On October 9, 2016 Important clinical study results from one of Eli Lilly and Company’s (NYSE: LLY) ongoing immuno-oncology collaborations with Merck (known as MSD outside the U.S. and Canada) were reported today at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology (Press release, Eli Lilly, OCT 9, 2016, View Source [SID:SID1234515675]). Specifically, data released from KEYNOTE-021, Cohort G, which evaluated ALIMTA (pemetrexed) plus carboplatin in combination with Merck’s KEYTRUDA (pembrolizumab) in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC), showed that the combination of ALIMTA, KEYTRUDA and carboplatin demonstrated superior efficacy compared to ALIMTA and carboplatin – standard of care – alone.

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In KEYNOTE-021, Cohort G, which included patients with advanced nonsquamous NSCLC regardless of PD-L1 expression level, the combination of pemetrexed, pembrolizumab and carboplatin achieved a 55 percent objective response rate (ORR) compared to 29 percent for pemetrexed-plus-carboplatin alone, and reduced the risk of disease progression or death by 47 percent. Median progression-free survival (PFS) was 13.0 months with the pemetrexed-pembrolizumab-carboplatin combination. To date, this combination of pemetrexed-pembrolizumab-carboplatin is the only anti-PD-1-containing regimen to demonstrate superior efficacy compared to chemotherapy alone in NSCLC patients receiving first-line treatment.

"These randomized study data of ALIMTA and KEYTRUDA in first-line nonsquamous non-small cell lung cancer build on the early results we’ve seen in this combination and are very encouraging," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "To see a near-doubling in the number of patients responding to this combination gives us hope for what may be able to be achieved above and beyond what is seen with the ALIMTA-containing standard-of-care regimen. These types of clinical advancements are truly exciting as we continue our pursuit to bring meaningful benefits to patients facing cancer."

Dr. Gaynor added, "These data also reflect the progress that Lilly is making in its oncology R&D strategy to develop cancer treatments across three key areas of disease modification: tumor cell signaling, tumor microenvironment and immuno-oncology. This approach allows for testing of combinations of internally derived agents to address tumor heterogeneity and drug resistance, through our own efforts and research collaborations."

KEYNOTE-021, Cohort G, included 123 previously untreated patients with advanced nonsquamous NSCLC regardless of PD-L1 expression and whose tumors did not have EGFR mutations or ALK translocations. Patients were randomized to receive the pemetrexed-pembrolizumab-carboplatin combination (n=60) or pemetrexed-plus-carboplatin (n=63). Patients randomized to the pemetrexed-plus-carboplatin control arm had the option of crossing over to pembrolizumab monotherapy upon disease progression. The median follow-up was 10.6 months (range, 0.8-19.3).

The findings demonstrated that ORR nearly doubled with the pemetrexed-pembrolizumab-carboplatin combination, with an ORR of 55 percent (n=33/60), compared to 29 percent (n=18/63) for the control arm alone (treatment difference 26%, 95% CI, 9-42% p=0.0016); all responses were partial. Median duration of response was not reached in either group (range, 1.4+-13.0+ for the pemetrexed-pembrolizumab-carboplatin combination; 1.4+-15.2+ for the control arm). Responses in both groups were durable, with 88 percent (n=29/33) of responders in the pemetrexed-pembrolizumab-carboplatin combination group and 78 percent (n=14/18) of responders in the control arm group experiencing ongoing response at the time of data cut-off.

Additionally, the pemetrexed-pembrolizumab-carboplatin combination significantly reduced the risk of disease progression or death compared to the control arm (hazard ratio 0.53, 95% CI, 0.31-0.91, p=0.0102). Median PFS was 13.0 months with the pemetrexed-pembrolizumab-carboplatin combination compared to 8.9 months in the control arm. Overall survival (OS) was similar between the two arms, with 92 percent survival at six months in both, and 75 percent and 72 percent survival at 12 months in the pemetrexed-pembrolizumab-carboplatin combination and control arm, respectively.

Of treated patients on the pemetrexed-pembrolizumab-carboplatin combination arm, 47 percent remained on treatment as of the cut-off date, compared to 31 percent on the control arm. Of the treated patients who discontinued treatment on the control arm, 52 percent (n=32/62) subsequently received anti-PD-L1 therapy, with 32 percent crossing over to pembrolizumab monotherapy as allowed by the study protocol and 19 percent receiving it outside of study crossover.

