-based CT for stage III/IV disease in non progressing patients. This trial was negative with no difference in overall survival and in PFS. However, in a prespecified multivariate analysis, there was an improved survival for patients who were randomized within 12 weeks after CT and for patients who received prior radiation therapy. TG4010 is a suspension of a recombinant modified vaccinia virus strain Ankara coding for the MUC1 TAA and IL2. Feasibility of either upfront combination of TG4010 with cisplatine-vinorelbine or TG4010 alone until progression has been demonstrated in a phase II study(17). Sixty-five patients were randomized. Response rate was 30 % in the combined upfront schedule, MST was 12.7 months and one-year survival rate 53%. Taking into account these results, a phase II randomized study (18)comparing CT with cisplatin and gemcitabine to the same CT + TG4010 was performed. One hundred and forty eight patients with stage IIIB or IV disease were included. The primary endpoint was 6-month PFS with the hypothesis that it will be at least 40% in the combined arm. This objective was met with a 6-months PFS of 43% compared to 35.1% in the CT alone arm. There was a non significant trend toward a higher response rate and a longer time to progression in the combined arm. An exploratory analysis of the subgroups defined by the level of activated NK cells (CD16+CD56+CD69+lymphocytes or TrPAL) shows that a better outcome was observed for those patients with normal level of TrPAL and that the vaccine might be deleterious for those with high level of TrPAL. A phase IIB was then performed to confirm the role of the level of TrPAL(19). 222 patients were randomly allocated to CT+TG4010 or CT+placebo. Median PFS was 5.9 months in the TG4010 group versus 5.1 months in the placebo group (HR 0.74, 95%CI 0.55-0.98, p= 0.019). In patients with TrPAL values less or equal ULN, the HR for PFS was 0.75 (95%CI 0.51-1.03) with a posterior probability of HR being <1 of 98.4% and thus the primary endpoint was met. In patients with high level of TrPAL, there was no deleterious effect but no benefit as the HR for PFS was 0.77 (95%CI 0.42-1.40). As a conclusion, all studies with vaccines have been quite disappointing. To the best of my knowledge, the only vaccine still under investigation remains TG4010, but....phase III trial is not implemented at this time. In each vaccine study some efficacy has been observed in subgroups of NSCLC patients but mostly in post hoc analyses. All vaccine studies have shown that there is no safety problems. The fact that nowadays, considerable interest has been developed toward checkpoint inhibitors, probably explains the disaffection toward vaccines. Hopefully it will be only transient and the already long story of therapeutic vaccines will continue.

      Product Trials conducted Author (ref)
      Tecemotide (Stimuvax*) Merck Serono Phase IIB maintenance study in stage III/IV NSCLC Phase III maintenance therapy after CT-RT in non resectable stage III disease Butts(10) Butts(11) Mitchell(12) Wu(13)
      MAGE A3 GSK Adjuvant treatment after surgery Phase II randomized study Phase III study (Magrit trial) Vansteenkiste(14) Vansteenkiste(15)
      Belagenpumatucel Lucanix* NovaRx Phase III study as maintenance in stage IV disease after 1st line CT Giaccone(16)
      TG4010 Transgene In combination with first line CT in stage IV disease NSCLC Phase II study Phase IIB randomized study Phase IIB/III randomized study Ramlau(17) Quoix(18) Quoix(19)
      Table 1 Phase II and III vaccine studies in NSCLC References 1. Kawai O, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 2008;113:1387–95. 2. Engels EA, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA 2011;306:1891–901. 3. Hleyhel M, et al. Risk of non-AIDS-defining cancers among HIV-1-infected individuals in France between 1997 and 2009: results from a French cohort. AIDS 2014;28:2109–18. 4. El-Osta H,et al. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment. OncoTargets Ther. 2016;9:5101–16. 5. Coley WB. The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med. 1910;3(Surg Sect):1–48. 6. Zacharski LR, Sukhatme VP. Coley’s toxin revisited: immunotherapy or plasminogen activator therapy of cancer? J Thromb Haemost 2005;3:424–7. 7. Maurer LH, et al. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study. J Clin Oncol 1985;3:969–76. 8. Giaccone G, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer. J Clin Oncol 2005;23:6854–64. 9. Robinson E, et al.. Combined-modality treatment of inoperable lung cancer (i.v. immunotherapy, chemotherapy, and radiotherapy). Cancer Treat Rep. 1985;69:251–8. 10. Butts C, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 2005;23:6674–81. 11. Butts C, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:59–68. 12. Mitchell P, et al. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. Ann Oncol 2015;26:1134–42. 13. Wu Y-L, et al. INSPIRE: A phase III study of the BLP25 liposome vaccine in Asian patients with unresectable stage III non-small cell lung cancer. BMC Cancer. 2011;11:430. 14. Vansteenkiste J, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results. J Clin Oncol 2013;31:2396–403. 15. Vansteenkiste JF, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17:822–35. 16. Giaccone G, et al. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 2015;51:2321–9. 17. Ramlau R, et al. A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV Non-small cell lung cancer. J Thorac Oncol 2008;3:735–44. 18. Quoix E, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol. 2011;12:1125–33. 19. Quoix E, et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. Lancet Oncol. 2016;17:212–23.

