Background

Genotyping on cfDNA offers potential advantages in clinical practice for pt selection and serial monitoring of treatment (Tx) efficacy. Clinical relevance of sequential RASmut in cfDNA at different time points during 1L of pt with RASwt solid biopsies (SB) was evaluated.

Methods

Prospective, multi-center study in mCRC pt with RASwt according to SB and treated following standard practice. Liquid biopsies (LB) were collected before starting 1L, at 20 (± 2) weeks (w) and at disease progression (PD). Beaming PCR was used for cfDNA analysis; 3 mutant allele fraction (MAF) cutoffs were considered: 1%, 0.1% & 0.02%.

Results

Median progression-free survival (PFS) was 11.7 months (m) (9.9-13.0) (n = 102). There were no differences in the overall response rate (ORR) according to baseline LB at any cut off, being at MAF 0.02%: 78.7% (68.2- 87.1) in RASwt pt (n = 80) vs 61.5% (31.6 - 86.1) in RASmut pt (n = 13) (OR: 2.32; p = 0.180). MAF was not correlated with total cfDNA levels (p = 0.957). The % of mut cfDNA pt varied along time, with the smallest % at 20 w (Table). There were no emergent mutations at 20 w. Ten pt wt according to baseline LB presented mutations at PD. ORR was 76.9% (63.2 - 87.5) in pt always wt (n = 52) vs 76.2% (52.8 - 91.8) in pt with mut cfDNA at any time point (n = 21) (p = 1.0). There were also no differences in PFS between these 2 groups of pt: 13.0 m (10.9 - 15.4) vs 11.4 m (7.1 – 13.7) at MAF 0.02% (p = 0.095).Table:

531PD

Conclusions

RAS mutational status assessed in cfDNA before starting 1L or sequentially during P+CT Tx in pt with RASwt SB was not a significant predictor of PFS and ORR in none of the cutoffs considered, although in RASmut pt clinical results tended to increase as MAF decreased. The highest proportion of mutated pt was observed at PD, which may be linked to the emergence of resistance. Mutated cfDNA by itself did not predict a lack of clinical benefit to CT and P in our study.

Editorial acknowledgement

Marta Muñoz-Tudurí (TFS, S.L.).

Legal entity responsible for the study

Amgen S.A.

Funding

Amgen S.A.

Disclosure

M. Valladares-Ayerbes: Honoraria (self): Amgen, Merck, Roche, Servier, Bayer, Bristol-Myers; Advisory / Consultancy: Merck, Sanofi, Amgen; Speaker Bureau / Expert testimony: Roche, Servier, Bayer; Research grant / Funding (self): Roche; Travel / Accommodation / Expenses: Merck, Servier, Amgen, Roche. J.M. Viéitez: Travel / Accommodation / Expenses, attendance at conferences: Amgen, Roche, Servier; Research grant / Funding (self): Roche, Amgen. J.J. Cruz-Hernández: Honoraria (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche Farma; Advisory / Consultancy, Advisory Board: Bristol-Myers Squibb, Merck, MSD, Roche Farma, Pfizer, Janssen Cilag; Advisory / Consultancy, Consulting: Roche Farma. M. Llanos: Advisory / Consultancy, collaboration in lectures: Servier, Roche, Ipsen, Merck, Bristol, Sanofi, Eisai; Advisory / Consultancy: Amgen. A. Lloansí Vila: Shareholder / Stockholder / Stock options, employee and stakeholder of Amgen S.A: Amgen. All other authors have declared no conflicts of interest.

Background

Pem, an immune checkpoint inhibitor, has been demonstrated to be active in various neoplasms with MMRd. No data exist about its efficacy in MMRd glioma patients.

Methods

MMRd HGG patients relapsed after receiving RT and CT were treated with Pem. MMR status was analyzed by immunohistochemistry, including the MLH1, MSH2, MSH6, and PMS2 markers. MMR deficiency was defined as presence of a weak (wMMRd) or absent (aMMRd) signal on immunohistochemistry for at least one MMR protein. Other inclusion criteria were: ECOG PS 0-2, histologically confirmed gliomas, dexamethasone ≤4 mg. Pem was administered at 200 mg every 3 weeks until disease progression or unacceptable toxicity. Tumor response was evaluated by brain MRI every 10 weeks according to the RANO criteria. OS and PFS were evaluated by Kaplan-Meier curves. CTCAE v4.0 was used for toxicity assessment.