Additional Safety Information from KEYNOTE-021, Cohort G
The most common treatment-related adverse events (occurring in at least 15% of patients) for the pemetrexed-pembrolizumab-carboplatin combination were fatigue, nausea, anemia, rash, vomiting, diarrhea, increased AST, constipation, decreased appetite, increased ALT, dysgeusia, and decreased neutrophils. Grade 3-4 treatment-related adverse events in this arm included fatigue, nausea, anemia, rash, vomiting, increased AST, increased ALT, and decreased neutrophils. The most common immune-mediated adverse events in patients receiving the pemetrexed-pembrolizumab-carboplatin combination were hypothyroidism and hyperthyroidism. Additionally, pneumonitis, infusion reactions, and severe skin toxicity were noted. These immune-mediated adverse events occurred at similar rates to patients receiving pembrolizumab as a single agent. There was one treatment-related death from sepsis in a patient receiving the pemetrexed-pembrolizumab-carboplatin combination, and two (one from sepsis and one from pancytopenia) in patients on the control arm.

About KEYNOTE-021, Cohort G
Cohort G of the multicenter, open-label, phase 1/2 multi-cohort KEYNOTE-021 study evaluated the efficacy and safety of pembrolizumab in combination with pemetrexed and carboplatin compared with pemetrexed and carboplatin in patients with advanced, nonsquamous, EGFR- and ALK-negative NSCLC in the first-line treatment setting. Patients were randomized 1:1 to four cycles of pembrolizumab (200 mg) plus pemetrexed (500 mg/m2 every three weeks) plus carboplatin AUC 5 (5 mg/mL/min), or pemetrexed plus carboplatin alone, followed by maintenance pemetrexed with or without pembrolizumab. Randomization was stratified by PD-L1 expression (positive expression defined as TPS of one percent or more; negative expression defined as TPS of less than one percent). Patients randomized to the control arm were allowed to cross over to pembrolizumab monotherapy if they experienced disease progression. Response was assessed by blinded, independent central review using RECIST 1.1 every six weeks for the first 18 weeks, every nine weeks through the first year, and every 12 weeks in the second year. The primary endpoint was ORR; secondary endpoints included PFS, duration of response, and OS.

About KEYNOTE-189, a Phase 3 Trial of Pemetrexed-Pembrolizumab-Platinum Combination
KEYNOTE-189, a randomized Phase 3 study evaluating pemetrexed-plus-platinum chemotherapy (carboplatin or cisplatin) with and without pembrolizumab as initial therapy in NSCLC patients, is currently enrolling. The first results from this study could be available before the end of 2017.

Pemetrexed (marketed under the brand name ALIMTA) is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides.

Pembrolizumab (marketed under the brand name KEYTRUDA) is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells.

NOTES TO EDITORS

About ALIMTA (pemetrexed)
In 2004, ALIMTA received consecutive approvals: it was the first agent to be approved in combination with cisplatin as a treatment for patients with malignant pleural mesothelioma, whose disease is unresectable or who are otherwise not candidates for curative surgery, and then as a single agent for the treatment of patients with locally advanced or metastatic NSCLC after prior treatment.

In 2008, ALIMTA, in combination with cisplatin, was approved as an initial chemotherapy treatment for locally advanced or metastatic NSCLC for patients with nonsquamous histology. At the time of this initial treatment approval, the FDA also approved a change to the indication for subsequent treatment. ALIMTA is now indicated as a single agent for the treatment of patients with locally advanced or metastatic, nonsquamous NSCLC after prior therapy.

In 2009, ALIMTA was approved as a maintenance therapy for locally advanced or metastatic NSCLC, specifically for patients with a nonsquamous histology whose disease has not progressed after four cycles of platinum-based initial chemotherapy.

In 2012, ALIMTA was approved by the FDA as maintenance therapy for locally-advanced or metastatic NSCLC, following initial ALIMTA-plus-cisplatin treatment for locally advanced or metastatic nonsquamous NSCLC.

ALIMTA is not indicated for treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Indications and Important Safety Information for ALIMTA (pemetrexed for injection)

Indications
ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

Important Safety Information

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Contraindication
ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and Precautions
Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities.

Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance < 45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function.

Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Drug Interactions
See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency.

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

Use in Specific Patient Populations
It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dosage and Administration Guidelines
Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA.

