On September 29, 2019 Novartis reported results from the MONALEESA-3 trial, which showed Kisqali (ribociclib) achieved statistically significant improvement in overall survival (OS) (Press release, Novartis, SEP 29, 2019, View Source [SID1234539885]). This is the second Phase III trial in which Kisqali combination therapy met the secondary endpoint of overall survival at the pre-planned interim analysis. MONALEESA-3 evaluated efficacy and safety of Kisqali plus fulvestrant in postmenopausal women with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer. These data will be presented as a late-breaker oral presentation in the Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2019.

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"Seen now in two Phase III trials, ribociclib consistently and significantly prolongs life among premenopausal and postmenopausal women, and in combination with an aromatase inhibitor and fulvestrant. These results arm oncologists with more evidence to make a confident treatment choice for their hormone receptor-positive metastatic breast cancer patients," said Dennis J. Slamon, MD, Director of Clinical/Translational Research, University of California, Los Angeles Jonsson Comprehensive Cancer Center.

Kisqali in combination with fulvestrant met its secondary endpoint of overall survival, demonstrating a statistically significant improvement in survival with a 28% reduction in risk of death (median OS not reached vs. 40.0 months; HR=0.724; 95% CI: 0.568-0.924; p=0.00455). The significant extension in survival met the early efficacy stopping criteria at a pre-specified interim analysis. At 42 months, estimated rates of survival were 58% for Kisqali combination treatment and 46% for fulvestrant alone. Results in the first-line and second-line subgroups, including in patients who relapsed within 12 months of adjuvant treatment, were consistent with the overall MONALEESA-3 patient population.

Median PFS in the first-line was also reached at this analysis and demonstrated that Kisqali in combination with fulvestrant has a median PFS of 33.6 months compared to 19.2 months in the placebo arm (HR=0.546; 95% CI: 0.415-0.718). Additionally, the need for chemotherapy was delayed in all patients who were prescribed Kisqali plus fulvestrant (HR=0.696; 95% CI: 0.551-0.879).

"The remarkable results from MONALEESA-3 and MONALEESA-7 make Kisqali the CDK4/6 inhibitor with consistently superior overall survival," said Susanne Schaffert, PhD, President, Novartis Oncology. "In nearly 25 years, the five-year survival rates in HR+ metastatic breast cancer have improved by less than 5%. We are committed to helping give these women more life and are reimagining a world where metastatic breast cancer becomes a curable disease."

MONALEESA-3 is the largest trial to evaluate a CDK4/6 inhibitor plus fulvestrant as initial therapy in postmenopausal women (N=726). The trial included women with no prior endocrine therapy, including those diagnosed de novo, women who relapsed within 12 months of adjuvant therapy and women who progressed on endocrine therapy for advanced disease. The most common grade 3/4 adverse events of special interest observed in this analysis in patients who received Kisqali plus fulvestrant compared to fulvestrant alone were neutropenia (57.1% vs 0.8%), hepatobiliary toxicity (13.7% vs 5.8%), QTc prolongation (3.1% vs 1.2%), respiratory disorders (2.3% vs 3.3%) and interstitial lung disease (0.2% vs 0%).

"Pre-clinical data show that Kisqali is distinct from other CDK4/6 inhibitors in its ability to more selectively target and inhibit CDK4," said Jeff Engelman, MD, PhD Global Head of Oncology Research, Novartis Institutes for BioMedical Research. "CDK4 is a major driver of breast cancer progression and inhibiting it has been shown to block the growth of breast cancer cells."

There currently remains no cure for advanced breast cancer. Breast cancer is the number one cause of cancer death in European women, claiming the lives of more than 150,000 women in 2018.[3]

About Kisqali (ribociclib)
Kisqali (ribociclib) is the CDK4/6 inhibitor with the largest body of first-line clinical trial evidence demonstrating consistent and sustained efficacy compared to endocrine therapy alone[1]. Kisqali is the only CDK4/6 inhibitor to achieve statistically significant overall survival in two Phase III trials with two distinct patient populations[1]. Overall survival results from MONALEESA-7 were presented at ASCO (Free ASCO Whitepaper) 2019, demonstrating Kisqali plus endocrine therapy significantly extends life in premenopausal women with HR+/HER2- advanced breast cancer. Overall survival follow-up is ongoing for the Phase III MONALEESA-2 trial.