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Author of

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    MA15 - Immunotherapy Prediction (ID 400)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA15.06 - Predictive Value of Measuring Somatic Mutations and Tumor Infiltrating Lymphocytes for PD-1 Axis Therapy in Non-Small Cell Lung Cancer (NSCLC) (ID 6255)

      14:56 - 15:02  |  Author(s): R. Herbst

      • Abstract
      • Slides

      Background:
      Diverse factors have been associated with clinical benefit to PD-1 axis blockers in NSCLC including PD-L1 protein expression by immunohistochemistry and increased mutation load/predicted class-I neoantigens. However, the association and predictive value of the tumor genomic landscape, composition of the tumor immune microenvironment and T-cell function remain unclear.

      Methods:
      We performed whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) for T-cells in pre-treatment FFPE samples from 45 NSCLC patients treated with PD-1 axis blockers (alone or in combination) in our institution. Genomic analysis was used to evaluate the mutational load and predicted class-I neoantigens. Multiplexed QIF-based immunoprofiling was used to measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3+ cells) and T-cell activation (Granzyme-B in CD3+ cells). We studied the association between the tumor somatic mutations, predicted neoantigens, T-cell infiltration/function and clinical benefit /survival.

      Results:
      Increased mutational load was positively associated with predicted class-I neoantigens, variants in DNA-repair genes, smoking and absence of activating mutations in EGFR; but not associated with the level of CD3+ T-cells, T-cell proliferation (Ki-67 in CD3+ cells) and function (Granzyme-B in CD3+ cells). Increased mutations and candidate class-I neoantigens were significantly associated with response to therapy (P=0.02 and 0.03, respectively), but not with overall survival at 3-years (median cut-point, log rank P=0.92 and 0.80, respectively). Higher CD3 positivity was not associated with response to therapy (P=0.17), but was significantly associated with overall survival (median cut-point, log rank P=0.03). Regardless of the mutational load and candidate neoantigen content, elevated CD3 with low Ki-67/Granzyme-B in CD3 predicted longer survival after PD-1 axis blockade than high CD3/high Ki-67/Granzyme-B in CD3, or low T-lymphocyte infiltration.

      Conclusion:
      Increased somatic mutations are associated with smoking and response to PD-1 agents, but not with tumor T-cell infiltration/activation and overall survival. Regardless of the mutational load, increased T-cell infiltration using QIF is significantly associated with longer survival after PD-1 axis blockade in NSCLC. The subgroup of NSCLC with the highest potential of benefit to immune reinvigoration using PD-1 axis blockade comprise tumors with elevated lymphocyte infiltration but low in situ activation/proliferation.

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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 2
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      MA16.02 - Mutational Landscape of TKI Naïve and Resistant EGFR Mutant Lung Adenocarcinomas (ID 5777)

      15:44 - 15:50  |  Author(s): R. Herbst

      • Abstract
      • Presentation
      • Slides

      Background:
      The identification and development of tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have revolutionized and greatly improved the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). Unfortunately, acquired resistance (AR) to these agents remains a major clinical problem hindering durable responses. Although significant work has been done to identify particular mechanisms of acquired resistance, little is known regarding the global mutational landscape of EGFR mutant tumors before therapy or at the manifestation of acquired resistance.

      Methods:
      Using specimens obtained in the IRB approved, Yale Lung Rebiopsy program, we completed whole exome sequencing of 15 EGFR mutant tumors with paired tissue obtained pre-treatment and at the time of AR to EGFR TKIs. An additional 5 unpaired AR samples were also analyzed. The mutational burden and copy number profile of the specimens were studied.

