Dominique Spaeth

Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study

PURPOSE Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs). PATIENTS AND METHODS This open-label, phase II study randomly assigned postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned. RESULTS The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%). CONCLUSION This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.

Abstract S1-6: TAMRAD: A GINECO Randomized Phase II Trial of Everolimus in Combination with Tamoxifen Versus Tamoxifen Alone in Patients (pts) with Hormone-Receptor Positive, HER2 Negative Metastatic Breast Cancer (MBC) with Prior Exposure to Aromatase Inhibitors (AI).

Background: Resistance to hormonal therapy may be associated with activation of the PI3K/AKT pathway. Preclinically, everolimus (RAD), an oral inhibitor of mTOR, has been shown to reverse resistance to tamoxifen (TAM). In a prior randomized phase II trial in estrogen-receptor positive operable breast cancer pts, RAD significantly increased neoadjuvant AI (letrozole) efficacy when given in combination. The objective of this randomized phase II study was to estimate the efficacy of the RAD+TAM combination in AI pretreated hormone-receptor positive/HER2 negative MBC pts based on the assumption that prior exposure to an AI might potentially enrich the proportion of pts whose tumor may be driven by an activation of the PI3K/AKT/mTOR pathway. Methods: Eligible patients were stratified by time to progression after prior AI treatment and randomized 1:1 to receive either TAM (20mg/day) alone or RAD+TAM (RAD: 10 mg/d; TAM: 20mg/d). The primary objective was to estimate clinical benefit rate (CB) defined as the absence of progression at 6 months in the RAD+TAM arm. Using a Simon two-stage Minimax design, with alpha=5% and power=90%, considering a gain in CB of 20% as the minimum needed to warrant further study for the combination and assuming a CB of 50% in the TAM arm, 53 evaluable patients were needed in both arms. Secondary endpoints included safety and time to progression (TTP). Results: In total, 111 pts (TAM: 57, RAD+TAM: 54) were randomized. Baseline characteristics were well balanced between the two treatment arms; median age was 64 years (range, 41-86); most pts were PS 0 (55 pts, 51%) or PS 1 (46 pts, 43%) Prior AI treatment had been given to 34 pts (31%) in the adjuvant setting; to 67 pts (60%) in the metastatic setting and 10 pts (9%) in both the adjuvant and metastatic setting. This population was poorly hormone sensitive as all but 10 pts (9%) had progressed either during AI or within 6 months after adjuvant AI. Furthermore, 57 pts (51%) and 28 pts (25%) had received prior chemotherapy in the adjuvant and/or metastatic setting, respectively. Efficacy: In an intent-to-treat analysis with a median follow-up of 13 months, CB was 42.1% (95% CI, 29.1-55.9) in the TAM arm and 61.1% (95% CI, 46.9-74.1) in the RAD+TAM arm. Median TTP was 4.5 months (95% CI, 3.7-8.7) with TAM and 8.5 months (95% CI, 6.01-13.9) with RAD+TAM (log-rank test: p=0.008, exploratory analysis). At the time of analysis, 17 pts had died in the TAM arm and 5 patients had died in the RAD+TAM arm (there was no toxic death). Safety: Safety data showed that toxicity was manageable in both groups. RAD had to be decreased to 5 mg/day for 15 pts (28%); 3 and 2 pts had to stop the treatment due to toxicities in the TAM and RAD+TAM arms respectively. Severe adverse events (G3-4) >10% were stomatitis (0/11%, TAM/RAD+TAM) and pain (19%/7%). Conclusions: RAD combined with tamoxifen provides significant improvement in the 6 months clinical benefit rate compared to tamoxifen alone. Based on these promising results, this combination warrants further study in hormone-receptor positive/HER2 negative MBC after progression on AI. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-6.

Phase II study of an oxaliplatin/vinorelbine combination in patients with anthracycline- and taxane-pre-treated metastatic breast cancer.

