晚期NSCLC靶向和化疗方案选择的几个问题

Lung cancer：肺腺癌向小细胞肺癌转化一例
患者，男性，80岁，2011年9月被确诊IB期肺癌。术前癌胚抗原（CEA）4.4ng/ml（CEA参考范围，<3.4），CYFRA21-1 3.63ng/ml（参考范围<3），特异性神经元烯醇化酶（NSE）17.9ng/ml（参考范围，<15）。术后未接受辅助化疗和CT评估。8个月后，自觉腰部和右季肋区疼痛。复查胸部和腹部CT显示L1椎旁肿块，右侧L1腰椎和第九肋骨质破坏。根据手术标本检测EGFR基因发现19号外显子缺失。然而，口服埃克替尼治疗25天后症状并没有缓解。相反，他觉得腰痛加剧，两下肢麻木，肌肉无力，便秘和排尿困难。 2012年6月复查腹部CT显示椎旁软组织和肝脏转移较前进展。CEA ，CYFRA21-1和NSE分别上升至29.50 ng/ml，27.53 ng/ml和211.40ng/ml。通过CT引导下经皮穿刺活检，证实转移性肿块为小细胞肺癌，考虑来源于肺。进一步检测EGFR基因，发现19号外显子有相同的缺失。随后予以依托泊苷和顺铂联合化疗外加局部放疗。治疗后，病人疼痛缓解CEA，CYFRA21-1和NSE水平分别为每毫升减少到16.81ng/ml，7.69ng/ml和23.15ng/ml。6个月后复查显示患者病情稳定。

EMCTO 2013: A study of simultaneous occurrence of EGFR mutations and HER2 gene amplifications in large series of NSCLC
http://ecancer.org/news/4075-emc ... series-of-nsclc.php
13 May 2013

In a molecular profile analysis of 2271 cases of non-small cell lung cancer (NSCLC), EGFR was mutated in 12% and KRAS in 32% of cases. HER2 gene amplification was confirmed as a rare event in NSCLC (4%).

Coexistence of HER2 gene amplification and EGFR mutation was identified in 3 cases, while KRAS was mutated in 7 HER2-amplified cases. Double EGFR mutations were however found in only 2 cases.

NSCLC with HER2 amplification were frequently (39%) associated with KRAS activating mutation. A rare A859T mutation was found in one case and was associated with HER2 gene amplification. This mutation was previously associated with resistance to tyrosine kinase inhibitors (TKIs).

This novel molecular insight in large sample of NSCLC cases was presented by Dr Zoran Gatalica, Adjunct Professor of Pathology at Creighton University School of Medicine, Omaha, USA and Director of Oncologic Pathology at Caris Life Sciences International at the European Multidisciplinary Conference in Thoracic Oncology (EMCTO).

HER2 is a member of the EGFR family of receptor tyrosine kinases. It forms heterodimers with other family members enhancing kinase-mediated activation of the downstream signaling pathways.

HER2 amplification has been implicated as a mechanism of acquired resistance to EGFR-TKIs that occurs in a subset of tumours that do not show the acquired, somatic resistance EGFRT790M mutation.

Activating mutations in the tyrosine kinase domain of HER2 have been described in a subset of lung adenocarcinomas and as mutually exclusive with EGFR and KRAS mutations. Arcila et al. previously reported (CCR 2012) that HER2 mutation was significantly associated with NSCLC patients who were never smokers but did not associate with sex, race or disease stage.

They concluded that HER2 mutations identify a distinct subset of lung adenocarcinomas. Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting HER2, they advocated that routine clinical genotyping of lung adenocarcinoma should include HER2. However, no association between HER2 mutation and HER2 overexpression was shown in their study or in results reported by Stephens, et al. (Nature 2004) who determined the prevalence of HER2 mutations in primary NSCLC to be 4.2%, with prevalence increasing to 9.8% in patients with adenocarcinoma.

