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.

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 28, 2019 Bayer reported that updated clinical data for Vitrakvi (larotrectinib) in adult and pediatric patients with TRK fusion cancer demonstrated an overall response rate (ORR) of 79 percent (n=121; 95% CI, 72–85), including 16 percent complete responses (CR) and 63 percent partial responses (PR) per investigator assessment (Press release, Bayer, SEP 28, 2019, View Source [SID1234553278]). In 12 evaluable patients with brain metastases, the ORR was 75 percent (n=9; 95% CI, 43–95, all PR).1 These results build on Vitrakvi’s original pooled analysis and now include 153 evaluable patients (data cut-off of February 19, 2019), making this the largest dataset of any TRK inhibitor to date.1 Vitrakvi demonstrated a median duration of response (DOR) of 35.2 months (n=108 confirmed responses; 95% CI, 22.8–NE) and key secondary endpoints showed a median progression free survival of 28.3 months (95% CI, 22.1–NE) and a median overall survival of 44.4 months (95% CI, 36.5–NE), with 88 percent (95% CI, 83–94) of patients still alive at one year after the start of therapy.1 These data were presented in a poster discussion at the 44th European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2019, taking place September 27 to October 1 in Barcelona, Spain.

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Vitrakvi is approved in the U.S. for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. This indication is approved under accelerated approval based on ORR and DOR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.2 Vitrakvi is also approved in the European Union, Canada and Brazil.

"As we continue to study the efficacy and safety of larotrectinib across a wide range of solid tumor types and ages, including patients with CNS tumors, it is encouraging to see the consistency in larotrectinib’s responses in patients with TRK fusion cancer," said David Hyman, M.D., chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center. "The responses we have seen with larotrectinib underscore the need to test our patients for genomic alterations, such as NTRK gene fusions, to provide them with meaningful treatment options."

The safety data presented at the ESMO (Free ESMO Whitepaper) 2019 Congress encompassed the entire Vitrakvi safety database in cancer patients (N=260). The majority of adverse events (AE) reported were grade 1 or 2 for AEs that occurred at any grade in at least 15 percent of patients, or at grade 3 or 4 in at least three percent of patients.1

"With a patient population that is now three times our initial analysis, Vitrakvi continues to demonstrate impressive efficacy," said Scott Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer’s Pharmaceutical Division. "We are committed to bringing Vitrakvi to patients around the world, as demonstrated through the recent approvals in multiple global markets."

About Vitrakvi (larotrectinib)
Vitrakvi (larotrectinib) is indicated for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.2

Following the acquisition of Loxo Oncology by Eli Lilly and Company in February 2019, Bayer has obtained the exclusive licensing rights for the global development and commercialization, including in the U.S., for Vitrakvi and the investigational TRK-inhibitor selitrectinib (previously BAY 2731954 and LOXO-195) progressing through clinical development.

Important Safety Information for VITRAKVI (larotrectinib)

Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurologic adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).2

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed.2

Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.2

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.2

Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily.2

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.2

Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).2

Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.2

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.2

Please see the full Prescribing Information for VITRAKVI (larotrectinib).

About TRK Fusion Cancer
TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein.2 The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade.2 These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless of where it originates in the body.2 TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body.2 TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).2,3

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now expands to six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

On September 28, 2019 G1 Therapeutics, Inc. (Nasdaq: GTHX), a clinical-stage oncology company, today reported preliminary overall survival (OS) data from the company’s randomized Phase 2 trial of trilaciclib in combination with chemotherapy for the treatment of metastatic triple-negative breast cancer (mTNBC) (Press release, G1 Therapeutics, SEP 28, 2019, View Source [SID1234539978]). In the trial, median overall survival for patients treated with trilaciclib in combination with a chemotherapy regimen of gemcitabine/carboplatin (GC) was 20.1 months, compared with 12.6 months for patients receiving chemotherapy alone. These data were reported as part of a late-breaking oral presentation (LBA22) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress and featured in a concurrent publication in The Lancet Oncology.

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Updated data from a separate randomized Phase 2 trial of trilaciclib in small cell lung cancer (SCLC) will be presented during a poster session (1742PD) on Sunday, September 29 at ESMO (Free ESMO Whitepaper) 2019 in Barcelona, Spain.