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC)
The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy
The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/desquamation (10% vs 3%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy
The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

Abbreviated Adverse Reactions (% incidence) – 2nd-line advanced NS NSCLC
The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5% vs 40%); leukopenia (4% vs 27%); thrombocytopenia (2% vs 0%); anemia (4% vs 4%); fatigue (5% vs 5%); nausea (3% vs 2%); anorexia (2% vs 3%); vomiting (2% vs 1%); increased ALT (2% vs 0%); increased AST (1% vs 0%); and stomatitis/pharyngitis (1% vs 1%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34% vs 36%); nausea (31% vs 17%); anorexia (22% vs 24%); anemia (19% vs 22%); vomiting (16% vs 12%); stomatitis/pharyngitis (15% vs 17%); rash (14% vs 6%); diarrhea (13% vs 24%); leukopenia (12% vs 34%); thrombocytopenia (8% vs 1%); increased ALT (8% vs 1%); increased AST (7% vs 1%); constipation (6% vs 4%); fever (8% vs 8%); pruritus (7% vs 2%); alopecia (6% vs 38%); and neutropenia (11% vs 45%).

Abbreviated Adverse Reactions (% incidence) – MPM
The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, for the treatment of patients with malignant pleural mesothelioma (MPM) were neutropenia (23% vs 3%); leukopenia (15% vs 1%); thrombocytopenia (5% vs 0%); anemia (4% vs 0%); nausea (12% vs 6%); vomiting (11% vs 4%); fatigue (10% vs 9%); creatinine elevation (1% vs 1%); stomatitis/pharyngitis (3% vs 0%); anorexia (1% vs 1%); diarrhea (4% vs 0%); constipation (1% vs 1%); dyspepsia (1% vs 0%); dehydration (4% vs 1%); neuropathy-sensory (0% vs 1%); rash (1% vs 0%); and creatinine clearance decrease (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus cisplatin alone, respectively, were neutropenia (56% vs 13%); leukopenia (53% vs 17%); anemia (26% vs 10%); thrombocytopenia (23% vs 9%); nausea (82% vs 77%); vomiting (57% vs 50%); fatigue (48% vs 42%); creatinine elevation (11% vs 10%); creatinine clearance decreased (16% vs 18%); conjunctivitis (5% vs 1%); anorexia (20% vs 14%); diarrhea (17% vs 8%); constipation (12% vs 7%); dyspepsia (5% vs 1%); dehydration (7% vs 1%); neuropathy-sensory (10% vs 10%); taste disturbance (8% vs 6%); rash (16% vs 5%); alopecia (11% vs 6%); and stomatitis/pharyngitis (23% vs 6%).

On October 9, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported a poster presentation of updated data on its lead clinical program, an NY-ESO SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell receptor therapy, in patients with synovial sarcoma at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress (Press release, Adaptimmune, OCT 9, 2016, View Source;p=RssLanding&cat=news&id=2210294 [SID:SID1234515673]).

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"These data help clarify the design of our upcoming pivotal studies in sarcoma," said Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "We have seen durable tumor responses to our SPEAR T-cells and the preliminary benefit:risk profile appears favorable. Further, although the data are preliminary, we do see activity against tumors with lower levels of NY-ESO expression, which we hope will further expand the utility of this therapy, and we have evidence that fludarabine is required in the pre-conditioning regimen. With these data in hand, we will initiate Cohort 4 with our modified fludarabine pre-conditioning regimen, and continue toward our goal of bringing this novel TCR-based immunotherapy to sarcoma patients."

In a poster presentation entitled, "Open Label Non-Randomized Multi-Cohort Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO SPEAR T-cells in HLA-A*02+ Patients with Synovial Sarcoma," Crystal Mackall, M.D., Professor of Pediatrics and Medicine; Associate Director of the Stanford Cancer Institute, provided an update on the following synovial sarcoma cohorts:

Cohort 1: Subjects with high (≥50 percent 2+/3+ by IHC) NY-ESO-1 antigen expression and lymphodepletion with cyclophosphamide and fludarabine
Cohort 2: Subjects with low (>1 percent to <50 percent 2+/3+ by IHC) NY-ESO-1 antigen expression and lymphodepletion with cyclophosphamide and fludarabine
Cohort 3: Subjects with high (≥ 50 percent 2+/3+ by IHC) NY-ESO-1 antigen expression and lymphodepletion with cyclophosphamide alone (no fludarabine)
Cohort 4: Subjects with high (≥ 50 percent 2+/3+ by IHC) NY-ESO-1 antigen expression and lymphodepletion with a modified (lower) dose than Cohort I of cyclophosphamide and fludarabine
Cohort 1
Adaptimmune has previously announced that in the first cohort of synovial sarcoma patients, NY-ESO SPEAR T-cells demonstrated a robust clinical response, including a 50 percent (6/12) response rate, and a 60 percent response rate (6/10) in those who received the target dose of at least 1×109 transduced cells. The median duration of response is reported to be approximately 31 weeks (August 31 data cutoff). Ongoing NY-ESO SPEAR T-cell persistence has been observed for up to 36 months.