In this latest analysis, Dr Gatalica headed a team of investigators from Caris Life Sciences, Phoenix, USA and Basel, Switzerland in characterising the molecular profiles of 2271 patients with NSCLC. They used the Molecular Intelligence&#8482; technique to evaluate samples for HER2 protein expression (immunohistochemistry), HER2 gene amplification (FISH), EGFR and KRAS gene mutations (sequencing). Their goal was to analyse the frequency of the simultaneous occurrence of EGFR mutations and HER2 gene amplifications.

As determined by sequencing, EGFR was mutated in 12% and KRAS mutations were seen in 32% of NSCLC patients. Consistent with earlier reports, HER2 gene amplification (HER2/CEP17>2.2) was detected by FISH in 22 (4%) of 589 tested cases, associated with 3 protein expression. There was no evidence that HER2 amplification associated with T790M mutation.

Coexistence of HER2 gene amplification and KRAS mutations were seen in 7 cases. Simultaneous HER2 gene amplification and EGFR mutation was demonstrated in 3 cases (L858R, A859T and E746_A750del, respectively). Double EGFR mutations (L858R/T790M and E746_A750del/T790M) were also rare and found in only 2 cases.

The most frequent association was seen between HER2 amplification and KRAS activating mutation, which occurred with a frequency of 39%. One sample showed the rare A859T mutation, which had been reported by Han et al. (JCO 2005) to associate with resistance to TKIs (HER2 status was unknown); however this mutation was associated with HER2 gene amplification in the current analysis.

The authors speculated that previously reported resistance to TKIs may have been due to HER2 gene amplification rather than an effect of the EGFR mutated protein.

Since earlier studies have suggested that HER2 amplification may cause resistance to erlotinib and gefitnib, NSCLC patients with HER2 amplification and activating EGFR mutation may respond better to afatinib, which inhibits both HER2 and EGFR activity. In January afatinib was granted priority review by FDA for treatment of patients with advanced NSCLC harbouring EGFR (HER1) mutations.

The study authors advocate for using a comprehensive biomarker evaluation in formulating a targeted treatment strategy for patients with NSCLC to obtain the maximum treatment benefit together with minimum side effects. All authors are employed by Caris Life Sciences which funded this study.

Besides this recent recognition that HER2 amplification may be a mechanism of acquired resistance to EGFR-TKI that occurs in a subset of tumours lacking the acquired, somatic resistance EGFRT790M mutation, the amount of research dedicated to HER2 in NSCLC is increasing. At the recent ESMO Signalling Pathways Symposium entitled “Targeting the HER/EGFR family: Focus on breast, lung and colorectal cancers” and data publication in the JCO (2013), it has been acknowledged that HER2 mutated NSCLC represent a small distinct subgroup of oncogene addicted cancers with specific demographics and potentially outcomes.

Results of that largest analysis to date in patients with NSCLC and HER2 mutations, despite limitations of studying data retrospectivelly, provide important insights into HER2-driven NSCLC. Furthermore, this largest study in HER2-mutated NSCLC reinforced the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.

ACTIVITY OF AFATINIB IN UNCOMMON EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTATIONS IN LUX-LUNG 3, A PHASE III TRIAL OF AFATINIB OR CISPLATIN/PEMETREXED IN EGFR MUTATION-POSITIVE LUNG CANCER
ESMO 2012
Background
Afatinib (A) is an irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 with in vitro activity against activating and resistant EGFR mutations. LUX-Lung 3 demonstrated superiority of A vs cisplatin/pemetrexed (CP) in 345 treatment-naive pts with EGFR mutation-positive NSCLC; median progression-free survival (PFS) 11.1 vs 6.9 mo, HR 0.58, p &equals; 0.0004 (ITT cohort) and 13.6 vs 6.9 mo, HR &equals; 0.47, p < 0.0001 for pts with common (Del19/L858R) mutations (n &equals; 308). Here we present data from pts with uncommon EGFR mutations, detected by central EGFR screening assay (Theracreen29).

