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E. Quoix
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.02 - Neratinib ± Temsirolimus in HER2-Mutant Lung Cancers: An International, Randomized Phase II Study (ID 4302)
16:00 - 17:30 | Author(s): E. Quoix
- Abstract
- Presentation
Background:
Combined inhibition of HER2 and mTOR is synergistic in models of HER2 (or ERBB2)-mutant lung cancers. PUMA-NER-4201 is an adaptive, multinational, randomized phase II study comparing the pan-HER inhibitor neratinib (Puma Biotechnology) ± the mTOR inhibitor temsirolimus in patients with advanced HER2-mutant lung cancers. In stage 1 of the study, neratinib + temsirolimus met predefined criteria for expansion into stage 2 [Besse et al. ESMO 2014].
Methods:
Patients with stage IIIB/IV locally determined HER2-mutant cancers were randomized to receive oral neratinib 240 mg once daily ± intravenous temsirolimus 8 mg once weekly (escalated to 15 mg/week after a 3-week cycle if tolerated) with loperamide prophylaxis. Primary endpoint: overall response rate (RECIST v1.1). Secondary endpoints: duration of response, progression‑free survival, overall survival, toxicity assessments (NCI-CTCAE, v4.0). ClinicalTrials.gov: NCT01827267.
Results:
Of 62 randomized patients, 60 received ≥1 dose of neratinib: neratinib alone (n=17); neratinib + temsirolimus (n=43). Baseline characteristics: male/female 32%/68%; median age 66 years; never smokers 60%; adenocarcinoma 98%. HER2 (or ERBB2) mutation type: exon 20 insertions 93.5%; missense substitutions 3.2%; unspecified 3.2%. The most common HER2 allelic variant was A775_G776insYVMA. Exploratory biomarker analysis from available tumor and plasma samples will be presented at the meeting. Efficacy and safety results are shown in the table. With loperamide prophylaxis, the incidence of grade 3 diarrhea was 12% with neratinib and 14% with neratinib + temsirolimus, which lasted for a median duration of 1.5 (interquartile range, 1.0‒2.0) days and 4.0 (interquartile range, 2.0‒16.0) days, respectively. Figure 1
Conclusion:
Neratinib (240 mg/day) + temsirolimus (8 or 15 mg/week) produced responses lasting 2 to 18+ months in 19% of patients with HER2‑mutant lung cancers. Correlative data will be presented at the meeting. Diarrhea was manageable with loperamide prophylaxis.
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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
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-037 - Prognostic Impact of 1st-Line Treatment and Molecular Testing in Advanced NSCLC in France - Results of the IFCT-PREDICT.amm Study (ID 5628)
14:30 - 15:45 | Author(s): E. Quoix
- Abstract
Background:
In 2013, recommendations for 1st line treatment in advanced NSCLC included a platinum based chemotherapy (pCT) with or without bevacizumab (BEV-pCT), an EGFR-TKI, or a non-platinum based CT (non-pCT) depending on clinical, pathological and molecular characteristics. Molecular testing for KRAS, EGFR and ALK, is routinely performed in France for advanced non-squamous NSCLC. However, the prognostic impact of the molecular status knowledge before beginning 1st line treatment is unknown.
Methods:
After a cross-validation study, KRAS, EGFR and ALK molecular status were assessed in 843 consecutive patients (pts) with previously untreated advanced NSCLC (all histologic subtypes) and categorized as: EGFR/ALK+, KRAS+, wild-type (WT), undetermined (UD) and not done (ND). Treatments from the 1st to 3rd line were separated into 4 groups: p-CT, BEVA-pCT, EGFR/ALK TKI and non-pCT. Demographic, clinical and pathological characteristics were collected and pts were followed-up until death. Overall survival (OS) and progression-free survival (PFS) for each line were determined. Prognostic factors including treatment categories (p-CT as reference) and biomarkers status (WT as reference) were studied by Cox model.
Results:
Treatments were analyzed in 767 (91.0%) of the 843 pts enrolled between 01/2013 and 02/2014. Pts were 93.1% Caucasians, 66.2% males. Median age was 62.4 yr (28-92). 13.4% were never smokers. PS ≥2 were 21.4% and 90.3% were stage IV. 76.5% had adenocarcinoma, 14.5% squamous cell carcinoma and 9% others with WT=40.4%, KRAS+=23.1%, EGFR/ALK+=10.2%, UD=5.1%, ND=21.2%. 1st line treatments were: p-CT=75.9%, BEVA-pCT=14.2%, EGFR/ALK TKI=7.8% and non-pCT=2.1%. With a 30.3 months (mo) median of follow-up, median OS and PFS were 10.7 mo and 5.3 mo, respectively. Factors independently associated with shorter OS were PS≥2 (HR=2.08, p<.0001), KRAS+, UD and ND mutation status (HR=1.40, p=.002; 1.53, p=.02; 1.29, p=.02), and non-pCT as 1st line treatment (HR=1.92, p=.01), while EGFR/ALK+ (HR=.38, p<.0001) and BEVA-pCT (HR=.54, p<.001) were associated with better survival. There was no interaction effect between biomarkers status and OS treatment groups. However, BEVA-pCT in 1st line therapy in KRAS+ and WT NSCLC (p<.0001 and <.0003, respectively) was associated with longer survival compared to p-CT, while giving a TKI or p-CT in 1st line therapy in EGFR/ALK+ NSCLC did not affect OS.
Conclusion:
Results from the IFCT-PREDICT.amm study suggest that prognosis of advanced NSCLC might be optimized in 1st line setting by the knowledge of EGFR/ALK molecular status and the opportunity to give a BEVA-pCT regimen, especially in patients with KRAS+ and WT tumor.
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SC05 - Novel Drugs in Thoracic Cancers (ID 329)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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SC05.04 - Lung Cancer Vaccines: An Update (ID 6620)
11:00 - 12:30 | Author(s): E. Quoix
- Abstract
- Presentation
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.
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.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)
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