Cohort 2
Four subjects of a targeted 10 are currently enrolled in the second cohort; three patients have been treated with NY-ESO SPEAR T-cells. As of August 31, 2016 best responses seen in these three patients were: one partial response (PR), one stable disease (SD), and one progressive disease (PD).

Cohorts 3 and 4
Five patients are currently enrolled in the third cohort; no objective responses have been observed to date. As pre-specified in the protocol, enrollment in cohort 3 has ceased, and company has initiated enrollment in Cohort 4.

Tolerability
NY-ESO SPEAR T-cells continue to demonstrate a generally acceptable benefit: risk profile in all treated patients to date. The most common (>30%) related adverse events include pyrexia, lymphopenia, decreased white blood cell (WBC), nausea, anemia, neutropenia, fatigue, decreased platelet count (PLT), sinus tachycardia, and rash. Most common toxicities related to therapy can be monitored and managed with medical intervention and supportive care. While there are differences in the patient populations, incidence of cytokine release syndrome (CRS) with NY-ESO-1c259 SPEAR T appears to be of lower frequency and severity than reported with CD19 CAR-T therapy. As previously reported at the 2016 Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting, there was one fatal SAE of bone marrow failure in Cohort 2 of our synovial sarcoma trial. Internal investigations have not identified a mechanism by which NY-ESO SPEAR T-cells may have caused bone marrow failure.

Adaptimmune’s SPEAR T-cell candidates are novel cancer immunotherapies that have been engineered to target and destroy cancer cells by strengthening a patient’s natural T-cell response. T-cells are a type of white blood cell that play a central role in a person’s immune response. Adaptimmune’s goal is to harness the power of the T-cell and, through its multiple therapeutic candidate, significantly impact cancer treatment and clinical outcomes of patients with solid and hematologic cancers.

On October 9, 2016 Boehringer Ingelheim reported results from the LUX-Lung 7 trial that directly compared the efficacy and safety of second-generation EGFR-directed therapy Gilotrif (afatinib) and first-generation Iressa (gefitinib), in the first-line treatment of patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) (Press release, Boehringer Ingelheim, OCT 9, 2016, View Source [SID:SID1234515672]). The trial investigated overall survival (OS) as a primary endpoint and a reduction in the risk of death (14%) was observed for patients treated with afatinib versus gefitinib. The median survival of patients treated with afatinib was 27.9 months compared to 24.5 months for those receiving gefitinib, without reaching significance. The OS outcomes observed with afatinib were consistent across common EGFR mutation types.

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Details of the analysis will be presented today at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen, Denmark, October 7 – 11 (abstract #LBA43 – Oral presentation, NSCLC, metastatic 1, Sunday, October 9, 11:45 – 12:00 CEST (5:45 – 6:00 ET)).

"The LUX-Lung 7 trial provides new insight into first-line treatment options for EGFR mutation-positive NSCLC patients and is the first global head-to-head trial directly comparing two EGFR-directed therapies," commented Shirish Gadgeel, M.D., leader of the Thoracic Oncology Multidisciplinary, Karmanos Cancer Center, Detroit. "These study findings may help inform treatment decisions for patients whose tumors have EGFR mutations."

Updated results also confirmed the primary analysis that showed the global Phase IIb LUX-Lung 7 trial met two of its three co-primary endpoints of progression-free survival (PFS) by independent review and time to treatment failure (a measure of time between start and discontinuation of treatment for any reason). Results from the primary analysis, presented in 2015, showed that afatinib significantly reduced the risk of lung cancer progression and the risk of treatment failure, both by 27% versus gefitinib. The improvement in PFS became more pronounced over time. After two years of treatment, more than twice as many patients on afatinib were alive and progression-free than those on gefitinib (after 18 months; 27% vs 15% and after 24 months; 18% vs 8%). Additionally, significantly more patients experienced an objective response (ORR; a clinically meaningful decrease in tumor size) with afatinib when compared to gefitinib.