Kisqali is approved for use in more than 75 countries around the world, including the United States and European Union member states. Kisqali was initially approved by the US Food and Drug Administration (FDA) in March 2017 and by the European Commission (EC) in August 2017, as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor based on findings from the pivotal MONALEESA-2 trial. Kisqali in combination with an aromatase inhibitor was approved for the treatment of pre-, peri- or postmenopausal women as initial endocrine based therapy, and also indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women by the FDA in July 2018 and by the EC in December 2018. Regulatory filings are underway with other health authorities worldwide[1].

Novartis is continuing to reimagine cancer by investigating Kisqali in early breast cancer. The NATALEE study is a Phase III clinical trial of Kisqali with endocrine therapy in the adjuvant treatment of HR+/HER2- early breast cancer being conducted in collaboration with Translational Research In Oncology (TRIO)[1].

Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About Novartis in Advanced Breast Cancer
Novartis tackles breast cancer with superior science, collaboration and a passion for transforming patient care. We’ve taken a bold approach to our research by including patient populations often neglected in clinical trials, identifying new pathways or mutations that may play a role in disease progression and developing therapies that not only maintain, but also improve, quality of life for patients. Our priority over the past 30 years and today is to deliver treatments proven to improve and extend lives for those diagnosed with advanced breast cancer.

Important Safety Information FROM THE Kisqali EU SmPC
Kisqali (ribociclib) is a prescription medicine approved in combination with an aromatase inhibitor as initial endocrine – based therapy in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer or fulvestrant as initial endocrine – based therapy or following disease progression on endocrine therapy in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. It is not known if Kisqali is safe and effective in children or adolescents. Kisqali can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Kisqali is not indicated for concomitant use with tamoxifen due to an increased risk of QT prolongation. Patients should tell their health care provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. Kisqali can cause serious liver problems. Patients should tell their health care provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking Kisqali and may result in infections that may be severe. Patients should tell their health care provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking Kisqali, patients should tell their health care provider if they are pregnant, or plan to become pregnant as Kisqali can harm an unborn baby. Females who are able to become pregnant and who take Kisqali should use highly effective birth control during treatment and for at least 3 weeks after the last dose of Kisqali. Do not breastfeed during treatment with Kisqali and for at least 3 weeks after the last dose of Kisqali. Patients should tell their health care provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with Kisqali. Patients should avoid grapefruit or grapefruit juice while taking Kisqali. The most common side effects (incidence >=20%) include infections, white blood cell count decreases, headache, cough, nausea, tiredness, diarrhea, vomiting, constipation, hair loss and rash. The most common Grade 3/4 side effects (incidence >5%) were infections, low neutrophils, low leukocytes, low red blood cells, abnormal liver function tests, low lymphocytes, low phosphate levels and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

On September 29, 2019 Seattle Genetics, Inc. (Nasdaq:SGEN) reported that initial data were presented from the single arm phase 2 clinical trial known as MOUNTAINEER (Press release, Seattle Genetics, SEP 29, 2019, View Source [SID1234539888]). The trial is evaluating the investigational agent tucatinib in combination with trastuzumab (Herceptin) in patients with HER2-positive (HER2+), RAS wild-type metastatic colorectal cancer (mCRC) after treatment with first- and second-line standard-of-care therapies. The regimen demonstrated encouraging antitumor activity and was well tolerated.

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Tucatinib is an oral, small molecule tyrosine kinase inhibitor that is highly selective for HER2. HER2 amplification or overexpression occurs in approximately three-to-five percent of all patients with mCRC.1,2 The results were presented during a poster discussion session today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress in Barcelona, Spain (Abstract #527PD).

Initial results from 23 patients evaluable for clinical/radiographic response are below.