      Results:
      We found that the mutational burden of pre-treatment EGFR mutant tumors varies widely between tumors. TKI treatment, however, does not significantly alter the overall or non-synonymous mutation load at AR. Interestingly, EGFR[L858R]tumors had a significantly higher mutation burden at acquired resistance to EGFR TKIs than EGFR[Δ19] tumors. The higher mutation burden in EGFR[L858R] tumors compared to those harboring EGFR[Δ19 ]mutations was further confirmed through analysis of TCGA data. Recurrently altered genes shared in the pre- and AR specimens include TP53, EGFR and AKT1. Alterations in EGFR (T790M), MYCBP2, WHSC1L1, AXL, MET, HGF, MYC and NTRK1 were found at exclusively at AR.

      Conclusion:
      Collectively, these data provide valuable insight into the mutational landscape of EGFR mutant NSCLCs as they evolve on TKIs and identify potential resistance candidate genes for further investigation.

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      MA16.10 - Lung-MAP (S1400) Lung Master Protocol: Accrual and Genomic Screening Updates (ID 3995)

      15:20 - 15:26  |  Author(s): R. Herbst

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung-MAP (S1400), is a master protocol that incorporates genomic testing of tumors through a next generation sequencing (NGS) platform (Foundation Medicine) and biomarker-driven (matched) therapies for patients with squamous cell lung cancer (SCCA) after progression on first-line chemotherapy.

      Methods:
      The Lung-MAP trial, activated June 16, 2014, includes 3 matched- and 1 non-match study. Matched studies include: S1400B evaluating taselisib, a PI3K inhibitor, S1400C evaluating palbociclib, a CDK 4/6 inhibitor and, S1400D evaluating AZD4547, an FGFR inhibitor. The non-match study S1400I tests nivolumab + ipilimumab vs. nivolumab. Two studies have closed: S1400E evaluating rilotumumab an HGF monoclonal antibody + erlotinib closed 11/26/2014 and S1400A evaluating MEDI4736 in non-match pts, closed 12/18/2015.

      Results:
      From June 16, 2014 to June 15, 2016, 812 pts were screened and 292 pts registered to a study: 116 to S1400A, 27 to S1400B, 53 to S1400C, 32 to S1400D, 9 to S1400E and 55 to S1400I. Demographics: Screening was successful for 705 (87%) of screened eligible pts. Median age 67 (range 35-92); male 68%; ECOG PS 0-1 88%, PS 2 10%; Caucasian 85%, Black 9%, other 5%; never/former/current smokers 4%/58%/36%. Table 1 displays biomarker prevalence; 39% of pts matched; 33.9%, 4.8%, and 0.3% with 1, 2, and all 3 biomarkers, respectively. Tumor mutation burden (TMB) was available for 636 (90.4%) of eligible pts. The distribution of TMB is: 126 (19.8%) low (≤5 mutations Mb), 415 (65.1%) intermediate (6-19 mutations/Mb), and 96 (15.1%) high (≥20 mutations/Mb). The median TMB was 10.1.

      Conclusion:
      Genomic screening is feasible as part of this master protocol designed to expedite drug registration, confirm anticipated prevalence of targeted alterations in SCCA and reveal intermediate or high TMB in most (80.2%) pts. Treatment results are not yet available as patients continue to accrue. Clinical trial information: NCT02154490

      Total FGFR CDK PIK3CA
      FGFR (15.9%) 12.9% 2.4% 0.6%
      CDK (18.8%) 14.6% 1.8%
      PIK3CA (8.8%) 6.4%
      Biomarker prevalence and overlap.


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    OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      OA03.07 - KEYNOTE-010: Durable Clinical Benefit in Patients with Previously Treated, PD-L1-Expressing NSCLC Who Completed Pembrolizumab  (ID 6769)

      12:05 - 12:15  |  Author(s): R. Herbst

      • Abstract
      • Presentation
      • Slides

      Background:
      Checkpoint inhibitors such as the anti–PD-1 monoclonal antibody pembrolizumab have demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Although checkpoint inhibitors are rapidly becoming a standard-of-care therapy in multiple tumor types, the optimal treatment duration has not been established. We assessed outcomes in patients who completed the maximum 24 months of pembrolizumab in the phase 3 KEYNOTE-010 study (NCT01905657), in which pembrolizumab provided superior OS over docetaxel in patients with previously treated, PD-L1–expressing advanced NSCLC.