Both afatinib and gefitinib demonstrated similar improvements in patient-reported outcome measures in the LUX-Lung 7 trial with no significant differences in health-related quality of life with afatinib compared to gefitinib treatment. Treatment with both afatinib and gefitinib were generally tolerable, leading to an equal rate of treatment-related discontinuation in both arms (6%). Adverse events (AEs) observed in the trial were consistent with the known safety profiles of both treatments. The overall frequency of serious AEs was 44.4% for afatinib and 37.1% for gefitinib. The most common grade ≥3 related AEs with afatinib were: diarrhea (13%) and rash/acne (9%), and with gefitinib: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increase (9%) and rash/acne (3%). Drug-related interstitial lung disease was reported for four patients on gefitinib and no patients on afatinib. Dose modification of afatinib was available in patients who met a set criteria in order to better manage AEs. As gefitinib is only available in one dose formulation, no dose reduction was administered.

"We believe that the latest results of the LUX-Lung 7 trial data adds to the growing body of evidence that reinforces the treatment benefits of afatanib in patients with these types of tumors," said Martina Flammer, M.D., Vice President, Clinical Development & Medical Affairs Specialty Care, Boehringer Ingelheim.

Afatinib is approved in over 70 countries for the first-line treatment of EGFR mutation-positive NSCLC. Approval of afatinib in this indication was based on the primary endpoint of PFS from the LUX-Lung 3 clinical trial where afatinib significantly delayed tumor growth when compared to standard chemotherapy. In addition, afatinib is the first treatment to have shown an OS benefit for patients with specific types of EGFR mutation-positive NSCLC compared to chemotherapy. A significant OS benefit was demonstrated independently in the LUX-Lung 3 and 6 trials for patients with the most common EGFR mutation (del19) compared to chemotherapy. Afatinib is also approved in the U.S., EU and other markets for the treatment of patients with advanced squamous cell carcinoma (SqCC) of the lung whose disease has progressed on or after treatment with platinum-based chemotherapy. Approval of afatinib in this indication is based on results of the LUX-Lung 8 study, which showed a significantly improved overall survival and progression-free survival compared to Tarceva (erlotinib) in patients with SqCC of the lung.

About the LUX-Lung 7 trial
LUX-Lung 7 is the first global, head-to-head trial comparing second- and first-generation EGFR-directed therapies (afatinib and gefitinib respectively) for patients with EGFR mutation-positive NSCLC who received no prior treatment. The Phase IIb trial included 319 patients with advanced stage NSCLC harboring common EGFR mutations (del19 or L858R). The trial’s co-primary endpoints were PFS by independent review, time to treatment failure and OS; and the secondary endpoints included ORR, disease control rate, tumor shrinkage, patient-reported outcomes and safety.

Results from the primary analysis: compared to gefitinib, afatinib significantly improved:

PFS (HR=0.73; 95% CI, 0.57‒0.95; p=0.017; median: 11.0 months [afatinib] versus 10.9 months [gefitinib]). The improvement in PFS with afatinib was consistent across pre-defined clinical subgroups, including gender, age, race and EGFR mutation type
Time to treatment failure (HR=0.73; 95% CI, 0.58‒0.92; p=0.0073; median: 13.7 months [afatinib] versus 11.5 months [gefitinib])
ORR (70% vs 56%, p=0.0083)
Data from the trial showed a reduction in the risk of death for patients treated with afatinib compared to gefitinib, without reaching significance (HR=0.86; 95% CI, 0.66‒1.12; p=0.2580; median: 27.9 months [afatinib] versus 24.5 months [gefitinib]). These OS data have a maturity of 71%, with further analysis to follow once full maturity has been reached.

What is GILOTRIF?

GILOTRIF is a prescription medicine used to treat people with non-small cell lung cancer (NSCLC):

that has certain types of abnormal epidermal growth factor receptor (EGFR) genes. Your doctor will perform a test to check for certain types of abnormal EGFR genes, and make sure that GILOTRIF is right for you. GILOTRIF may be used when you have not had previous treatment for cancer that has spread to other parts of the body. It is not known if GILOTRIF is safe and effective in treating lung cancer with other abnormal EGFR genes.
or

that is squamous type and has spread to other parts of the body after you have tried chemotherapy that contains platinum.
It is not known if GILOTRIF is safe and effective in children.