"Triple-negative breast cancer is the most aggressive form of breast cancer and tends to have a poorer prognosis than other breast cancers. We need new therapeutic approaches that improve outcomes for women diagnosed with triple-negative breast cancer," said Joyce A. O’Shaughnessy, M.D., Baylor University Medical Center, Texas Oncology, U.S. Oncology, and lead investigator for the trial. "As an oncologist specializing in triple-negative breast cancer, I am encouraged that trilaciclib has the potential to improve the survival of patients diagnosed with this disease."

"Trilaciclib is a first-in-class therapy that has improved outcomes for people with cancer being treated with chemotherapy in four randomized Phase 2 trials. The findings from these trials in small cell lung cancer and triple-negative breast cancer indicate that the clinical benefits of trilaciclib are meaningful and context-dependent," said Raj Malik, M.D., Chief Medical Officer and Senior Vice President, R&D. "In metastatic triple-negative breast cancer, the benefit manifests as improved overall survival. In small cell lung cancer, patients experience myelopreservation benefits, including reduced rates of neutropenia, anemia and other chemotherapy-related side effects, and a corresponding decrease in the use of rescue therapies required to address those toxicities. Importantly, patient-reported outcome measures across all of our trials showed that trilaciclib improved the patient experience on chemotherapy."

Mark Velleca, M.D., Ph.D., Chief Executive Officer, added: "Based on feedback from our pre-NDA meeting with the FDA, we will begin a rolling NDA submission for small cell lung cancer in the fourth quarter of this year, which we expect to complete in the second quarter of 2020. We have also had initial discussions with the FDA regarding development of trilaciclib in triple-negative breast cancer, including the preliminary design of a Phase 3 trial. In 2020, we plan to initiate a Phase 3 trial in triple-negative breast cancer and a Phase 3 trial in colorectal cancer, with the goal of demonstrating the benefits of trilaciclib to patients receiving chemotherapy for multiple tumor types."

Overall survival benefit in mTNBC

The randomized, open-label Phase 2 study (NCT02978716) of trilaciclib in combination with GC, a current standard of care for TNBC, enrolled 102 patients who had received up to two prior chemotherapy regimens for locally recurrent or metastatic TNBC. In this three-arm trial, all three groups received a chemotherapy regimen of GC. Patients were randomized to receive GC only (Group 1) or GC plus one of two dosing schedules of trilaciclib: trilaciclib administered on the day of chemotherapy (Group 2) or trilaciclib administered the day prior to and the day of chemotherapy (Group 3). Primary endpoints for the trial included myelopreservation measures; secondary endpoints included additional myelopreservation measures and anti-tumor efficacy measures of overall response rate (ORR), progression-free survival (PFS) and OS. Myelopreservation and preliminary anti-tumor efficacy results from the trial were reported at the 2018 San Antonio Breast Cancer Symposium (press release here). Topline OS findings were announced in June 2019 (press release here); detailed OS results were reported for the first time at ESMO (Free ESMO Whitepaper) 2019.

Updated results from the trial showed:

The addition of trilaciclib to chemotherapy resulted in a significant increase in OS in both treatment groups compared to chemotherapy alone.

Compared to GC alone (Group 1), OS was improved for both trilaciclib arms (Groups 2 and 3) with median OS of 12.6 months, 20.1 months and 17.8 months, respectively (Group 2: HR=0.33, p=0.0283; Group 3: HR=0.34, p=0.0023). The median OS for Groups 2 and 3 combined was 20.1 months (HR=0.36, p=0.0015). The median OS for GC alone (Group 1, 12.6 months) was consistent with historical data.

PFS and ORR were consistent with previously reported data.

The safety and tolerability of trilaciclib were consistent with previously reported data.

There have been no serious adverse events attributed to treatment with trilaciclib in this trial.

Patient-reported outcome (PRO) measures related to anemia were improved in patients receiving trilaciclib versus patients receiving chemotherapy alone.

As previously reported, primary endpoints (myelopreservation measures) were not met.

Trilaciclib in SCLC

On Sunday, September 29, G1 Therapeutics will present updated results from its randomized, double-blind, placebo-controlled Phase 2 trial (NCT03041311) evaluating trilaciclib in extensive-stage SCLC patients receiving first-line chemotherapy and the checkpoint inhibitor Tecentriq (atezolizumab). The findings were consistent with previously reported data (press release here):

Trilaciclib demonstrated myelopreservation benefits, as shown by statistically significant and clinically meaningful improvement in reduction of myelosuppression endpoints, reduction of chemotherapy side effects and reduction of rescue interventions.

Trilaciclib was well tolerated, with fewer ³ Grade 3 adverse events (AEs) compared to placebo.