Results

Among 167 glioma patients, we found 22 MMRd gliomas. 12 PTS were treated with Pem: 8 wMMRd and 4 aMMRd. According to Bethesda criteria, all PTS had microsatellite stability. Tumor histologies included 5 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, 6 glioblastoma (GBM). MSH2 deficiency was found in 6 cases, MSH6 deficiency in 9 cases, PMS2 and MLH1 deficiency in 2 cases. Median number of prior lines of chemotherapy was 1 (range 1-5). Stable disease (SD) was reported in 4 PTS (33%); 8 PTS showed progressive disease (PD). PTS with anaplastic gliomas showed a statistically significant association with SD (p = 0.03, OR = 3); all GBM PTS reported PD; status of MMRd (weak/absent), IDH (mutated/wild-type), MSH2 and MLH6 (deficient/proficient) were not associated with SD. Median follow up was 14.7 ms. OS was 5.6 ms (95% CI 0.1-13.8), PFS 2.4 ms (95% CI 1.8-2.9). OS was 2.8 ms and 5.6 ms (p = 0.9), PFS was 1.8 ms and 3.1 ms (p = 0.5) in PTS with wMMRd and aMMRd. PTS reporting SD and PD had PFS of 7.4 ms (95% CI 4.6-10.2) and 1.8 ms (95% CI 0.2-3.4), p = 0.002; OS was “not reached” and 2.8 ms in PTS having SD vs PD (p = 0.04). Grade ≥3 adverse events were reported in 8% of PTS.

Conclusions

A subgroup of recurrent MMRd HGG patients might benefit from Pem, especially those with anaplastic gliomas. There was a trend for a longer PFS and OS in PTS with aMMRd. Analyses for identifying additional molecular predictive factors is ongoing.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Malignant pleural mesothelioma (MPM) is a rapidly progressive tumor with a poor prognosis. The benefit of first-line standard pemetrexed – platinum chemotherapy in MPM has been established. Currently, second-line chemotherapy is increasingly use, because many patients are fit at the progression of the disease. No standard second/further line chemotherapy exit for MPM after failure of first-line pemetrexed based chemotherapy. This study aimedat evaluating the clinical activity of weekly epirubicin as second/further line chemotherapy in elderly patients with MPM.

Methods

From July 2014 to March 2018, in Medical Oncology Department of Asst-rhodense Hospital, 22 patients (15 males and 7 females with a median age of 78 years, range 74-86) with MPM were eligible for analysis. Histology was epithelioid in 17 pts, sarcomatoid in 3 and biphasic in 2 patients. A Carboplatin-(AUC:4) pemetrexed doublet was administered in 14 pts and 8 pts received gemcitabine as single agent how first-line. Gemcitabine was given as second-line in 9 pts. Epirubicin was always administered with the same schedule at 20 mg/m2 day 1, 8, 15 every 28 until disease progression/intolerance.

Results

Overall response rate was as follows: 4 PR (18 %), 10 SD (45 %) and 8 PD (40%). Median time to progression was 5 months (range 3 – 11). No life threatening event occurred. No grade 3-4 toxicities were observed. Liver toxicity grade 1-2 in 2 pts (10%), thrombocytopenia grade 1 in 2 pts (9%), neutropenia grade 1-2 in 8 pts (40 %), fatigue grade 2 in 7 pts (32%), nausea grade 1 in 4 pts (20%).

Conclusions

Epirubicin has a modest clinical activity in pre-treated elderly patients with MPM in progression after one or two regimens, with an acceptable toxicity profile. It could be considered as a palliative treatment.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Perivascular epithelioid cell tumors (PEComa) are exceedingly rare mesenchymal neoplasms arising in a variety of anatomic sites. mTOR inhibitors are active in these neoplasms. However, no other effective treatments are available in those patients progressing to them. The PI3K–Akt–mTOR signaling pathway modulates neoplastic growth through signaling activation of ER and the EGF receptor family of receptor tyrosine kinases. ER drives PI3K/AKT activation in response to mTORC1 inhibition. This provides a rationale for combining anti-estrogens and mTORC1 inhibitors.

Methods

We retrospectively identified patients with advanced PEComa treated with mTOR inhibitors since January 2002 at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan – Italy. In a subgroup of them, exemestane was added at the time of progression.