IMPORTANT SAFETY INFORMATION ABOUT GILOTRIF

Before you take GILOTRIF, tell your doctor if you:

have kidney or liver problems
have lung or breathing problems other than lung cancer
have a history of severe dry eye or any other eye problems. Tell your doctor if you wear contact lenses.
have heart problems
have any other medical conditions
are pregnant or plan to become pregnant. GILOTRIF can harm your unborn baby. You should not become pregnant while taking GILOTRIF.
Women who are able to become pregnant should use effective birth control during treatment with GILOTRIF and for at least 2 weeks after your last dose of GILOTRIF. Talk to your doctor about birth control methods that may be right for you.
Tell your doctor right away if you become pregnant or think you are pregnant while taking GILOTRIF.
are breastfeeding or plan to breastfeed. It is not known if GILOTRIF passes into your breast milk. Do not breastfeed while taking GILOTRIF and for 2 weeks after your last dose of GILOTRIF. Talk to your doctor about the best way to feed your baby if you take GILOTRIF.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. GILOTRIF may affect the way other medicines work, and other medicines may affect the way GILOTRIF works.

What to avoid while taking GILOTRIF

Limit your time in the sun. GILOTRIF can make your skin sensitive to the sun. You could get or have worsening rash or acne. You could get a severe sunburn. Use sunscreen and wear a hat and clothes that cover your skin while you are taking GILOTRIF if you have to be in sunlight.

GILOTRIF may cause serious side effects, including:

Diarrhea. Diarrhea is common with GILOTRIF and may sometimes be severe. Severe diarrhea can cause loss of body fluid (dehydration) and kidney problems that can sometimes lead to death. During your treatment with GILOTRIF, your doctor should prescribe medicines to treat diarrhea. Take this medicine exactly as your doctor tells you to. Tell your doctor if you have diarrhea. Get medical attention right away if your diarrhea does not go away or becomes severe.
Skin reactions. GILOTRIF can cause redness, rash, and acne. It is important to get treatment for skin reactions as soon as you notice them. Take medicines to help skin reactions exactly as your doctor tells you to. Get medical attention right away if you develop severe skin reactions such as peeling or blistering of the skin, or blisters in your mouth.
Lung or breathing problems. GILOTRIF may cause inflammation of the lung that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your doctor right away if you have any new or worsening lung problems, or any combination of the following symptoms: trouble breathing or shortness of breath, cough, or fever.
Liver problems. GILOTRIF can cause liver problems that can sometimes lead to death. Tell your doctor right away if you have any symptoms of a liver problem which may include:
yellowing of your skin or the white part of your eyes (jaundice)
dark or brown (tea-colored) urine
pain on the upper right side of your stomach area (abdomen)
bleeding or bruising more easily than normal
feeling very tired
Your doctor will do blood tests to check your liver function during your treatment with GILOTRIF.

Eye problems. Tell your doctor right away if you have symptoms of eye problems. Symptoms may include:
eye pain, swelling, redness, or tearing
blurred vision
sensitivity to light
other changes in your vision
Heart problems. Tell your doctor right away if you have any symptoms of a heart problem which may include:
new or worsening shortness of breath while at rest or with activity
cough
tiredness
swelling of your ankles, feet, or legs
feeling that your heart is pounding or racing (palpitations)
sudden weight gain
The most common side effects of GILOTRIF include diarrhea, rash, mouth sores, nail inflammation, dry skin, acne, decreased appetite, nausea, vomiting, itching.

GILOTRIF may cause decreased fertility in females and males. Talk to your doctor if you have concerns about your fertility.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of GILOTRIF. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088 .

Please see the full Prescribing Information, including Patient Information.

On October 9, 2016 Astellas Pharma Europe Ltd., a subsidiary of Tokyo-based Astellas Pharma Inc. (TSE:4503), reported the presentation of new data that reaffirms the role of XTANDITM▼ (enzalutamide) in extending time to prostate specific antigen (PSA) progression in men with advanced prostate cancer. The data presented today at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper), held in Copenhagen, Denmark, from 7-11 October, confirms the efficacy of enzalutamide vs placebo in Asian men (Press release, Astellas, OCT 9, 2016, View Source [SID:SID1234515671]).