A phase II study was conducted to evaluate the safety and efficacy of an oxaliplatin (OXA)/vinorelbine (VNB) combination in metastatic breast cancer (MBC) patients pre-treated with anthracyclines and taxanes. Patients received OXA at 130 mg/m2 (2-h i.v.), day 1, and VNB days 1 and 8 at 24–26 mg/m2 repeated every 3 weeks. Forty-two patients (median age 54; 64% with liver metastasis, 67% taxane resistant/refractory and 38% anthracycline resistant/refractory) were treated. A median of 4 cycles of treatment was given per patient, with 31% receiving 6 or more. Eleven partial responses and 16 patients with stable disease (five lasting more than 4 months) in 41 eligible patients were seen, for an overall response rate of 26.8% (95% confidence interval 14.2–42.9). Median follow-up was 15.9 months (7.2–30.6), median time to progression was 3.4 months and estimated overall survival was 12.7 months (20 events). Thirty-three patients experienced (National Cancer Institute Common Toxicity Criteria version 2) grade 3–4 neutropenia (one case of febrile neutropenia) and three patients had severe constipation requiring hospitalization. Nine patients developed grade 3 OXA-specific neurotoxicity. There were no treatment-related deaths. We conclude that OXA 130 mg/m2 (day 1) and VNB 24 mg/m2 (day 1 and 8) combination given every 3 weeks is effective with a good safety profile in MBC patients previously treated with anthracyclines and taxanes.

Epoetin β Once-Weekly Therapy in Anemic Patients with Solid Tumors and Non-Myeloid Hematological Malignancies Receiving Chemotherapy

Objectives: This study aimed to provide further clinical evidence for the efficacy and safety of epoetin β once weekly across a wide range of cancer types. Methods: This was a multicenter, open-label, prospective, single-arm study in patients with either a solid tumor or non-myeloid hematological malignancy, receiving or scheduled to receive further chemotherapy. Patients received epoetin β 30,000 IU subcutaneously once weekly for 16 weeks. The primary efficacy endpoint was the change in hemoglobin (Hb) level according to the patient’s baseline Hb level. Results: A total of 691 patients were included in the intent-to-treat population. Epoetin β effectively increased Hb levels (a mean increase from baseline of 1.1 g/dl by week 4 and 2.2 g/dl by week 12). Hb response was achieved in 60.4% of all patients and 61.2% of those with baseline Hb <11 g/dl. Hb response was similar in patients with solid tumors (60.5%) and non-myeloid hematological malignancies (60.2%). Type of chemotherapy and baseline platelet count were independent predictive factors for response. Epoetin β treatment was well tolerated. Conclusions: Epoetin β 30,000 IU once weekly effectively increases Hb levels, is well tolerated and has similar efficacy in anemic patients with solid tumors or non-myeloid hematological malignancies.

A potentially neuroprotective role for erythropoietin with paclitaxel treatment in ovarian cancer patients: a prospective phase II GINECO trial

PurposeA prospective phase II multicenter study was performed in two steps in paclitaxel-treated ovarian cancer patients in France. A French version of the four-item Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire was validated. This was then used to evaluate neurotoxicity in relation to erythropoietin treatment.MethodsPatients received standard second-line paclitaxel-based chemotherapy and erythropoietin for anemia. Neurotoxicity and hemoglobin levels were evaluated every cycle with the FACT/GOG-Ntx and NCI-CTCAE. The translated questionnaire was tested in 20 patients to confirm the translation accuracy. The final questionnaire was validated in 98 patients with internal consistency (Cronbach’s coefficient) and item correlation (Pearson’s r coefficient) tests. Neurotoxicity severity was analyzed according to erythropoietin intake (first three cycles versus no or late intake) and correlated with anemia.ResultsPatients received a median of six paclitaxel cycles (range 1–9). Neurotoxicity was validated in 484 questionnaires. Internal consistency was excellent with Cronbach’s coefficients of ≥0.89 at inclusion, after 3 cycles and at study end. Inter-question correlation was high with Pearson’s coefficients of 0.65–0.85. FACT/GOG-Ntx and NCI-CTCAE severity scoring was similar. Globally, the incidence of severe neurotoxicity (FACT/GOG-Ntx and NCI-CTCAE) was found significantly higher in patients with severe anemia. Of 98 evaluable patients, 31 received erythropoietin during the first three cycles. Mean hemoglobin level was significantly lower in this group from baseline to cycle 4; however, these anemic patients with early EPO intake did not develop an increase rate of severe neurotoxicity.ConclusionsThe French FACT/GOG-Ntx questionnaire is a reliable and valid tool for assessing chemotherapy-induced neuropathy. This study raises the possibility that erythropoietin might play a neuroprotective role when administered with paclitaxel.

AUCtox: A new method to evaluate the safety of anticancer drugs.

2534Background: The evaluation of anticancer drugs safety currently relies on the NCI-CTCAE classification. Most often in clinical trials, attention is focused on severe adverse events (AE) i.e. gr...