Objective response rate (ORR) was 52.2 percent (95% Confidence Interval [CI], 30.6-73.2) with a median duration of response of 10.4 months (95% CI, 6.0-NE)
Median progression-free survival (PFS) was 8.1 months (95% CI, 3.8-NE)
Median overall survival (OS) was 18.7 months (95% CI, 12.3-NE)
The combination of tucatinib and trastuzumab was well tolerated. The most common treatment-related adverse events were Grade 1 in severity and included increased aspartate aminotransferase (AST, 38.5 percent; all Grade 1) increased alanine aminotransferase (ALT, 23.1 percent; all Grade 1), and diarrhea (23.1 percent; one Grade 1, four Grade 2, one Grade 3). There were no Grade 4 or 5 treatment-related adverse events.
"It’s exciting to see the initial results from the MOUNTAINEER trial. Tucatinib is a potent and selective inhibitor of HER2, and the combination of tucatinib and trastuzumab demonstrated significant activity for heavily pre-treated patients with HER2-positive metastatic colorectal cancer," said John H. Strickler, M.D., Duke University Medical Center.

"There is an unmet clinical need for new treatments for patients with HER2-positive metastatic colorectal cancer," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "The trial demonstrated that tucatinib has the potential to play a role in the treatment of colorectal cancer. We look forward to developing tucatinib in combination with trastuzumab and other therapies for the treatment of HER2-positive metastatic colorectal cancer."

About MOUNTAINEER

MOUNTAINEER is a multi-center, open label, single-arm phase 2 clinical trial of tucatinib in combination with trastuzumab in patients with HER2-positive, RAS wildtype metastatic or unresectable colorectal cancer. The primary endpoint of the trial is objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 criteria. Progression-free survival, duration of response, overall survival and safety and tolerability of the combination regimen are secondary objectives. Results for 26 patients were evaluated in this analysis, and enrollment is ongoing. Three of the 26 patients who are on active treatment were recently enrolled at the time of this analysis and had not yet received first radiographic assessment of response.

MOUNTAINEER is a Seattle Genetics-sponsored multi-site clinical trial initiated by the Academic and Community Cancer Research United (ACCRU) Network. ACCRU is a non-profit cancer research network comprised of more than 100 academic and community cancer centers across the United States. Seattle Genetics is now responsible for this ongoing clinical trial.

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab.3,4 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, ovarian, colorectal and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tumors that overexpress HER2 are more aggressive and historically have been associated with poor overall survival compared with HER2-negative cancers. Tucatinib has been granted orphan drug designation by the FDA for the treatment of HER2-positive metastatic colorectal cancer and breast cancer patients with brain metastases.

About Colorectal Cancer

Colorectal cancer is the second leading cause of cancer death in the United States (U.S.).5 In 2019, it is estimated there will be 145,600 new cases and 51,020 deaths in the U.S.5 Approximately 21 percent of U.S. patients with colorectal cancer are diagnosed at the advanced stage. 5 According to the U.S. Centers for Disease Control and Prevention, the most effective way to reduce the risk of colorectal cancer is routine screening beginning at age 50.In colorectal cancer, human epidermal growth factor receptor 2 (HER2) is overexpressed in three-to-five percent of patients.1,2 There are currently no therapies approved that specifically target HER2 in colorectal cancer.

On September 29, 2019 Clovis Oncology, Inc. (NASDAQ: CLVS) reported updated data from the Phase 2 TRITON2 trial at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2019, reinforcing the potential of Rubraca (rucaparib) for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with a BRCA1/2mutation (Press release, Clovis Oncology, SEP 29, 2019, View Source [SID1234539874]). The data show a 43.9% confirmed objective response rate (ORR) by investigator assessment in 57 RECIST*/PCWG3** response-evaluable patients with a BRCA1/2 mutation. When assessed by independent radiological review, the response rate was similar (40.4%). In addition, a 52.0% confirmed prostate-specific antigen (PSA) response rate was observed in 98 response-evaluable patients with a BRCA1/2 mutation. Confirmed radiographic responses were durable, with 60 percent lasting 24 weeks or longer (15/25).