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Data from a study examining the efficacy and safety of enzalutamide versus placebo in 409 Asian patients from China, South Korea, Taiwan and Hong Kong with asymptomatic/mildly symptomatic progressive advanced prostate cancer following androgen deprivation therapy (ADT) found that enzalutamide significantly improved time to PSA progression, compared with placebo (7.46 months vs 2.86 months, respectively (HR* 0.36; 95% CI 0.27**, 0.5; P<0.0001)).1 PSA blood tests are used to monitor the progression of prostate cancer.2

Secondary end points included overall survival, defined as time from randomisation to death from any cause, and radiographic progression free survival (rPFS) defined as the time from randomisation to radiographic progression or death from any cause.a Although the median overall survival was not yet reached at the time of the data cut-off in either treatment arm, enzalutamide significantly reduced the risk of death (HR 0.35; 95% CI 0.17, 0.70; p=0.0021). At data cut-off, enzalutamide significantly reduced the risk of rPFS events with 19.6% (41/209) of patients receiving enzalutamide and 36% (72/200) of patients in the placebo arm experiencing a rPFS event – i.e, spreading of the cancer. While slightly more patients treated with enzalutamide reported at least one treatment-emergent adverse event, enzalutamide was generally well tolerated in the trial.1 These results are consistent with data from the pivotal PREVAIL trial, which considered a patient population with similar clinical characteristics. In the PREVAIL trial, enzalutamide was found to increase the median overall survival in asymptomatic or mildly symptomatic patients with advanced prostate cancer who had not received chemotherapy, compared with placebo.3

__________________

aWithin 168 days of treatment discontinuation, whichever occurred first, assessed during the screening, at day 57, 113, 169 and 253 and every subsequent 12 weeks.

Dr Simon Chowdhury, Consultant Medical Oncologist, Guy’s and St Thomas’ NHS Foundation Trust, "The findings presented today show that enzalutamide can increase the time to PSA progression – an important marker used to monitor disease progression in prostate cancer – compared with placebo, in Asian men. Historically there has been a lack of studies considering this group of men and so these results provide reassurance of enzalutamide’s efficacy and tolerability across the broad population that we tend to see across Europe."

An additional five abstracts focusing on enzalutamide were also presented today, adding further to the body of data supporting the safety and efficacy profile of enzalutamide as a treatment option for advanced prostate cancer.

Enzalutamide data presentation details:

Ye D, Ahn H, Pu Y-S, et al. Efficacy and safety of enzalutamide (ENZ) vs placebo (PL) in chemotherapy-naïve patients (pts) with progressive metastatic castration-resistant prostate cancer (mCRPC) following androgen deprivation therapy (ADT): an Asian multinational study. Poster 760P; 9 Oct 2016 (Sun); 13:00-14:00; Hall E
Chowdhury S, Shore N, Saad f, et al. Fatigue in men with metastatic castration-resistant prostate cancer treated with enzalutamide: data from randomised clinical trials. Poster 739P; 9 Oct 2016 (Sun);13:00-14:00;Hall E
Heidenreich A, Shore N, Villers A, et al. Prognostic factors in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZA) or bicalutamide (BIC) in TERRAIN. Poster 759P; 9 Oct 2016 (Sun); 13:00-14:00; Hall E
Bryce A, Alumkal J, Armstrong A, et al. A post hoc analysis of radiographic progression with nonrising prostate-specific antigen in patients with metastatic castration-resistant prostate cancer (mCRPC) in the PREVAIL study. Poster 760P; 9 Oct 2016 (Sun); 13:00-14:00; Hall E
Stenzl A, Krivoshik A, Baron B, et al. Efficacy and safety of enzalutamide plus androgen deprivation therapy vs placebo plus androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: the ongoing ARCHES trial. Poster 767TiP;9 Oct 2016 (Sun);13:00-14:00; Hall E
Miller K, Mulders P, Freedland S, et al. EMBARK: A phase 3, randomized, efficacy and safety study of enzalutamide plus leuprolide, enzalutamide monotherapy and placebo plus leuprolide in men with high-risk nonmetastatic prostate cancer progressing after definitive therapy. Poster 770TiP; 9 Oct 2016 (Sun); 13:00-14:00; Hall E
About PREVAIL

PREVAIL was a Phase 3, randomised, double-blind, placebo-controlled trial of enzalutamide versus placebo in patients with mCRPC who had not received chemotherapy.3

About AFFIRM

AFFIRM was a Phase 3, randomised, double-blind, placebo-controlled study of enzalutamide in patients with mCRPC who had previously been treated with docetaxel-based chemotherapy.4

About TERRAIN

TERRAIN was a Phase 2, randomised, double-blind, efficacy and safety study of enzalutamide vs. bicalutamide in patients with mCRPC.5