Results

Twenty-eight patients with advanced PEComa treated with mTOR inhibitors were identified. Twenty–six were evaluable for response. Twelve out 26 (46%) had a PR and seven (27%) a SD, with a median PFS of 7 months. At the time of progression to sirolimus, 5 patients received a combination of sirolimus and exemestane and one of sirolimus, exemestane and GnRH. Three patients out 6 had a PR, 2 out 6 had a SD, and 1 out 6 had a PD, with a median PFS of 6 months. In this subgroup of patients treated with the combination, previous PFS to mTOR inhibitors was 6.6 months.

Conclusions

In this small retrospective series, the combination of mTOR inhibitors and exemestane obtained a reversion of resistance to mTOR inhibitors in one half of patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R. Sanfilippo: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Advanchen Laboratories; Research grant / Funding (institution): Amgen Dompe; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Epizyme Inc; Research grant / Funding (institution): Galxo; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer. C. Fabbroni: Research grant / Funding (institution): Advanchen Laboratories; Research grant / Funding (institution): Amgen Dompe’; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Epizyme Inc; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): Karyopharm Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): PharmaMar. E. Fumagalli: Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Amgen dompe’; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): karyopharm Pharmaceuticals; Research grant / Funding (institution): Pfizer. R. Bertulli: Research grant / Funding (institution): Karyopharm Pharmaceuticals; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Amgen dompe’; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo ; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): PharmaMar. S. Stacchiotti: Research grant / Funding (institution): Karyopharm Pharmaceuticals; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Advenche Laboratories; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Pfizer. P.G. Casali: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Deciphera; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Blueprint Midicines; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Amgen dompe’; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): KaryopharmPharmaceuticals; Research grant / Funding (institution): PharmaMar. All other authors have declared no conflicts of interest.

Background

We have recently shown that breast cancer tissue cultures with higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB) were inhibited by antiprogestins. This highlights the relevance of determining the PRA/PRB ratio to identify patients that may benefit from this therapy. The aim of this study was to evaluate the concordance between the PR isoform ratio determined by western blots (WB) in core biopsies and in surgical samples from the same breast cancer patients (n=48) from the Hospital “Magdalena V Martínez” from General Pacheco, Buenos Aires. The protocol has been approved by Institutional Review Boards.

Methods

We determined the PRA/PRB ratio by WB using nuclear extracts from frozen tissues (biopsy and surgery) and the percentage of cells expressing PR measured by immunohistochemistry (IHC) was obtained from the clinical records (surgical samples). The analysis of the concordance between the core biopsy and surgical categorization was performed using the Cohen's Kappa coefficient. To categorize samples according to the PRA/PRB ratio, we considered samples enriched in PRA (PRA-H) those with PRA/PRB ≥ 1.2, those enriched in PRB, (PRB-H) with PRA/PRB ≤ 0.83, and equimolar (EQUI) samples, those with ratios in between 1.2 and 0.83.

Results

A 93% of coincidence was observed between WB and IHC data. The discordant samples had low PR levels determined by IHC (<20%) and proved negative in WB. When these 3 groups of PR+ samples, together with PR negative samples, were analyzed comparing the core biopsy and the surgical categorization, a 77% of concordance and a Kappa coefficient of 0.637 (N=48, p< 0.01) was obtained. However, when PR+ cases in which an agreement with the IHC and the WB data was observed, this value rose to 0.724 (N=18, p<0.01).

Conclusions

This study indicates that the PR isoform categorization from core biopsy specimens reflects the PRA/PRB ratio in the tumor in cases in which PR status observed by IHC and WB from biopsy cores are coincident suggesting the possible use of this tool to potentially predict antiprogestin response in case of neoadjuvant treatment.

Background

D and E demonstrated to be efficacious in the treatment of mCRPC pts. Due to different antitumor mechanism of action of these agents, it could be postulated that their combination can improve disease control. CHEIRON study tried to demonstrate the candidate efficacy of chemo-hormonal combination D+E versus D in mCRPC first-line.

Methods

Eligibility criteria included mCRPC diagnosis, ECOG PS ≤ 2, adequate renal, hepatic and hematological functions, no prior treatment for mCRPC. Pts were randomized to receive D 75 mg/m² IV d1 q3w plus prednisone 5 mg PO BID for 8 courses alone or plus E 160 mg PO daily for 24 weeks. Stratification criteria were presence of pain and visceral metastases. The primary endpoint of the study was the rate of pts without disease progression (according to PCWG2) at 6 mos after randomization.