      Methods:
      1034 patients with advanced NSCLC that progressed after ≥2 cycles of platinum-based chemotherapy (and an appropriate therapy for targetable EGFR and ALK aberrations if present) and had a PD-L1 tumor proportion score ≥1% were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg Q3W or to docetaxel 75 mg/m[2] until disease progression, intolerable toxicity, or physician or patient decision; the maximum duration of pembrolizumab was 24 months of uninterrupted treatment or 35 cycles, whichever was later. Response was assessed per RECIST v1.1 by independent central review every 9 weeks. After completion of 24 months/35 cycles, patients continued to undergo imaging every 9 weeks; patients with subsequent disease progression were eligible for a second treatment course if they did not receive other anticancer therapy after stopping pembrolizumab.

      Results:
      In the overall population, median OS was longer (10.5 months for pembrolizumab Q2W, 13.4 months for pembrolizumab Q3W, and 8.6 months for docetaxel) and 24-month OS rates were higher (30.1%, 37.5%, and 14.5%, respectively) with pembrolizumab compared with docetaxel. Of the 691 patients allocated to pembrolizumab, 47 patients received 35 cycles of pembrolizumab and were included in this analysis. As of the September 30, 2016 data cutoff date, all patients had completed all 35 cycles of treatment, but one withdrew from the study treatment after completing 35 cycles. Best overall response (ORR) among these 47 patients was complete response (CR) in 3 (6%) patients and partial response (PR) in 39 (83%) patients, for an ORR of 89%; 5 (11%) patients experienced stable disease (SD). Two of these patients experienced disease progression since stopping pembrolizumab and two of these patients resumed pembrolizumab therapy. As of the cutoff date, none of the 47 patients had died.

      Conclusion:
      With long-term follow-up, the OS benefit has been maintained and pembrolizumab continues to demonstrate superiority over docetaxel. Pembrolizumab provides durable clinical benefit with few patients progressing after completing two years of therapy.

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
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      P1.05-017 - The Prognostic Impact of EGFR, KRAS and TP53 Somatic Mutations in Curatively Resected Early-Stage Lung Adenocarcinomas (ID 4527)

      14:30 - 14:30  |  Author(s): R. Herbst

      • Abstract

      Background:
      As the 5-year survival among individuals undergoing curative-intent resection for early-stage lung cancer approaches 50%, identification of prognostic biomarkers useful for risk stratification is a priority. While somatic mutation profiling drives treatment choice in advanced disease, its usefulness among early-stage patients is not well-established.

      Methods:
      From May 2011 through December 2014, The Yale Lung Cancer Biorepository enrolled 192 individuals who underwent curative-intent complete resection for Stage IA-IIIA adenocarcinoma. Demographics and lifestyle choices were ascertained by interview using validated questionnaires. Pathologic characterization of index tumors, including CLIA Laboratory-assayed EGFR/KRAS status, was extracted from the medical record. A custom targeted resequencing panel covering all coding exons from 93 lung adenocarcinoma-related genes was designed. Buffy coat-derived germline DNA and tumor DNA, extracted from the FFPE surgical specimen, were sequenced on the Ion Torrent platform with >90% of the assayed amplicons achieving >30x coverage in both tumor and germline from each case. Somatic nonsynonymous tumor variants were identified using the Torrent Variant Caller. Bivariate associations were evaluated by Chi-square or ANOVA. Survival analyses were conducted using Cox modeling.

      Results:
      181/192 (94.3%) participants underwent EGFR/KRAS somatic mutation profiling with 43 EGFR mutations and 71 KRAS mutations detected. EGFR mutations were more common among well- and moderately-differentiated lesions (p=0.06) and among never or former light smokers (p=0.0007). Seventy-two percent of EGFR and 81.7% of KRAS mutations were found among female patients (p=0.0008). The joint distribution between smoking and gender favored EGFR mutations among female never/former smokers, KRAS mutations among female ever-smokers and EGFR/KRAS wild-type status among male ever-smokers (p=0.0002). After adjustment for AJCC 7[th] edition Tstage, Nstage and presence of lymphovascular invasion, KRAS mutations (HR=2.14; 95% CI:1.04-4.43; p=0.04) but not EGFR mutations (p=0.63) were prognostic for poorer disease-free survival. Targeted resequencing data is available on 148 cases. The nonsynonymous mutation burden ranged from 0-7 with 84% of cases having ≤3. In addition to KRAS and EGFR, frequent mutations were noted in p53 (n=40; 27.0%), STK11 (n=10; 6.8%) and PIK3CA (n=7; 4.7%) with 4 genes mutated in 6 cases. TP53 mutations were associated with high nonsynonymous mutation burden (p<0.0001) and the joint distribution with EGFR/KRAS status revealed the highest burden among KRAS[mut]/TP53[mut] (3.94±1.57) followed by EGFR[mut]/TP53[mut] (3.07±1.61) and EGFR_KRAS[wt]/TP53[mut] (2.20±1.40; p<0.0001).