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The TRITON2 data will be used to support the filing of Clovis Oncology’s planned supplemental NDA to the Food and Drug Administration (FDA) for Rubraca in BRCA1/2-mutant advanced prostate cancer.

"The updated data from the TRITON2 trial confirm the potential role of rucaparib in treating metastatic castration-resistant prostate cancer," said Wassim Abida, M.D., Medical Oncologist, Memorial Sloan Kettering Cancer Center, and principal investigator for the TRITON2 study. "These data specifically demonstrate the efficacy of rucaparib in eligible mCRPC patients with a BRCA1/2 mutation and reinforce the known safety profile in this treatment setting, showing it has the potential to offer clinical benefit to eligible patients."

Confirmed investigator-assessed RECIST* and PSA responses were also observed in patients with alterations in other DDR genes, including ATM, CDK12, CHEK2, PALB2, BRIP1, FANCA, and RAD51B.

The median duration of follow-up (as of July 2, 2019) for patients in TRITON2 was 13.1 months (range 4.1–28.5 months) with the safety profile consistent with prior reports. The most common any-grade treatment-emergent adverse events (TEAE) >20% in the TRITON2 trial were asthenia/fatigue (55.3%), nausea (49.5%), anemia/decreased hemoglobin (37.9%), decreased appetite (27.9%), transient increased aspartate transaminase/alanine aminotransferase (ALT/AST) (24.7%), constipation (24.7%), vomiting (22.1%) and diarrhea (21.1%).

Clovis Oncology is further evaluating the potential of Rubraca to treat advanced prostate cancer in the TRITON3 clinical trial – a multicenter, randomized, open-label Phase 3 study of Rubraca versus physician’s choice of therapy – for patients with mCRPC. TRITON3 is currently enrolling patients with BRCA1/2-mutant and ATM-mutant (both inclusive of germline and somatic) tumors with a primary objective of assessing radiographic progression-free survival (PFS) in these patients.

Rubraca in Recurrent Ovarian Cancer

An exploratory data analysis from the pivotal Phase 3 ARIEL3 trial evaluating Rubraca for the maintenance treatment of recurrent ovarian cancer assessed PFS in the subgroups who had achieved a partial response (PR) or complete response (CR) on the most recent platinum regimen. The data show that PFS was longer in patients receiving Rubraca than placebo regardless of whether patients achieved a CR or PR on their last platinum-based regimen. Patients in the intent-to-treat population who received rucaparib treatment had a significantly greater reduction in risk for progression or death versus placebo whether they had achieved a CR (hazard ratio of 0.33 [95% CI, 0.23-0.49]; rucaparib, n=126; placebo, n=64) or a PR (hazard ratio of 0.38 [95% CI, 0.30-0.49]; rucaparib, n=249; placebo, n=125) to their last platinum-based therapy. Improvements in investigator-assessed PFS were also demonstrated in patients from the BRCA mutant and BRCA mutant or BRCA wild type/high loss of heterozygosity populations who were treated with Rubraca compared with placebo. The safety profile in Rubraca-treated patients who had either a CR or PR to their last platinum-based chemotherapy was consistent with that of the ITT population reported. Among patients with residual disease at baseline, confirmed RECIST responses were seen in a number of patients treated with rucaparib, including 23/104 (22.1%) patients with non-measurable but assessable disease at baseline.

An integrated analysis of safety data from Study 10, ARIEL2 and ARIEL3 are consistent with the known safety profile of Rubraca in patients with platinum-sensitive, recurrent ovarian cancer, in both the treatment and maintenance settings. The analysis included 937 patients treated with Rubraca in the treatment (Study 10 and ARIEL2, n=565) and maintenance (ARIEL3, n=372) settings. Overall, 102/937 (10.9%) patients discontinued due to any grade treatment-related TEAE (treatment setting: 53/565 [9.4%]); (maintenance setting: 49/372 [13.2%]). The most frequent any grade adverse events leading to discontinuation were asthenia/fatigue (23/937 [2.5%]), anemia/ hemoglobin decreased (20/937 [2.1%]) and thrombocytopenia/platelets decreased (19/937 [2.0%]). The most frequent grade ≥3 treatment-related TEAE leading to discontinuation was anemia/hemoglobin decreased (15/937 [1.6%]) and asthenia/fatigue (7/937 [0.7%]).