Results

Between 09/2014 and 10/2017, 246 pts (median age 70 years, range 44-88, pain reported by 54 pts, visceral metastases present in 50 pts) were randomized to DE (120) or D (126). The rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm (89.1% vs 72.8%; p = 0.002). Similarly, a higher proportion of DE pts achieved a PSA reduction ≥ 50% compared to the baseline values compared to the D pts (92% vs 69%; p < 0.0001). No differences were observed in terms of objective response rate. Major haematological toxicities consisted of grade 3-4 neutropenia (19 pts DE – 15 pts D); febrile neutropenia was observed in 10 DE pts and in 7 D pts. At a median follow-up of 24 mos, the median progression free survival was 10.1 mos and 9.1 mos in DE and D arm, respectively (p = 0.01). In DE arm the median overall survival was 33.7 mos compared to 29.6 mos of the standard arm (p NS).

Conclusions

The present study was the first phase II randomized trial, which tested the addition of a new generation hormone agent to D compared to D alone. From this data, DE improved the 6-mo disease control with a prolongation of PFS compared to the standard chemotherapy.

Clinical trial identification

NCT02453009.

Legal entity responsible for the study

The authors.

Funding

Astellas.

Disclosure

O. Caffo: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: AstraZeneca. D. Gasparro: Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Pfizer. R. Iacovelli: Advisory / Consultancy: Astellas; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Novartis. U.F.F. De Giorgi: Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Janssen; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi. G. Pappagallo: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy: Genzyme; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. M. Aglietta: Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): PharmaMar; Travel / Accommodation / Expenses: Tesaro. All other authors have declared no conflicts of interest.

Background

The combination of sunitinib (SU) and nivolumab (NI) showed to be safe in the previous phase I of IMMUNOSARC study. We present the results of the phase II of the combination of SU-NI in the advanced STS (pts) cohort.

Methods

Pretreated progressing pts, ECOG 0-1, with UPS, synovial (SS), clear cell (CCS), angio(AS)/epithelioid hemangioendothelioma (EH), solitary fibrous tumor (SFT), epithelioid sarcoma (ES), extraskeletal myxoid chondrosarcoma (ECM) or alveolar soft part sarcoma (ASPS) were eligible. SU 37.5 mg/d as induction was given days 1-14 and then reduced to 25mg/d continuously. NI was administered at 3 mg/Kg every 2 weeks from week 3. SU-NI was maintained up to progression or intolerance. Primary end-point was progression-free survival rate (PFSR) at 6 months (m) by RECIST. Secondary end-points: overall survival (OS), objective response rate (ORR) by RECIST and CHOI and toxicity.

Results

From Nov 2017 to Dec 2018, 50 eligible pts were included in 8 centres: (M/F 30/20), median age 45y (19-77). Diagnosis was: SS in 9 (18%), CCS in 7 (14%), SFT in 7 (14%), UPS in 6 (12%), ES in 6 (12%), AS in 5 (10%), ECM in 4 (8%), ASPS in 3 (6%) and other in 3 (6%). With a median FU of 6.1 m (0-13), 23 pts (46%) progressed based on RECIST with a median PFS of 5.9 m (95% IC 2.7-9.1) and 9 pts (18%) died, with median OS not reached yet. PFSR at 3 and 6 m based on local evaluation were 69% and 50% respectively and OS at 3 and 6 m were 86% and 77%. Based on central radiological review (RECIST, 43 evaluable pts), there were 1 CR (2.3%), 3 PR (7%), 26 SD (60%, 12 pts showing shrinkage) and 13 PD (30%). By CHOI (31 evaluable), there were 19 PR (61.3%), 8 SD (25.8%) and 4 PD (13%). Most relevant G3/4 toxicities were: AST increase 6 (11.8%), ALT increase 5 (9.8%), neutropenia 5 (9.8%), fatigue 3 (5,9%), thrombocytopenia 2 (3.9%), diarrhea 2 (3.9%), renal function impairment 2 (3.9%), without toxic deaths.

Conclusions

The trial met its primary endpoint. SU-NI is an active combination for the treatment of advanced selected STS patients, with 50% of patients free of progression at 6m. Further exploration of immunomodulatory strategies is warranted in selected sarcoma subtypes.

Clinical trial identification

NCT03277924.

Legal entity responsible for the study

Grupo Español de Investigación en Sarcomas (GEIS).

Funding

Pfizer and BMS.