PRO measures related to anemia were improved in patients receiving trilaciclib versus patients receiving placebo.

Trilaciclib did not adversely impact chemotherapy anti-tumor efficacy as measured by ORR, PFS and OS.

Additionally, data from another randomized Phase 1b/2 trial of trilaciclib in patients with SCLC receiving first-line chemotherapy were recently published in Annals of Oncology, the official journal of ESMO (Free ESMO Whitepaper). Data in this trial demonstrated the myelopreservation benefits of trilaciclib as indicated by statistically significant reduction in clinically relevant consequences of myelosuppression compared to placebo, resulting in fewer supportive care interventions and dose reductions. Trilaciclib did not adversely impact the anti-tumor efficacy of chemotherapy.

Webcast and Conference Call Details

G1 Therapeutics will host a webcast and conference call of its investor and analyst event on Sunday, September 29, 2019, at 6:45 p.m. CEST (12:45 p.m. ET) to review the data being presented at ESMO (Free ESMO Whitepaper) 2019, as well as long-range development plans for all three of its clinical-stage therapies and commercial plans for trilaciclib. The live call may be accessed by dialing 866-763-6020 (domestic) or 210-874-7713 (international) and entering the conference code: 5878315. A live and archived webcast will be available on the Events & Presentations page of the company’s website at www.g1therapeutics.com. The webcast will be archived on the same page for 90 days following the event.

About Trilaciclib

Trilaciclib is a first-in-class investigational therapy designed to improve outcomes for people with cancer treated with chemotherapy. Based on results from three randomized trials in patients with small cell lung cancer, trilaciclib has received Breakthrough Therapy Designation, and G1 Therapeutics expects to submit marketing applications in the U.S. and Europe for myelopreservation in small cell lung cancer in 2020. In a randomized trial of women with metastatic triple-negative breast cancer, trilaciclib improved overall survival when administered in combination with chemotherapy compared with chemotherapy alone. The company plans to initiate a Phase 3 clinical trial in triple-negative breast cancer and a Phase 3 clinical trial in colorectal cancer in 2020.

On September 28, 2019 Immunomedics, Inc. (NASDAQ: IMMU) ("Immunomedics" or the "Company"), a leading biopharmaceutical company in the area of antibody-drug conjugates (ADC), reported at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress interim data from the 100-patient cohort of cisplatin-eligible patients of the Company’s TROPHY-U-01 open-label Phase 2 study (Press release, Immunomedics, SEP 28, 2019, View Source [SID1234539913]). In this interim report, sacituzumab govitecan produced an overall response rate (ORR) of 29 percent in 35 patients with metastatic urothelial cancer (mUC) who have relapsed or are refractory to immune checkpoint inhibitors (CPI) and platinum-based chemotherapy.

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"Patients with mUC who have cancer progression after platinum-based and CPI therapy have poor outcomes and limited treatment options. Together with the prior clinical data, I believe the favorable benefit/risk profile of sacituzumab govitecan has the potential to change the treatment landscape of UC," commented Dr. Scott T. Tagawa, the Richard A. Stratton Associate Professor in Hematology and Oncology, Associate Professor of Clinical Medicine and of Clinical Urology, member of the Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, who presented the interim results from TROPHY-U-01 at the ESMO (Free ESMO Whitepaper) 2019 Annual Congress in Barcelona, Spain.

The 29 percent ORR included two confirmed complete responses, six confirmed partial responses (PRs) and two additional PRs pending confirmation. At the time of data cutoff on August 5, 2019, eight of ten responders have ongoing response. Median time to onset of response was 1.5 months (range, 1.2-2.8). For patients with liver metastases, ORR was 25 percent.

"These interim results, in a larger number of CPI-experienced patients, are consistent with previously reported efficacy of sacituzumab govitecan in mUC, and also show encouraging benefits observed in patients relapsed on enfortumab vedotin," stated Dr. Behzad Aghazadeh, Executive Chairman of Immunomedics. "Based on these data, the Company will be exploring registrational pathways with the FDA."

Consistent with the Company’s previous observations, sacituzumab govitecan was well tolerated with a predictable safety profile. Treatment-related Grade 3 and 4 adverse events were mostly hematologic and gastrointestinal related, including neutropenia (54%) and diarrhea (9%). Importantly, there were no grade 2 or above neuropathy or rash, no interstitial lung disease, and no treatment-related deaths.