Methods
All pts (n &equals; 345) were stratified according to mutation (Del19, L858R, other) and randomized 2:1 to oral A 40 mg daily or IV CP (75 mg/m2 &plus; 500 mg/m2 q21 days up to 6 cycles) until progression. Other mutations were categorized into 5 groups: T790M, G719X, S768I, exon 20 insertions, L861Q; the first 3 groups included double mutant pts. PFS, best overall response and tumour shrinkage by independent review were described per pt within these 5 groups.

Results
Uncommon mutations comprised 10.7&percnt; (n &equals; 37, A: 26, CP: 11) of the trial population. Breakdown into the 5 groups was: de novo T790M (A:11, CP:2), exon 20 insertions (A:6, CP:3), G719X (A:3, CP:3), L861Q (A:3, CP:3), S768I (A:3, CP:0). Baseline imbalances between the A and CP arms were noted for smoking status (never smoker 65&percnt; vs 82&percnt;, respectively) and presence of brain (27&percnt; vs 0&percnt;) and liver metastases (27&percnt; vs 18&percnt;). Of 32 pts with target lesions, 19/23 on A and 8/9 on CP had measurable shrinkage. The small size of the uncommon mutation cohort, its molecular heterogeneity and numeric imbalances within genetic subgroups limited formal statistical analyses. Tumour response and prolonged PFS were noted in A-treated pts with L858R &plus; T790M (1PR, 11.0 mo; 3SD, 9.6&plus; mo, 8.5 mo and 6.7 mo); L861Q (1SD, 8.3 mo); G719X (1PR, 10.8 mo); S768I &plus; L858R (1PR, 13.8&plus; mo); S768I (1PR, 19.2&plus; mo).

Conclusions
RECIST responses and prolonged disease control were observed in pts with most types of uncommon EGFR mutations. The efficacy of A in uncommon EGFR mutations should be explored in larger cohorts in future studies.

Initial detection of the double epidermal growth factor receptor (EGFR) mutation (L858R or deletion in exon 19 [del 19] plus T790M) in non-small cell lung cancer (NSCLC) patients (p) with brain metastases (mets) and the influence of first-line chemotherapy on outcome to erlotinib.
http://meeting.ascopubs.org/cgi/ ... 15_suppl/7590?rss=1
Background: Progression-free survival (PFS) in EGFR-mutant NSCLC p treated with erlotinib is unpredictable at the individual level. The initial presence of double mutations (EGFR L858R or del 19 plus T790M) is associated with shorter PFS. We hypothesized that the site of mets and/or prior chemotherapy could also influence outcome in these p with double EGFR mutations. Methods: The T790M mutation was assessed in 129 advanced NSCLC p by TaqMan assay in the presence of a peptide-nucleic acid designed to inhibit the amplification of the wild-type allele. Results: De novo T790M mutations were identified in 35% (45 of 129) of EGFR-mutant p before receiving erlotinib. PFS was 12 months (m) for p with double mutations and 18 for p with only L858R or del 19 (P=0.02). The T790M mutation was detected more frequently in p with bone mets (35.6% vs 16.7%; P=0.03). No effect on PFS or MS was observed in p with the T790M mutation according to bone, lung, liver or pleura mets. However, when p with T790M were divided according to the presence of brain mets, PFS was 1 m for 4 p with brain mets vs 13 m for 41 p without brain mets (P=0.002), and MS was 6 m for p with brain mets vs 36 m for those without (P=0.009). Overall, in the multivariate analysis, the presence of the double mutation did not affect the risk of shorter MS (HR, 1.3; P=0.49), but p who had received prior chemotherapy had significantly longer MS (HR, 0.48; P=0.02). Conclusions: The initial double EGFR mutation (EGFR L858R or del 19 plus T790M) is a marker for poor prognosis in p with brain mets. In addition, initial chemotherapy can play a role in the management of NSCLC p with the double EGFR mutation.