Disclosure

J. Martin Broto: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self): Bayer; Honoraria (self): Amgen; Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Eisai; Research grant / Funding (self): GlaxoSmithKline . N. Hindi: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis. G.E. Grignani: Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Novartis. A. Redondo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Clovis; Research grant / Funding (institution): Eisai. C. Valverde: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bluprint; Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Decyphera; Research grant / Funding (institution): Incyte. A. Lopez Pousa: Travel / Accommodation / Expenses: PharmaMar. S. Stacchiotti: Research grant / Funding (institution): Pfizer . E. Palmerini: Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Bristol-Myers Squibb (BMS); Research grant / Funding (institution): Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Takeda. D.S. Moura: Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Novartis. L. D’Ambrosio: Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: PSI. J.A. Lopez Martin: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties: PharmaMar; Advisory / Consultancy: Chobani; Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

Background

Non-small cell lung cancer (NSCLC) patients carrying epidermal growth factor receptor (EGFR) mutations are sensitive to tyrosine kinase inhibitors (TKIs); nonetheless, about 20% of patients show primary resistance to TKIs. We previously demonstrated the association between TP53 mutations and primary resistance to first-line TKIs in EGFR-mutated adenocarcinoma (ADC) patients. Here we analyze a validation case series of ADC patients treated with first-line TKIs to confirm our previous data, and we assess the association between TP53 status and the prognosis of ADC patients treated with third generation TKIs.

Methods

We considered 136 ADC EGFR-mutated patients treated with a TKI in the first-line setting. Also, we analyzed 42 patients who developed T790M mutation and were treated with a third generation TKI in second- or further line setting. EGFR and TP53 mutation analyses were performed by Sanger Sequencing or Next Generation Sequencing methodologies. TP53 mutations were evaluated in relation to disease control rate (DCR: complete response [CR], partial response [PR] or stable disease [SD]), objective response rate (ORR: CR, PR), progression-free survival (PFS) and overall survival (OS).

Results

Of 136 patients, we found 42 (31%) TP53 mutations: 12 mutations in exon 5 (28.6%), 6 in exon 6 (14.3%), 13 in exon 7 (30.9%), and 11 in exon 8 (26.2%). DCR and ORR were 31.8% and 32.5% in TP3-mutated patients with respect to 68.6% and 67.4% in TP53 wild-type (wt) patients, respectively. Exon 8 TP53-mutated patients had a worse PFS with respect to TP53 wt patients (HR 3.19 [1.62-6.27], p = 0.001), but not OS. Moreover, we assessed TP53 status in 42 patients who developed a T790M mutation and received a third generation TKI in second or additional lines of treatment. In 30 patients with evaluable clinical response, DCR and ORR were 62.5% and 25% in TP53 mutated patients, with respect to 77.2% and 54.5% in the TP53 wt patients, respectively. Data analyses of PFS and OS are ongoing.

Conclusions

EGFR-mutated NSCLC patients with concomitant TP53 mutations had a worse clinical response to first-, second-, and third generation TKIs, administrated in any line of treatment.

Legal entity responsible for the study

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Mature oocyte vitrification and storage is currently used to help patients preserving their ability to have offspring either for fertility preservation (FP) before gonadotoxic treatment such as chemotherapy or for elective purposes. Our meta-analysis investigated whether letrozole co-administration during controlled ovarian stimulation (COS) for FP is effective and safe.

Methods

A literature search using PubMed was conducted up to March 8^th, 2019 to retrieve information from studies that compared the performance of COS with or without letrozole co-administration for FP. Mean or median values and 95% confidence intervals (CIs) or standard deviations (SDs) were collected for efficacy (number of collected oocytes, number of mature oocytes, maturation rate) and safety (peak estradiol levels [E2], total gonadotropin dose, number of stimulation days) endpoints. Statistical analysis was conducted with random-effects model.

Results

A total of 10 articles were eligible including 1930 patients undergoing COS with or without letrozole. Studies compared COS with and without letrozole in cancer or infertile cohorts (N = 9) and infertile cohort only (N = 1). The total number of oocytes and mature oocytes collected were similar between letrozole and no letrozole groups while the peak estradiol was significantly higher in the standard COS without letrozole (Table).Table:

1829P

Conclusions

Letrozole co-administration during COS resulted to be as effective as standard COS but with significantly decreased peak estradiol levels, suggesting its increased safety especially for hormone-sensitive cancer patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Myoepithelial tumors of soft tissues (MT) and Extraskeletal Myxoid Chondrosarcoma (EMC) are closely related pathological entities whose overlapping features, in terms of morphology and immunoprofile, make differential diagnosis challenging. Different fusion genes have been described in MT. Instead, the rearrangement of NR4A3 is conventionally considered an exquisite feature of EMC. Nevertheless, whether there is a biological overlap between MT and EMC is still controversial. In order to shed light on this issue we compared the transcriptional profiles of the two entities.