"The ARIEL3 data presented at ESMO (Free ESMO Whitepaper) this year demonstrate that rucaparib contributes to a significant increase in progression-free survival over placebo, irrespective of whether a patient had CR or PR to previous platinum-based therapy and provides strong evidence for efficacy in women with recurrent ovarian cancer in the second-line maintenance setting," said Professor Jonathan Ledermann, M.D., Professor of Medical Oncology, UCL Cancer Institute and UCL Hospitals, London, Global Principal Investigator for non-U.S. sites in the ARIEL3 study. "The current data provide physicians with a compelling argument to make maintenance therapy essential for all eligible patients, including women who have had a complete response."

Data from the Study 10, ARIEL2 and ARIEL3 trials supported the approvals of Rubraca for the treatment and maintenance treatment of recurrent ovarian cancer in the U.S. and EU. The European Commission authorization of Rubraca, resulted in Rubraca being the first poly (ADP ribose) polymerase (PARP) inhibitor to be approved for both treatment and maintenance treatment among eligible women with ovarian cancer in the EU.

"Rubraca continues to demonstrate meaningful clinical benefit in the recurrent ovarian cancer treatment and maintenance settings, and our updated prostate data are highly consistent with the data presented at ESMO (Free ESMO Whitepaper) last year," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We are moving forward with plans to file an sNDA in advanced mCRPC by the end of 2019, and we believe that, similar to its ovarian cancer profile, Rubraca may offer an important treatment option for patients with advanced prostate cancer, for whom new options are needed. We are committed to further exploring the potential of Rubraca and look forward to starting the tumor-agnostic study before year-end and furthering our combination studies that are now enrolling patients."

Clovis Oncology’s ESMO (Free ESMO Whitepaper) Rubraca poster presentations are available online at clovisoncology.com.

Clovis Analyst/Investor Event at ESMO (Free ESMO Whitepaper) Webcast Details

In addition, the Company will present greater detail about its planned sNDA filing and regulatory strategy in mCRPC at its Investor/Analyst event today at 6:30pm CEST, which will be webcast live and available via replay from the following link: View Source

About Rubraca (rucaparib)

Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 that is being developed in multiple tumor types, including ovarian and mCRPC, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Rubraca U.S. FDA approved indications

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in CR or PR to platinum-based chemotherapy.

Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutations (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with ≥2 chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

Select important safety information

MDS/AML occurs uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long-term follow-up. Of these, five occurred during treatment or during the 28-day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA-damaging agents. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (grade ≥1).

Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (>4 weeks), interrupt Rubraca or reduce dose (see Dosage and Administration [2.2] in full Prescribing Information) and monitor blood counts weekly until recovery. If the levels have not recovered to grade 1 or less after 4 weeks, or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample cytogenetic analysis. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥20%, grade 1–4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%) and neutropenia (20%).

Most common laboratory abnormalities in ARIEL3 (≥25%, grade 1–4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in ALT (73%), increase in AST (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%) and decrease in lymphocytes (29%).

Most common adverse reactions in Study 10 and ARIEL2 (≥20%, grade 1–4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%) and thrombocytopenia (21%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥35%; grade 1–4) were increase in creatinine (92%), increase in ALT (74%), increase in AST (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%) and decrease in absolute neutrophil count (35%).

Co-administration of Rubraca can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio monitoring. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.

Click here for full Prescribing Information and additional important safety information.

Rubraca (rucaparib) European Union (EU) authorized use and Important Safety Information

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

Rubraca is indicated as monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with ≥2prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.

Efficacy of Rubraca as treatment for relapsed or progressive EOC, FTC, or PPC has not been investigated in patients who have received prior treatment with a PARP inhibitor. Therefore, use in this patient population is not recommended.