谢谢老马！

RET-mutated NSCLC as a new niche indication – Newly identified RET mutation (1-2% of NSCLC) represents a new niche indication for cabozantinib, which is also a RET inhibitor. At ASCO, a group from Memorial Sloan Kettering will report updated clinical experience with cabozantinib in this rare subset. Initial findings from this trial were recently published and showed promising activity in 3 patients with RET mutation, who appear to derive benefit from cabo (2 partial responses, 1 durable SD, see figure from the article below).

-------------------------------------
RET Fusions in NSCLC
Surgical series of 936 patients examined by PCR (with IHC and FISH validation)
13 cases found (1.4%)
     - 11 adenos, 2 adenosquamous
     - 7 women, 6 men
     - 9 KIF5B-RET, 3 CCDC6-RET, 1 NCOA4-RET
     - More often poorly differentiated, young (<60 yrs), never smokers (82%), solid subtype

ASCO: Melanoma Tx May Be Option in Lung Cancer
By Charles Bankhead, Staff Writer, MedPage Today
Published: June 05, 2013
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
CHICAGO -- A drug developed for melanoma has demonstrated activity in a subgroup of patients with non-small cell lung cancer (NSCLC), a preliminary clinical study showed.

Eight of 20 patients had objective responses to treatment with dabrafenib (Tafinlar), an inhibitor of the BRAF V600E mutation. The study provided the first evidence that BRAF V600E is a viable therapeutic target in NSCLC, as it is in melanoma.

The drug's safety profile was consistent with expectations based on clinical experience in melanoma, David Planchard, MD, PhD, of Gustave Roussy Institute in Villejuif, France, reported here at the American Society of Clinical Oncology meeting.

"The preliminary efficacy data from the first 20 patients is the first demonstration of clinical activity of a BRAF inhibitor in BRAF V600E non-small cell lung cancer," said Planchard. "The study has expanded the sample size and now allows enrollment of first-line patients."

The discovery that the BRAF V600E mutation occurs in at least half of all melanomas spurred development of several agents that inhibit the gene protein. BRAF V600E also occurs in NSCLC, but with an estimated frequency of 2% or fewer tumors.

In a phase III study of patients with BRAF V600E-mutant metastatic melanoma, treatment with dabrafenib induced tumor regression in almost all of the 187 patients who received the drug. Half of the patients had confirmed objective responses, and the dabrafenib-treated group had a median progression-free survival almost double that of the control group (Lancet. 2012; 380: 358-365).

To evaluate dabrafenib activity in BRAF V600E NSCLC, investigators in 12 countries enrolled patients with stage IV BRAF-mutant tumors treated with one or more prior systemic regimens.

The ongoing trial comprised two stages of investigation: If as many as three of the first 20 patients achieved investigator-assessed responses, the trial would continue to stage 2, which would expand by an additional 20 patients, including patients with previously untreated melanoma.

Planchard presented results for 25 enrolled patients, including 20 evaluable for efficacy. He said 13 of the 25 patients had discontinued, primarily because of disease progression (10 of 13). Two patients stopped treatment because of adverse events.

Review of baseline characteristics showed that eight patients were nonsmokers, 12 a smoking history ≤40 pack years, and five had a history exceeding 40 pack years. All 25 patients had adenocarcinoma, and treatment history consisted of one prior therapy in 17 patients, four patients each who had received two prior regimens or three or more.

The median time from initial diagnosis was 12 months, and the median time since first-line treatment for metastatic disease was 8.9 months.

Planchard reported that all but three of the first 20 patients had some degree of tumor regression, including eight who had at least 50% tumor shrinkage (partial response). All of the responses occurred in nonsmokers and patients with a smoking history ≤40 pack years. The three patients who had no tumor regression all had smoking histories >40 pack years.

Response duration ranged from 4 to 16 months

Four additional patients had stable disease, resulting in a disease control rate of 60%.