Methods

A series of EMC (12 cases) and MT (7 cases), retrieved from the pathology files, was selected for the study. The diagnosis was made according to the WHO classification. FISH analyses confirmed that all EMC harbored NR4A3 rearrangement (7 EWSR1-NR4A3 and 5 TAF15-NR4A3); 4 EWSR1 and 1 FUS rearrangement were detected in MT. No rearrangement was detected in 2 cases. RNA was extracted from FFPE specimens with tumor cellularity >70%. RNA-sequencing was carried out on an Illumina Hiseq1000 platform (average 70 million reads/sample). Diverse algorithms and bioinformatic suites were employed to identify fusion transcripts and functional annotation analysis.

Results

RNA-seq analysis confirmed the rearrangements detected by FISH and identified one PTCH1-GLI1 fusion in a MT. Principal component analysis and unsupervised hierarchical clustering indicated that MT and EMC feature a distinct transcriptional profile. Functional annotation of the genes differentially expressed highlighted Hedgehog (HH) and WNT signaling as significantly enriched pathways in MT compared to EMC, with canonical GLI1 and WNT target genes upregulated in MT. Ectopic expression in cell models of the PTCH1-GLI1 chimeric transcript identified in the MT sample correlated with the induction of GLI1 target genes.

Conclusions

This study corroborates the notion that MT and EMC represent two distinct biological entities, with MT featuring a distinctive activation of HH and WNT pathways. The PTCH1-GLI1 fusion represents one possible mechanism of HH pathway activation in MT.

Legal entity responsible for the study

The authors.

Funding

Fondazione AIRC per la Ricerca sul Cancro, CRO Intramural Grant, Italian Ministry of Health.

Disclosure

P.G. Casali: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Deciphera; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Nektar Therapeutics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Amgen Dompé; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Epizyme Inc.; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): Karyopharm Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): PharmaMar. A.P. Dei Tos: Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer. All other authors have declared no conflicts of interest.

Background

Abemaciclib, a selective CDK4 & 6 inhibitor, demonstrated single-agent activity in NSCLC and melanoma (Patnaik et al., 2016). Clinical data demonstrate abemaciclib penetrates the blood brain barrier resulting in comparable concentrations in tissues and plasma (Sahebjam et al., 2016).

Methods

Study JPBO is a Simon 2-stage trial evaluating abemaciclib in 6 pt cohorts with BM secondary to HR+ breast cancer, NSCLC, or melanoma. Here, we report NSCLC and melanoma cohorts. Pts with ≥1 new or not previously irradiated BM ≥ 10mm or a progressive BM previously irradiated were eligible. Abemaciclib was orally administered BID on a continuous dosing schedule. Primary endpoint was objective intracranial response rate (OIRR; [confirmed CR+PR]) based on Response Assessment in Neuro-Oncology BM response assessment criteria (RANO-BM). Secondary endpoints included intracranial clinical benefit rate, PFS, OS, and safety.

Results

28 (NSCLC) and 23 (MEL) pts were enrolled and 23 (NSCLC) and 22 (MEL) were evaluable. Pts had a median of 2 prior systemic therapies in the metastatic setting. 35% (NSCLC) and 46% (MEL) of pts had prior whole brain radiotherapy. 35% (NSCLC) and 27% (MEL) pts had stereotactic radiotherapy. Median time from radiation to study enrollment was 4.8 (NSCLC) to 5.6 (MEL) months. No confirmed intracranial response was observed (OIRR 0% for both cohorts). 21.7% (NSCLC) and 13.6% (MEL) of pts showed a decrease in the sum of their intracranial target lesions. ICBR (CR+PR+SD persisting for > 6 months) was 26.1% (NSCLC) and 9.1% (MEL). Median PFS was 1.5 months (95% CI, 1.4-2.8) for NSCLC and 1.2 months (95% CI, 1.0-1.6) for MEL. Median OS was 7.1 months (95% CI, 3.7-9.4) for NSCLC and 2.9 months (95% CI, 1.2-4.3) for MEL. Based on efficacy results, enrollment closed at end of stage 1. Safety and tolerability were similar as previously reported for abemaciclib.