      Conclusion:
      KRAS[mut], like EGFR[mut], is associated with female gender but only KRAS[mut] is prognostic following curative-intent resection. Elevated mutation burden observed among KRAS[mut]/TP53[mut] may offer novel therapeutic options following recurrence.

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-046 - Quantitative Measurement of B7-H3 Protein Expression and Its Association with B7-H4, PD-L1 and TILs in NSCLC (ID 4288)

      14:30 - 14:30  |  Author(s): R. Herbst

      • Abstract
      • Slides

      Background:
      B7-H3 (CD276) is a type I transmembrane protein that belongs to the B7 immunoregulatory family including PD-L1 (B7-H1) and is upregulated in multiple malignancies including Non-Small Cell Lung Cancer (NSCLC). Clinical activity of monoclonal B7-H3 blocking antibodies such as Enoblituzumab are under investigation. In this study we measured the levels of B7-H3 protein in NSCLC and studied its association with major tumor infiltrating lymphocyte (TIL) subsets, levels of PD-L1, B7-H4 and clinico-pathological characteristics in three independent NSCLC cohorts.

      Methods:
      We used automated quantitative immunofluorescence (QIF) to assess the levels of B7-H3 (clone D9M2L, CST), PD-L1 (clone SP142, Spring), B7-H4 (Clone D1M8I, CST) CD3, CD8 and CD20 in 634 NSCLC cases from 3 retrospective cohorts represented in tissue microarray format. The targets were selectively measured in the tumor and stromal compartments using co-localization with cytokeratin. Associations between the marker levels, major clinic-pathological variables and survival were analyzed.

      Results:
      Expression of B7-H3 protein was found in 80.4% (510/634) of the cases and the levels were higher in the tumor than in the stromal compartment. High B7-H3 protein expression level (top 10 percentile) was associated with poor survival in two out of three of the cohorts (p <0.05). Elevated B7-H3 was consistently associated with smoking history across the 3 cohorts, but not with sex, age, clinical stage and histology. Co-expression of B7-H3 and PD-L1 was found in 17.6% of the cases (112/634) and with B7-H4 in 10% (63/634). B7-H4 and PD-L1 were simultaneously detected only in 1.8% of NSCLCs (12/634). The expression of B7-H3 was not associated with the levels of CD3, CD8 and CD20 positive TILs.

      Conclusion:
      B7-H3 protein is expressed in the majority of NSCLCs and is associated with smoking history. High B7-H3 protein levels may have a prognostic effect in lung carcinomas. Elevated levels of B7-H3 are not associated with lymphocyte infiltration. Co-expression of B7-H3 with PD-L1 and B7-H4 is relatively low, suggesting a non-redundant biological role of these targets and possibilities for combination therapies using monoclonal antibodies.

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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03b-053 - Role of KRAS Mutation Status in NSCLC Patients Treated on SWOG S0819, a Phase III Trial of Chemotherapy with or without Cetuximab (ID 6113)

      14:30 - 14:30  |  Author(s): R. Herbst

      • Abstract

      Background:
      The S0819 phase III study of chemotherapy and bevacizumab (by patient/physician choice) with or without cetuximab in NSCLC showed no benefit from the addition of cetuximab, either overall or within the EGFR FISH-positive subset. Secondary analysis suggested an overall survival benefit in EGFR FISH-positive squamous cell carcinoma (SCC) (Herbst WCLC 2015, Hirsch ASCO 2016). In colorectal cancer (CRC), benefit from EGFR monoclonal antibodies such as cetuximab is limited to patients with RAS wild type (WT) tumors; however, in NSCLC, previous studies have not been sufficiently powered to make this determination. We prospectively incorporated KRAS mutation testing in S0819 to determine whether it predicts cetuximab efficacy. Since KRAS mutations are rare in SCC, we focused this analysis on nonSCC.