Adverse events have occurred in 24 of the 25 patients enrolled thus far, and 23 of the 24 were considered treatment related. Planchard said 11 patients had grade 3 adverse events, and none had grade 4. One adverse event was fatal. Serious adverse events occurred in 10 patients.

Five patients had adverse events that required dose reductions, and 10 patients had dose interruptions related to adverse events.

The most common adverse event was fatigue (10 patients), followed by decreased appetite (eight), and asthenia, rash, nausea, and anemia (six each). No type of grade 3 adverse event occurred more than once, with the exception of hypophosphatemia (two patients).

The results clearly demonstrate that BRAF V600E is "an actionable target beyond melanoma," said invited discussant Pasi A. Janne, MD, PhD, of Dana-Farber Cancer Institute in Boston.

The potential role of BRAF inhibitors in the treatment of NSCLC remains unclear, Janne continued. Durability of responses has yet to be determined, as the progression-free survival data with dabrafenib are immature. Experience with crizotinib (Xalkori) in NSCLC has shown a median PFS of less than 8 months.

Future studies are needed to determine whether the combination of a BRAF inhibitor and another targeted agent, such as a MEK inhibitor, has greater efficacy compared with either drug alone. Preclinical studies of BRAF V600E-mutant colorectal cancer have suggested synergistic activity with the combination of an anti-BRAF agent and an inhibitor of epidermal growth factor receptor.

cMet抑制剂列表

Pi3K突变和扩增

Abstract Number:
e13517

Citation:
J Clin Oncol 31, 2013 (suppl; abstr e13517)

Author(s):
William Rayford Gwin, Leihua Liu, Sumin Zhao, Wenle Xia, Neil Spector; Duke University Medical Center, Durham, NC



Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:


Background: Human epidermal growth factor receptor (HER) receptor tyrosine kinases play a key role in solid tumor oncogenesis. Despite broad expression of HER receptors in solid tumors, HER targeted therapies have not shown significant improvement in survival, calling into question the value of wild-type HER receptors as therapeutic targets. Here we found that an irreversible pan-HER tyrosine kinase inhibitor (TKI), neratinib, but not similar HER TKIs, induced morphologic changes in ovarian, TNBC, and prostate cancer cell lines consistent with induction of autophagy. Methods: SKOV3 (ovarian), OVCAR8 (ovarian), HBL-100 (TNBC), and LAPC4 (prostate) cancer cells were treated with lapatinib, gefitinib, CI-1033, afatinib, and neratinib (0.5mM-2.5mM). The activation state of HER2, EGFR, HER3, Akt, Erk, p70S6, 4EBP1, and Ulk1 was determined by Western blot analysis (WB) at various time points of neratinib treatment. LC3 was analyzed by immunofluorescence (IF) microscopy and WB. Analysis of proliferation, apoptosis, and cell cycle were performed using WST-1, annexin V, and PI staining, respectively. Results: Neratinib, but not similar HER TKIs, induced marked cytoplasmic vacuolization in tumors. The conversion of LC3-I to LC3-II in neratinib-treated cells was consistent with induction of autophagy. Moreover, PI3K/Akt, MAPK/Erk1/2 and mTORC1 signaling cascades were inhibited in neratinib-treated cells, and were associated with the inhibition of phospho-Ulk1, a key step in autophagy initiation. Treatment with neratinib alone resulted in G1 cell cycle arrest. Importantly, the combination of neratinib and chloroquine, an autophagy inhibitor, induced a statistically significant inhibition of cellular proliferation (p <0.01) and increased apoptosis compared to treatment with either drug alone. Conclusions: Our data suggest that more effective inhibition of wild-type HER receptors, can lead to mTORC1 inhibition, which in turn triggers autophagy. Here, autophagy appears to protect cells rather than inducing apoptosis. Consequently, targeting both HER receptors and autophagy represents an attractive therapeutic strategy to treat tumors expressing wild-type HER receptors.