Summary warnings and precautions:

Hematological toxicity

During treatment with Rubraca, events of myelosuppression (anemia, neutropenia, thrombocytopenia) may be observed and are typically first observed after 8–10 weeks of treatment with Rubraca. These reactions are manageable with routine medical treatment and/or dose adjustment for more severe cases. Complete blood count testing prior to starting treatment with Rubraca, and monthly thereafter, is advised. Patients should not start Rubraca treatment until they have recovered from hematological toxicities caused by previous chemotherapy (CTCAE grade ≥1).

Supportive care and institutional guidelines should be implemented for the management of low blood counts for the treatment of anemia and neutropenia. Rubraca should be interrupted or dose reduced according to Table 1 (see Posology and Method of Administration [4.2] of the Summary of Product Characteristics [SPC]) and blood counts monitored weekly until recovery. If the levels have not recovered to CTCAE grade 1 or better after 4 weeks, the patient should be referred to a hematologist for further investigations.

MDS/AML

MDS/AML, including cases with fatal outcome, have been reported in patients who received Rubraca. The duration of therapy with Rubraca in patients who developed MDS/AML varied from less than 1 month to approximately 28 months.

If MDS/AML is suspected, the patient should be referred to a hematologist for further investigations, including bone marrow analysis and blood sampling for cytogenetics. If, following investigation for prolonged hematological toxicity, MDS/AML is confirmed, Rubraca should be discontinued.

Photosensitivity

Photosensitivity has been observed in patients treated with Rubraca. Patients should avoid spending time in direct sunlight because they may burn more easily during Rubraca treatment; when outdoors, patients should wear a hat and protective clothing, and use sunscreen and lip balm with sun protection factor of 50 or greater.

Gastrointestinal toxicities

Gastrointestinal toxicities (nausea and vomiting) are frequently reported with Rubraca, and are generally low grade (CTCAE grade 1 or 2), and may be managed with dose reduction (refer to Posology and Method of Administration [4.2], Table 1 of the SPC) or interruption. Antiemetics, such as 5-HT3 antagonists, dexamethasone, aprepitant and fosaprepitant, can be used as treatment for nausea/vomiting and may also be considered for prophylactic (i.e. preventative) use prior to starting Rubraca. It is important to proactively manage these events to avoid prolonged or more severe events of nausea/vomiting which have the potential to lead to complications such as dehydration or hospitalization.

Embryofetal toxicity

Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of Rubraca to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 600 mg twice daily (see Preclinical Safety Data [5.3] of the SPC).

Pregnancy/contraception

Pregnant women should be informed of the potential risk to a fetus. Women of reproductive potential should be advised to use effective contraception during treatment and for 6 months following the last dose of Rubraca (see section 4.6 of the SPC). A pregnancy test before initiating treatment is recommended in women of reproductive potential.

Click here to access the current SPC. Healthcare professionals should report any suspected adverse reactions via their national reporting systems.

On September 29, 2019 MonTa Biosciences reported that attends the ESMO (Free ESMO Whitepaper) conference in Barcelona to meet with Key Opinion Leaders to plan phase I trial in patients (Press release, MonTa Biosciences, SEP 29, 2019, View Source [SID1234618629]).

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On September 29, 2019 Eli Lilly and Company (NYSE: LLY) reported data from the LIBRETTO-001 clinical trial intended to support the registration of oral selpercatinib1 monotherapy, also known as LOXO-292, for the treatment of RET-altered thyroid cancers (Press release, Eli Lilly, SEP 29, 2019, View Source [SID1234539875]). RET-altered thyroid cancers are comprised of two different populations, RET-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancers. In the RET-mutant MTC registration dataset consisting of the first 55 enrolled patients with prior cabozantinib and/or vandetanib2, selpercatinib treatment resulted in a 56 percent objective response rate (ORR) (95% CI: 42-70%). This population was heavily pretreated (53 percent previously treated with ≥2 prior multikinase inhibitors), and ORR was similar regardless of prior multikinase inhibitor therapy. As of the data cut-off date of June 17, 2019, median duration of response (DOR) was not reached (95% CI: 11.1-NE) and median progression-free survival (PFS) was not reached (95% CI: 11.3-NE). Selpercatinib therapy also resulted in robust biochemical response rates (BRR) for serum tumor markers calcitonin (91% BRR) and carcinoembryonic antigen (64% BRR). In a safety analysis of all 531 patients enrolled to LIBRETTO-001, selpercatinib was well-tolerated, with only nine patients (1.7%) discontinuing therapy due to treatment-related adverse events. The most commonly observed adverse events, regardless of attribution, were dry mouth, diarrhea, hypertension, increased liver enzymes, fatigue, constipation, and headache. These results were presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2019 in Barcelona, Spain, in session LBA93, Registrational Results of LOXO-292 in Patients with RET-Altered Thyroid Cancers, presented by Lori J. Wirth, M.D., medical director of head and neck cancers, Massachusetts General Hospital Cancer Center in Boston, Mass. Selpercatinib has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA).