      Methods:
      KRAS mutation status was determined using the Therascreen KRAS test (Qiagen), conducted in a CLIA-certified diagnostic laboratory at the UC Davis Comprehensive Cancer Center. This test is FDA-approved for KRAS diagnostics in metastatic CRC, and identifies 6 mutations at codon 12 (G12A,D,R,C,S,V) plus G13D.

      Results:
      KRAS mutation status was available for 448 nonSCC patients, and mutations were identified in 150 cases (33%). Amino acid substitutions matched the expected distribution for a NSCLC population, with 52% harboring G12C and 17% with G12V. No significant differences were observed between KRAS-mut and WT populations for PFS (HR=1.15 (0.94-1.42); p=0.18) or OS HR=1.10 (0.89-1.37); p=0.39). Furthermore, no differences in outcomes between arms were observed based on KRAS mutation status (Table). The KRAS WT, EGFR FISH+ molecular subset (hypothetically the most likely subgroup to benefit from cetuximab) showed no statistical differences in outcomes between arms. Figure 1



      Conclusion:
      Determination of KRAS mutation status did not identify a subgroup of nonSCC patients with differential outcome from addition of cetuximab to front-line chemotherapy. In contrast to CRC, cetuximab does not appear to confer benefit to patients with KRAS-WT nonSCC NSCLC.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 4
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      P3.02c-042 - IMpower110: Phase III Trial Comparing 1L Atezolizumab with Chemotherapy in PD-L1–Selected Chemotherapy-Naive NSCLC Patients (ID 5094)

      14:30 - 14:30  |  Author(s): R. Herbst

      • Abstract

      Background:
      For patients with advanced NSCLC without genetic driver alterations, cisplatin/carboplatin+pemetrexed is a standard-of-care first-line (1L) treatment for non-squamous histology; and cisplatin/carboplatin+gemcitabine for squamous histology. Although immunotherapies targeting PD-L1/PD-1 are currently available for 2L+ NSCLC, chemotherapy remains the main 1L option despite poor survival and toxicities. Atezolizumab, an anti–PDL1 mAb, prevents PD-L1 from interacting with its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy was demonstrated with atezolizumab in non-squamous and squamous NSCLC, with Phase I and II studies exhibiting durable responses and survival benefit that increases with higher PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110, a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of atezolizumab vs cisplatin/carboplatin+pemetrexed or gemcitabine as 1L therapy for PD-L1–selected chemotherapy-naive patients with advanced non-squamous or squamous NSCLC, respectively.

      Methods:
      Eligibility criteria include stage IV non-squamous or squamous NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally-assessed PD-L1 expression ≥1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, ≈65%). Exclusion criteria include active or untreated CNS metastases, prior immune checkpoint blockade therapy or autoimmune disease. Patients will be randomized 1:1 to receive atezolizumab or cisplatin/carboplatin+pemetrexed (non-squamous)/gemcitabine (squamous) for 4 or 6 21-day cycles. Patients in comparator arms can receive pemetrexed (non-squamous)/best supportive care (squamous) until RECIST v1.1 disease progression. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are PFS and OS. Key secondary efficacy endpoints include ORR, DOR, IRF-assessed PFS (RECIST v1.1) and TTD. Safety and PK will also be evaluated. Tumor biopsies at RECIST v1.1 progression will be assessed for immunologic biomarkers associated with responses to atezolizumab and to differentiate non-conventional responses from radiographic progression.

      Planned enrollment, N 570
      Histology Non-squamous Squamous
      Experimental arm Atezolizumab (1200 mg q3w)
      Comparator arm Cisplatin (75 mg/m[2] IV q3w) + pemetrexed (500 mg/m[2] IV q3w) or Carboplatin (AUC 6 mg/mL/min IV q3w) + pemetrexed (500 mg/m[2] IV q3w) Cisplatin (75 mg/m[2] IV q3w) + gemcitabine (1200 mg/m[2] IV days 1, 8) or Carboplatin (AUC 5 mg/mL/min IV q3w) + gemcitabine (1000 mg/m[2] IV days 1, 8)
      Stratification factors Sex ECOG Histology (non-squamous vs squamous) PD-L1 expression by IHC
      ClinicalTrials.gov identifier NCT02409342


      Results:
      Section not applicable

      Conclusion:
      Section not applicable

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      P3.02c-048 - A Phase I/II Trial Evaluating the Combination of Stereotactic Body Radiotherapy and Pembrolizumab in Metastatic NSCLC (ID 5249)

      14:30 - 14:30  |  Author(s): R. Herbst

      • Abstract

      Background:
      Immune checkpoint inhibitors are taking on a growing role in the treatment of patients with metastatic NSCLC. Pre-clinical evidence suggests that radiotherapy may increase the frequency, or enhance the strength of the host anti-cancer immune response. We report the preliminary results of an ongoing phase I/II trial combining stereotactic body radiotherapy (SBRT) and the anti-PD-1 antibody pembrolizumab in patients with metastatic NSCLC.