About STRIVE

STRIVE was a Phase 2, randomised, double-blind, efficacy and safety study of enzalutamide versus bicalutamide in patients with nonmetastatic or metastatic CRPC.6

About XTANDI (enzalutamide)

Enzalutamide is a novel, oral, once-daily androgen receptor signaling inhibitor. Enzalutamide directly targets the androgen receptors (AR) and exerts its effects on all three steps of AR signaling pathway:

Blocks androgen binding7
Androgen binding induces a conformational change that triggers activation of the receptor8
Prevents nuclear translocation7
Translocation of the AR to the nucleus is an essential step in AR-mediated gene regulation8
Impairs DNA binding7
Binding of the AR to the DNA is essential for modulation of gene expression8
Enzalutamide was first approved by the European Commission in June 2013 for the treatment of adult men with mCRPC whose disease has progressed on or after docetaxel therapy.9 Enzalutamide is also approved in Europe for the treatment of adult men with mCRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated.9

Important Safety Information for XTANDI (enzalutamide)

For important Safety Information for enzalutamide please see the full Summary of Product Characteristics at: View Source

On October 9, 2016 Pfizer Inc. (NYSE:PFE) reported data from an ongoing, investigational Phase 1b study of INLYTA (axitinib) combined with the checkpoint inhibitor pembrolizumab (A4061079, NCT02133742), a PD-1 inhibitor known as KEYTRUDA and marketed by Merck, known as MSD outside the United States and Canada, in treatment-naïve patients with advanced renal cell carcinoma (RCC) (Press release, Pfizer, OCT 9, 2016, View Source [SID:SID1234515670]). The study was designed to establish dosing and evaluate the safety and anti-tumor activity of INLYTA when combined with pembrolizumab in first-line treatment of advanced RCC.

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Preliminary results from a similar, separate study combining INLYTA with avelumab (JAVELIN Renal 100, NCT02493751), an investigational, fully human anti-PD-L1 IgG1 monoclonal antibody that is being co-developed by Merck KGaA, Darmstadt, Germany, and Pfizer were also presented. The data suggest evidence of anti-tumor activity for INLYTA in combination with avelumab and were presented during a poster discussion session at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology being held in Copenhagen, Denmark.

Based on these Phase 1 results, two independent global Phase 3 trials evaluating these combinations – INLYTA plus pembrolizumab and INLYTA plus avelumab – each compared with SUTENT (sunitinib) in first-line advanced RCC are now enrolling patients.

"Combining immunotherapy agents with currently approved therapies such as INLYTA may provide a meaningful improvement in outcome for patients with renal cancer," said Chris Boshoff, M.D., Ph.D., head of immuno-oncology, early development and translational oncology, Pfizer Global Product Development. "The results presented today indicate that there is a potential additive or synergistic effect between INLYTA and a checkpoint inhibitor in RCC."

Early indicators from the A4061079 study point to strong response rates with the INLYTA/pembrolizumab combination, with 37 patients (71.2%, confidence internal 56.9, 82.9) achieving objective responses (three complete responses and 34 partial responses); 10 patients had stable disease and 5 patients had disease progression.

Separately, in the JAVELIN Renal 100 study of INLYTA in combination with avelumab, five out of six patients treated so far had confirmed partial responses (objective response rate 83.3%, 95% confidence interval: 35.9, 99.6) and one patient with tumor shrinkage not meeting partial response criteria had stable disease.

INLYTA is an oral vascular endothelial growth factor (VEGF) receptor inhibitor for the treatment of patients with advanced RCC after failure of one prior systemic therapy approved in 63 countries. It was the first treatment to demonstrate superior progression-free survival benefit in a Phase 3 study versus sorafenib, a tyrosine kinase inhibitor, in second-line treatment of advanced RCC.

About Avelumab

Avelumab (also known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

About INLYTA (axitinib)

INLYTA is an oral therapy that is designed to inhibit tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors 1, 2 and 3; these receptors can influence tumor growth, vascular angiogenesis and progression of cancer (the spread of tumors). In the U.S., INLYTA is approved for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. INLYTA is also approved by the European Medicines Agency (EMA) for use in the EU in adult patients with advanced RCC after failure of prior treatment with sunitinib or a cytokine.

INLYTA Important Safety Information

Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis.

Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events.

Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.

Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment.

No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment.

For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment.

Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA.

Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided.

Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%).

The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%).

The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39% vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute) (33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs 22%), and increased AST (20% vs 25%).