Abstract CT153: A multicenter, prospective trial in progress exploring the association between low level of genomic alteration and exceptional and unexpected response to targeted therapies in patients with solid tumors

Background: Most targeted therapies in cancer have reached approval based on clinical studies performed in unselected patients. Small subsets of patients present exceptional responses (ER), which could be driven by a low level of genomic alterations in genes identified as causally implicated in cancer. Methods: This is an exploratory, multicenter, prospective trial conducted in adult patients with advanced solid cancers (breast cancer, lung adenocarcinoma or squamous cell carcinoma, colorectal cancer, ovarian cancer, renal clear cell cancer, skin cutaneous melanoma) having presented an ER to an approved antineoplastic targeted therapy will be included. ER is defined using the definition chosen by the NCI which combines the three criteria: - complete or partial response, - lasting > 6 months, - and not expected in > 10% of the patients in this drug - organ situation ER will be reviewed each month by the Response Confirmation Committee composed of the study coordinators and at least one expert of each organ. The primary objective is to identify whether tumors characterized by a low level of genomic alterations are associated with ER. A low level of genomic alteration is defined by the presence of less than the 5th quantile of genomic alterations to be expected in the given tumor type. For each tumor type, it is desired to test the null hypothesis H0: π=0.05 against the one-sided alternative hypothesis π>0.05. For each of six cohorts, a sample size of 44 patients is necessary to achieve 80% power at π=15 with a one-sided level 5% test. Results: As of January 2018, 152 patients were screened in 31 French centers. Forty-seven patients were included in the study (23 patients with breast cancer, 11 patients with kidney carcinoma, 5 with melanoma, 4 with lung cancer, 3 with colorectal cancer and 1 ovarian cancer). The 5 most frequent drugs were: sunitinib, everolimus, bevacizumab, trastuzumab and pazopanib. The EXPRESS study is still recruiting. Study completion date is estimated to be in August 2019. Conclusion The identification of molecular traits associated with ER might serve the development of predictive classifiers for precision medicine. This study also represents a unique opportunity to better understand cancer biology. Citation Format: Olivia Le Saux, Antoine Italiano, Dominique Spaeth, Pierre Heudel, Thomas Filleron, Laurence Albiges, Thomas Bachelot, Anthony Goncalves, Jean-Yves Pierga, Fabrice Barlesi, Valerie Boige, Celeste Lebbe, Laurent Mortier, Jean Sebastien Frenel, Olivier Tredan, Marta Jimenez, Francois Legrand, Charles Ferte. A multicenter, prospective trial in progress exploring the association between low level of genomic alteration and exceptional and unexpected response to targeted therapies in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT153.

Étude prospective de l’impact de l’utilisation du test de 21 gènes, le Recurrence Score, sur les décisions thérapeutiques prises chez les femmes ayant un cancer du sein à un stade précoce HER2 négatif et avec des récepteurs aux œstrogènes positifs

Le test de 21 genes, OncotypeDX® — Recurrence Score® (RS), est un test valide qui aide a choisir le meilleur traitement chez des femmes ayant un cancer du sein a un stade precoce Her2-negatif et avec des recepteurs aux oestrogenes positifs en situation adjuvante. Les attitudes therapeutiques varient considerablement entre les pays. Cette etude multicentrique est la premiere a evaluer l’impact de l’utilisation du tests OncotypeDX® dans le contexte francais.

Efficacité de l'époétine bêta hebdomadaire dans l'anémie des tumeurs solides sous chimiothérapie.

OBJECTIVE The aim of the study was to assess the efficacy and safety of epoetin beta once-weekly in anemic patients with solid tumors treated with chemotherapy. METHOD Prospective, open-label, multicenter, single-arm study of epoetin beta 30 000 I.U. once-weekly in anemic patients with solid tumors receiving chemotherapy (n = 365). RESULTS Epoetin beta increased mean haemoglobin (Hb) levels from 10.3 +/- 0.9 g/dL at baseline to 12.3+/-2.0 g/dL at week 12. The response rate was achieved in 61% (CI 95%: 55-68) of the patients. The mean Hb level increased was 1.8 g/dL (CI 95%: 1.5-2,0); in lung cancer patients (n = 102) Hb increase was 2.7 g/dL. Treatment with epoetin beta was well tolerated; only 1.4 % patients had thrombotic events. CONCLUSION Epoetin beta (30 000 I.U. once weekly) increased Hb levels and was well-tolerated to correct anemia in patients with solid tumors treated with chemotherapy.