Conclusions

There was limited intracranial clinical activity for abemaciclib monotherapy in NSCLC and MEL pts in this study; OIRR and short median PFS suggest that no further studies for abemaciclib monotherapy are warranted in this pt population.

Clinical trial identification

NCT02308020.

Editorial acknowledgement

Medical writing assistance was provided by Kristi Gruver, employee of Eli Lilly and Company.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

E. Le Rhun: Advisory / Consultancy, Research grant / Funding (institution), Oscar Lambert Center, Lille, FR: Mundipharma; Research grant / Funding (institution), University Hospital, Lille, FR: Amgen; Advisory / Consultancy, personal fees: Novartis; Advisory / Consultancy, personal fees: Daiichi Sankyo; Advisory / Consultancy, personal fees: Abbvie. G. Jerusalem: Advisory / Consultancy, Non-remunerated activity/ies, per patient investigator fee: Eli Lilly and Company; Research grant / Funding (self), Non-remunerated activity/ies, personal fees: Novartis; Research grant / Funding (self), Non-remunerated activity/ies, personal fees: Roche; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: Pfizer; Advisory / Consultancy, personal fees: Celgene; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: Amgen; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: BMS; Advisory / Consultancy, personal fees: Puma Technology; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: AstraZeneca; Advisory / Consultancy, personal fees: Daiichi Sankyo; Advisory / Consultancy, personal fees: Abbvie. D. Subramaniam: Advisory / Consultancy, personal fees: AstraZeneca; Advisory / Consultancy, personal fees: Takeda Oncology; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech. Y. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment, employee and stock options: Eli Lilly and Company. P.F. Conte: Research grant / Funding (self): Novartis; Travel / Accommodation / Expenses, travel grant: Eli Lilly and Company; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Travel / Accommodation / Expenses, travel grant: Celgene; Travel / Accommodation / Expenses, travel grant: Tesaro. All other authors have declared no conflicts of interest.

Background

The estimand framework requires a precise definition of the clinical question of interest (estimand) to account for “intercurrent” events, eg in RCC the appearance of second primary malignancies or the start of new therapy. Selection of the appropriate estimand will drive trial design and support discussions about relevant treatment effects, interpretation of study results, and the added value of drugs.

Methods

A cross-industry collaboration of statisticians and clinicians has worked on connecting estimand framework concepts to different applications. Data from previously reported phase 3, placebo-controlled studies S-TRAC (NCT00375674) and PROTECT (NCT01235962) will be used to illustrate the effect of different estimands on adjuvant treatment outcomes in RCC.

Results

Table shows the treatment outcomes for different estimands. Treatment outcomes were similar to the specified primary analysis irrespective of the clinical question asked; however, the studies were not powered to address each of these questions and not all reached statistical significance. The new framework clarifies that different analyses address different questions. The choice of the primary estimand impacts study design and may have regulatory implications. In RCC, considerations as to whether all second primary malignancies or non-disease related deaths should be considered disease-free survival events are required to further specify study objectives and to determine the events needed for the final analysis.Table:

980P

Conclusions

In S-TRAC and PROTECT, there are similar treatment effects irrespective of the estimand selected and the clinical question asked. However, this may not be the case in all trials and considerations should be given to the clinical question of interest during trial design. Dialogue between all stakeholders is required and physicians will play a key role in such discussions to select the appropriate estimand.

Clinical trial identification

NCT003756674 and NCT01235962.

Editorial acknowledgement

David Cope, PhD, of Engage Scientific Solutions and funded by Pfizer.

Legal entity responsible for the study

Pfizer.

Funding

Pfizer.

Disclosure

D.J. George: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Exelixis; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck; Research grant / Funding (self): Genentech/Roche; Research grant / Funding (self): Novartis; Research grant / Funding (self): Astellas; Research grant / Funding (self): Celldex; Research grant / Funding (self): Acerta; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Innocrin Pharma; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb. M. Casey: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. E. Degtyarev: Full / Part-time employment: Novartis. M.J. Lechuga Frean: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. P. Aimone: Full / Part-time employment: Novartis. A. Ravaud: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Merck Sharp & Dohme. R.J. Motzer: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Incyte; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): GlaxoSmithKline. All other authors have declared no conflicts of interest.