Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
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.
Keywords: new cytotoxics, small-cell lung cancer, non-small cell lung cancer
SC05: NOVEL DRUGS IN THORACIC CANCERS
MONDAY, DECEMBER 5, 2016 - 11:00-12:30
SC05.03 NOVEL TYROSINE KINASE INHIBITORS IN LUNG CANCER
Caicun Zhou
Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai/
China
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 openlabel,
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.
Keywords: EGFR; ALK; targeted therapy; lung cancer
SC05: NOVEL DRUGS IN THORACIC CANCERS
MONDAY, DECEMBER 5, 2016 - 11:00-12:30
SC05.04 LUNG CANCER VACCINES: AN UPDATE
Elisabeth Quoix
Pneumology, Hôpitaux Universitaires de Strasbourg Nouvel Hôpital Civil,
Strasbourg/France
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
S44 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017