      Methods:
      Eligible patients are those with metastatic NSCLC who have received no prior immune-directed therapy, and have at least 2 sites of measurable disease as per RECIST 1.1. PD-L1 expression is not required for study entry. All patients are treated with pembrolizumab at 200 mg every 3 weeks until development of progressive disease by immune-related RECIST criteria (irPD). After irPD, patients receive SBRT to a single site of disease and continue pembrolizumab. The primary endpoint is safety and tolerability. Secondary endpoints include the pre- and post-SBRT overall response rate.

      Results:
      27 patients with advanced NSCLC have enrolled and started trial therapy. The overall response rate (irPR and irCR) to the initial course of pembrolizumab is 35%. To date, 13 patients have had irPD: 5 were not eligible for SBRT and stopped study treatment (2 developed new brain metastases, 3 had decline in PS), and 8 patients received SBRT to a single site of disease (6 thoracic, 1 adrenal, 1 vertebral) and continued pembrolizumab. 5 of these patients are evaluable for post-SBRT response: 1 patient had confirmed irPD, 4 have irSD and continue pembrolizumab post-SBRT at a median duration of 3 months (range 1 to 5 months). 2 of the 4 patients with irSD have had > 20% decrease in the sum of diameters of their unirradiated targets, since SBRT. Regarding adverse events, in the pre-SBRT phase 6 of 27 patients (22%) developed grade 3 treatment-related toxicity (2 colitis, hepatitis, pneumonitis, hypothyroidism, conjunctivitis). In the SBRT and post-SBRT phases, there have been no grade 2 or greater treatment-related events.

      Conclusion:
      The addition of SBRT to pembrolizumab has not resulted in an increase in treatment-related toxicity. Several patients who had serially confirmed irPD to pembrolizumab monotherapy underwent SBRT and now have irSD, with some evidence of tumor regression. Updated results will be presented.

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      P3.02c-070 - Combination Immunotherapy with MEK Inhibitor for Treatment of Kras-Mutant Lung Cancer in Animal Model (ID 5503)

      14:30 - 14:30  |  Author(s): R. Herbst

      • Abstract

      Background:
      Lung cancer remains a major cause of cancer mortality. Malignant lesions are normally endogenously corrected by the immune surveillance system. However, tumors evade this immunity by inducing immunosuppressive microenvironments during cancer progression. Recent studies demonstrate that multiple cancer types, including melanoma, lung, kidney, bladder, and stomach, respond to immune checkpoint inhibitors, such as PD-L1 and PD-1 with 11-30% response rates and durable responses. However, a substantial number of patients still fail to respond to immunotherapy and the refractory mechanisms are largely unknown. In this study, we focus on KRas-driven lung cancers, as there are no clinically effective targeted drugs available for treating this type of lung cancer.

      Methods:
      We examined tumor infiltrated immune cells using FACS, CyTOF2, and Immunostaining of lung sections during the progression of lung tumors in KRas mutation and p53 knockout-driven lung cancer mouse models; KRas[G12D/+];p53[-/-] (KP). Using this mouse model, we determined the anti-cancer efficacy of combined inhibition of MEK and immune checkpoint molecules.

      Results:
      We demonstrate that there is a gradual increase in the number of myeloid derived suppressor cells (MDSC) and that the combination of either anti-PD-1 or anti-PD-L1 antibody along with a MEK inhibitor shows anticancer efficacy in these animal models. These combinations, in comparison to either single agent alone, effectively blocks the growth of subcutaneously injected syngeneic mouse lung cancer cells in immune competent transgenic KP mice, significantly increasing the survival rates: 37.5% (for anti-PD-1 antibody and MEK inhibitor), 62.5% (for anti-PD-L1 antibody and MEK inhibitor) vs. 0% single agents or control at the end of treatment. We find that the tumors in the control treated group harbor a substantial number of immune cells, including PD-L1 expressing MDSC.

