2019年 日本臨床腫瘍学会
やけに大上段に構えたシンポジウム名で、思わず参加してしまった。
冒頭はスイスの演者、トリは米国の演者。
米国の演者の方が、英語が聞きやすかった。
スイスの演者はドイツっぽい訛があるように感じた。
実地臨床で、どんな風に再生検をして、結果に基づいて次の治療を決めるか、ということを知りたかったのだが、そういった点ではがっかりした。
とったノートを書き起こしたら、やっぱり英語ばっかりになってしまった。
○SY10-1：Updated Treatment for ALK positive advanced NSCLC
・EML4-ALK had been identified 2007
・Prevalence: 2-5% of non-Sq NSCLC
・Clinical characteristics: brain mets, effusion, embolism inducing
・More frequent in young patients
・At speakers hospital, out of 6 patients younger than 30y.o., 4 patients harboring ALK rearrangement, and 2 patients harboring ROS1 rearrangement
・Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer.
J Clin Oncol. 2018 Apr 20;36(12):1199-1206
ALK rearrangement variant and lorlatinib efficacy
・ EML4-ALK variant affects ALK resistance mutations
J Clin Oncol 2018 Apr 20;36(12):1257-1259
PD時のcrizotinib treated patientsの70%がbrain metsを伴っていた
・Characteristics of new generation drugs
Bind more strongly to ALK
Wide spectrum of ALK variant inhibit potential
Integrated CNS penetration
・ALK inhibitors
Crizotinib: PROFILE 1007（2nd line）, PROFILE 1014（1st line）
Ceritinib: ASCEND studies
Alectinib: ALEX study (Peters et al., N Engl J Med 2017), J-ALEX study
Brigatinib: ALTA-1L (Camidge et al., N Engl J Med 2018)
・The difference of ALK inhibitor toxicities
…daily life QoL: Alectinib is the best option
・ongoing head to head study
Ensartinib vs Crizotinib
Lorlatinib vs Crizotinib
…but if these trials results in positive, Japanese clinical practice won’t change.
・Second line drug selection
Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study.
Oncotarget. 2017 Mar 28;8(13):21903-21917
2nd generation ALK-TKI＞1st generation ALK-TKI＞BSC
・1st line alectinib induces more G1202R resistant mutation（up to 30%）
・ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer.
J Clin Oncol. 2019 Jun 1;37(16):1370-1379
・Re-biopsy and liquid biopsy
Longitudinal analysis of plasma ALK mutations during treatment with next-generation ALK inhibitors.
Dagogo-Jack et al., Abst. #9068, ASCO 2019
・Brigatinib for alectinib-resistant ALK+NSCLC: ORR 67%
・Lorlatinib for any ALK-TKI resistant ALK+NSCLC: ORR>40%
・Re-biopsy for AKL-TKI resistant ALK+NSCLC: based on exploratory data…
If ALK rearrangement revealed…ALK-TKI recommended
If ALK rearrangement not revealed…Chemotherapy recommended
・Immunocheckpoint agents should not administered for ALKoma
○SY 10-2
・ROS1 rearrangement
1-2% of NSCLC
Adenocarcinoma, younger patients, no / light smoker
G2032R resistant mutation is common
Safety and preliminary clinical activity of repotrectinib in patients with advanced ROS1 fusion-positive non-small cell lung cancer (TRIDENT-1 study).
Abst. # 9011, Cho et al, ASCO 2019
・BRAF mutation
Of 50%...BRAF V600E mutation, smokers are frequently observed.
・RET rearrangement
Similar characteristics with ROS1 rearrangement
1st line setting: vandetanib, lenvatinib, cabozantinib, RXDX105
2nd line setting: LOXO292 (Drilon et al, ASCO 2018), BLU667 (Gainor et al, ASCO 2019)
・MET exon14 skipping mutation
3% of NSCLC, mostly adenocarcinoma, especially sarcomatoid carcinoma
1st line setting:
Phase II study of tepotinib in NSCLC patients with METex14 mutations.
Paik et al., ASCO 2019, Abst. #9005
Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study.
Wolf et al., ASCO 2019, Abst. #9004
○SY 10-5: Novel treatment strategy for EGFR-mutant Lung Cancer
・Advantage of osimertinib compared to other EGFR-TKIs:
Selectivity for mutant EGFR
CNS penetration potential
Toxicity
・Resistance mechanisms for osimertinib
Intrinsic mutation: C797S (7%), C797S+L718Q(1%), L718Q+Exon 20 ins(1%)
By-pass track: HER2 amplification(2%), MET amplification(15%)
Signal transduction change: PIK3CA mutation(7%)
Other mutation: SPTBN1-ALK rearrangement(1%), BRAF mutation(3%), KRAS mutation(3%)
・143 patients resistant mechanisms review
Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib.
Oxnard et al., JAMA Oncol 1527-1534, 2018
・ongoing trials and concepts
osimertinib + gefitinib
osimertinib + savolitinib, Sequist AACR 2019
SAVANNAH study, phase II
Osimertinib→PD→osimertinib + savolitinib
JNJ-61186372
JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC).
Haura et al., ASCO 2019 Abst. #9009
U3-1402
Safety and preliminary antitumor activity of U3-1402: A HER3-targeted antibody drug conjugate in EGFR TKI-resistant, EGFRm NSCLC.
Pasi A Janne et al., ASCO 2019 Abst. #9010
・ERK and MEK cause TKI resistance
osimertinib + ERK / MEK inhibitor
osimertinib + selumetinib
・osimertinib + chemo combo
Platinum + pemetrexed + osimertinib followed by pemetrexed + osimertinib pIII