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"Current therapeutic options are often challenging for patients with first-line RET-altered thyroid cancers and are limited for patients who relapse. The data for selpercatinib show demonstrative efficacy and safety in both the first-line and relapsed settings. Patients with thyroid cancer have long sought targeted therapy tailored to the molecular nature of their disease, and we are hopeful that selpercatinib may be used as the standard of care in the future," said Wirth, who is lead investigator on the trial.

Selpercatinib Data in Cabozantinib/Vandetanib-Naïve RET-Mutant MTC patients
Investigators also presented the results of selpercatinib in RET-mutant MTC patients who have received neither cabozantinib nor vandetanib. In this analysis of 76 patients, selpercatinib treatment resulted in a 59 percent ORR (95% CI: 47-70%). Median DOR and PFS were not reached in this treatment-naïve population, as the vast majority of patients remain in response or progression-free.

Selpercatinib Data in Heavily Pretreated RET Fusion-Positive Thyroid Cancer Patients
Investigators also presented the results of selpercatinib in heavily pretreated RET fusion-positive thyroid cancer patients. In this analysis of 26 patients, selpercatinib treatment resulted in a 62 percent ORR (95% CI: 41-80%). Median DOR and PFS were not reached in this population, as the vast majority of patients remain in response or progression-free.

"We’re pleased that selpercatinib may offer a meaningful advance for patients with RET-altered thyroid cancers," said Anne White, president of Lilly Oncology. "These patients have been a focus of the selpercatinib program from its beginning, as RET has been a known oncogene in these diseases for decades. With these data, selpercatinib has delivered on our vision, with unprecedented clinical outcomes in both first-line and relapsed patients, particularly in light of the difficult options for these patients."

Trial Background
The LIBRETTO-001 Phase 1/2 trial is the largest clinical trial of patients with RET-altered cancers treated with a RET inhibitor. The trial includes a dose escalation phase (Phase 1) and a dose expansion phase (Phase 2). The Phase 2 portion of the trial had a primary endpoint of objective response rate (ORR) and secondary endpoints of DOR, PFS and safety. The primary analysis set for MTC regulatory submissions, as defined with the FDA, consists of the first 55 enrolled patients with RET-mutant medullary thyroid cancer who have experienced prior cabozantinib and/or vandetanib. All data presented at ESMO (Free ESMO Whitepaper) were as of a data cut-off date of June 17, 2019, and all efficacy measures utilized investigator assessments.

About Selpercatinib (LOXO-292)
Selpercatinib, also known as LOXO-292, is a highly selective and potent, oral investigational new medicine in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. Selpercatinib was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms.

Selpercatinib has received breakthrough designation for the treatment of patients with:

Metastatic RET-fusion-positive non-small cell lung cancer who require systemic therapy and have progressed following platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 therapy;

RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options; and for

Advanced RET-fusion-positive thyroid cancer who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options.

About RET-Altered Cancers
Genomic alterations in RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 2 percent of non-small cell lung cancer, 10-20 percent of papillary and other thyroid cancers and a subset of other cancers. Activating RET point mutations account for approximately 60 percent of MTC. RET fusion cancers and RET-mutant MTC are primarily dependent on this single activated kinase for their proliferation and survival. This dependency, often referred to as "oncogene addiction," renders such tumors highly susceptible to small molecule inhibitors targeting RET.