      Conclusion:
      The combination treatment with either an anti-PD-1 or anti-PD-L1 antibody along with a MEK inhibitor dramatically modulates the composition and the activity of tumor infiltrated immune cells. Tumors in the combination treatment group show a significant decrease in PD-L1 expressing MDSC in comparison with control tumors. Additionally, combination treatment blocks PD-L1 activity of the infiltrated PD-L1 expressing MDSC in malignant tumors and thus lead to improved survival. These results point to a potential therapeutic opportunity for currently untargetable KRas-driven lung cancers.

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      P3.02c-088 - Acquired Resistance to Programmed Death-1 Axis Inhibitors in Non-Small Cell Lung Cancer (NSCLC) (ID 5625)

      14:30 - 14:30  |  Author(s): R. Herbst

      • Abstract

      Background:
      Programmed death-1 (PD-1) axis inhibitors are increasingly being used to treat patients with advanced NSCLC. Despite durable responses relative to chemotherapy, resistance to such therapy develops in the majority of responders, with median duration of response from 12-17 months. Mechanisms of acquired resistance (AR) to PD-1 axis inhibitors are poorly understood.

      Methods:
      Patients with advanced NSCLC and acquired resistance (AR) to PD-1 axis inhibitor therapy were enrolled to an IRB approved repeat biopsy protocol allowing collection of clinical data, archived and fresh tumor tissue, and blood for analysis. Molecular analyses including whole exome sequencing of pre- and post-treatment tumor specimens were performed.

      Results:
      Twelve cases were available for analysis (table 1). Eight and two patients developed resistance limited to lymph nodes (LNs) and adrenal gland respectively. The two remaining patients experienced tumor progression in LNs with other sites of tumor growth (one in liver, one in lung). Nine patients had sufficient archived pre- PD-1 axis inhibitor tumor tissue for analysis/ comparison, leaving three unpaired cases. Genomic analysis of tumor specimens identified two patients with acquired tumor beta-2-microglobulin (B2M) defects at resistance. A patient derived xenograft generated from one of the resistance samples (patient #6) lacked production of B2M protein and did not express surface MHC-1. Additional analyses including immunophenotyping with multiplexed quantitative immunofluorescence on these and other patient samples are ongoing. Figure 1



      Conclusion:
      Lymph nodes may be a particularly susceptible area to AR to PD-1 axis inhibitors. Defects in B2M leading to loss of tumor MHC-1 presentation may represent a unique mechanism of AR to immune checkpoint inhibitors. Further studies to determine the frequency of defects in antigen presentation machinery in tumors with resistance to PD1 axis inhibitors are warranted.

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    SC14 - Immunotherapy of NSCLC (ID 338)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      SC14.01 - Immunotherapy in the First-Line Setting of Advanced NSCLC (ID 6653)

      11:00 - 11:20  |  Author(s): R. Herbst

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Immunotherapy in the First-Line Setting of Advanced NSCLC Lung cancer remains the leading cause of cancer-related deaths worldwide. Advances in screening, surgery and treatment have helped to improve the median survival for patients with lung cancer over the past decade, however, the five-year survival rate remains less than 20%. The majority of patients are diagnosed with advanced stage disease, who are treated with platinum-based chemotherapy, followed by targeted, combination, or immunotherapies. Given the response rates seen with the use of immunotherapy in the second-line setting, it was appropriate to begin to explore if these agents could be given to patients earlier in their treatment. Immunotherapies have been found to be better tolerated than chemotherapy and have the potential for long-term survival, thus could benefit patients as first-line therapy, as some patients will never go on to receive second-line treatment. Two agents, nivolumab and pembrolizumab, both monoclonal antibodies targeting programmed cell death protein 1 (PD-1), are approved for use in patients with non-small cell lung cancer (NSCLC) who have received prior chemotherapy. The KEYNOTE-024 randomized phase III trial of pembrolizumab vs. standard of care (platinum-based chemotherapy), demonstrated superior progression-free survival (PFS) and overall survival (OS) for first-line treatment in patients with tumors expressing high levels of programmed cell death ligand 1 (PD-L1) (tumor proportion score ≥50%). The CheckMate-026 randomized, phase III study of nivolumab vs. standard of care in treatment-naïve patients with tumors expressing ≥5% PD-L1 did not meet the primary endpoint of PFS. For this presentation, the use of predictive markers in the front-line setting will be discussed and implications for combination therapy will be reviewed.

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