New Clinical Collaborations to Advance Sacituzumab Govitecan to Early-Line Treatment of Breast Cancer

In addition, the Company announced two clinical collaborations that address continuing unmet needs in breast cancer. The collaboration with Roche will evaluate the safety and efficacy of the combination of atezolizumab (Tecentriq), a programmed cell death ligand 1 (PD-L1)-blocking checkpoint inhibitor, and sacituzumab govitecan, as a frontline treatment of patients with metastatic or inoperable locally advanced TNBC.

"We are pleased to be partnering with Roche, a global leader in breast cancer therapy," said Dr. Aghazadeh. "With a favorable efficacy and safety profile, we believe sacituzumab govitecan is a strong combination partner and could provide an improved therapeutic option in earlier lines of therapy when combined with immune checkpoint inhibitors."

The open-label, multicenter, randomized Phase 1b/2 study will be conducted as part of MORPHEUS, Roche’s novel cancer immunotherapy development platform. Patients with newly-diagnosed mTNBC will be randomized to receive the combination of atezolizumab and sacituzumab govitecan or nab-paclitaxel plus atezolizumab as standard of care. MORPHEUS is a Phase 1b/2 adaptive platform to develop combinations of cancer immunotherapies more rapidly and efficiently. Roche will be responsible for conducting the randomized trial.

Further, Immunomedics and the GBG Forschungs-GmbH (GBG), Neu-Isenburg, Germany, have entered into a collaboration to develop sacituzumab govitecan as a treatment for newly-diagnosed breast cancer patients who do not achieve a pathological complete response (pCR) following standard neoadjuvant therapy.

"While pCR is now widely accepted as a very strong surrogate endpoint for event-free and distant disease-free survival (DDFS) in high-risk breast cancer, for patients who do not achieve a pCR following standard neoadjuvant therapy, the risk for developing metastatic disease is very high," said Professor Dr. med. Sibylle Loibl, MD, PhD, Chief Executive Officer of GBG. "We are very excited to be the first cooperative group worldwide to evaluate sacituzumab govitecan in this early stage of breast cancer treatment."

According to the medical literature, depending on the hormone receptor status, about 40% to 70% of HER2-negative breast cancer patients treated with neoadjuvant therapy do not achieve a pCR.1 For these patients, with the exception of those with the HER2-positive subtype, there is currently no approved standard of care, leaving them at high risk of distant relapse of their disease.

"We are extremely pleased to partner with GBG, the world-renowned cooperative group, to launch this exciting study which will introduce sacituzumab govitecan to breast cancer patients at an early stage of their disease," commented Dr. Aghazadeh. "We look forward to working closely with GBG to study the potential benefits of sacituzumab govitecan in a significantly larger population of breast cancer patients who have few viable alternatives today."

The multinational, post-neoadjuvant Phase 3 SASCIA study developed by GBG will be conducted under the sponsorship of GBG. Approximately 1,200 high-risk patients with newly-diagnosed HER2-negative breast cancer not achieving a pCR following standard neoadjuvant therapy will be randomized to receive either sacituzumab govitecan or treatment of physician’s choice. Primary endpoint is invasive DFS (iDFS) with overall survival, patient reported outcome/quality of life, circulating tumor DNA clearance, and safety serving as secondary endpoints.

"Given the high level of Trop-2 expression in breast cancer, we are hopeful that sacituzumab govitecan will be established as a new treatment standard for those high-risk patients who failed standard treatment," remarked Professor Dr. med. Frederik Marmé, MD, PhD, Section Lead for Gynecological Oncology, University Medical Center, Mannheim, Germany, and designated Principal Investigator of the SASCIA trial.

BLA Resubmission Timeline Update

Based on the remaining activities for compilation of the BLA, and preparations for a pre-approval inspection, the Company revised its re-submission guidance from early fourth quarter to the late November or early December timeframe.

Reference

Untch M, Jackisch C, et al. Nab-Paclitaxel Improves Disease Free Survival in Early Breast Cancer: GBG 69-GeparSepto. J Clin Oncol. 2019 September 1;37:2226-2234.
About Sacituzumab Govitecan

Sacituzumab govitecan, Immunomedics’ most advanced product candidate, is a novel, first-in-class antibody-drug conjugate (ADC) delivering SN-38, a potent topoisomerase I inhibitor, directly to tumor cells by targeting the Trop-2 antigen expressed by many solid cancers. Based on encouraging Phase 1/2 results, the U.S. Food and Drug Administration has granted sacituzumab govitecan Breakthrough Therapy Designation for the treatment of patients with metastatic triple-negative breast cancer who received at least two prior therapies for metastatic disease.