On May 19, 2021 Blueprint Medicines Corporation (NASDAQ: BPMC) reported the presentation of updated Phase 1/2 ARROW trial data demonstrating durable clinical benefits of GAVRETO (pralsetinib) in metastatic RET fusion-positive non-small cell lung cancer (NSCLC) and other advanced solid tumors (Press release, Blueprint Medicines, MAY 19, 2021, View Source [SID1234580330]). GAVRETO showed high response rates in treatment-naïve patients with RET fusion-positive NSCLC, clinical activity across a number of RET fusion-positive tumor types and a safety profile consistent with previously reported results. These data will be presented during the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, June 4-8.

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"Precision therapies have significantly improved outcomes in non-small cell lung cancer driven by actionable biomarkers, and these pralsetinib data show the transformative impact of targeting RET alterations in the front-line treatment setting," said Giuseppe Curigliano, M.D., Ph.D., Associate Professor of Medical Oncology at the University of Milano and the Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy. "In treatment-naïve metastatic NSCLC, these results are particularly encouraging, with many patients remaining in response. The data highlight the critical importance of identifying RET alterations before initiating treatment, so that more patients have the opportunity to benefit from targeted therapy."

"Updated data in metastatic RET fusion-positive non-small cell lung cancer underscore how GAVRETO may transform the standard of care, including in the first-line treatment setting," said Becker Hewes, M.D., Chief Medical Officer at Blueprint Medicines. "The results in treatment-naïve patients with RET fusion-positive NSCLC reflect the compelling clinical profile of GAVRETO, with high response rates and durability of response that have strengthened over time. In other RET-altered cancers, target lesions were reduced across a diverse range of tumor types, with the majority of patients responding to treatment. In collaboration with Genentech, we look forward to engaging with the FDA based on the strength of these data in metastatic RET fusion-positive solid tumors."

Clinical Activity Data

The ASCO (Free ASCO Whitepaper) data included response-evaluable populations comprising 216 patients with RET fusion-positive NSCLC who had measurable disease at baseline and received a starting GAVRETO dose of 400 mg once daily, and 19 patients with other RET fusion-positive solid tumors, as of a date cutoff date of November 6, 2020. Tumor response was assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and all responses were confirmed.

RET Fusion-Positive NSCLC

With a median follow-up of 17.1 months, GAVRETO showed durable clinical benefits in patients with RET fusion-positive NSCLC with or without prior therapy. In 68 treatment-naïve patients, the overall response rate (ORR) was 79 percent (95% CI: 68%, 88%). The complete response (CR) rate was 6 percent, 10 percent of patients had complete regression of target tumors, and 74 percent of patients had a partial response (PR). The median duration of response (DOR) was not reached (95% CI: 9.0 months, not reached).

For treatment-naïve patients, the initial study protocol limited enrollment to those determined by the investigator to be ineligible for standard platinum-based chemotherapy, which may be due to age, comorbidities or other poor prognostic factors. This eligibility restriction was removed in July 2019, with the goal of including a population more reflective of real-world practice. In an exploratory analysis of treatment-naïve patients enrolled after this expansion of inclusion criteria (n=25), the ORR was 88 percent (95% CI: 69%, 98%), and all responses were PRs.

In 126 patients who previously received platinum-based chemotherapy, the ORR was 62 percent (95% CI: 53%, 70%). The CR rate was 4 percent, 12 percent of patients had complete regression of target tumors, and 58 percent of patients had a PR. The median DOR was 22.3 months (95% CI: 15.1 months, not reached).

Other RET Fusion-Positive Solid Tumors

In a heavily pre-treated patient population who had a median follow-up of 12.1 months, GAVRETO showed clinical activity across multiple additional RET-driven tumor types. In 19 patients with a variety of RET fusion-positive solid tumors beyond NSCLC and thyroid cancer, the ORR was 53 percent (95% CI: 29%, 76%) and the median DOR was 19.0 months (95% CI: 5.5 months, not estimable). Tumor reductions were shown in patients with the following cancers – pancreatic, cholangiocarcinoma, colon, lung (except NSCLC), mesenchymal, salivary duct, sweat gland and thymus – as well as patients diagnosed with cancers of unknown primary origin. In the three patients with pancreatic cancer, a particularly difficult-to-treat tumor type, there was one CR and two PRs.

Safety Data

As of a data cutoff date of November 6, 2020, a total of 471 patients were enrolled with a GAVRETO dose starting at 400 mg once daily. Across tumor types, GAVRETO was well-tolerated with no new safety signals observed. The most common treatment-related adverse events (AEs) reported by investigators (≥20 percent) were neutropenia, increased aspartate aminotransferase (AST), anemia, decreased white blood cell count, increased alanine aminotransferase (ALT), hypertension, constipation and asthenia. Overall, 6 percent of patients discontinued GAVRETO due to treatment-related AEs.

These updated data will be reported in two ASCO (Free ASCO Whitepaper) poster presentations: one on RET fusion-positive NSCLC (Abstract #9089) and one on RET fusion-positive solid tumors (Abstract #3079). Copies of the data presentations will be available starting June 4, 2021 in the "Science―Publications and Presentations" section of Blueprint Medicines’ website.

About GAVRETO (pralsetinib)

GAVRETO (pralsetinib) is a once-daily oral targeted therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of three indications: adult patients with metastatic RET fusion-positive NSCLC as detected by an FDA approved test, adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, and adults and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). These indications are approved under accelerated approval based on ORR and DOR. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials. In addition, GAVRETO is approved by the National Medical Products Administration (NMPA) of China for the treatment of adult patients with locally advanced or metastatic RET fusion-positive NSCLC after platinum-based chemotherapy.

GAVRETO is not approved for the treatment of any other indication in the U.S. by the FDA or in China by the NMPA, or for any indication in any other jurisdiction by any other health authority.

GAVRETO is designed to selectively and potently target oncogenic RET alterations, including secondary RET mutations predicted to drive resistance to treatment. In preclinical studies, GAVRETO inhibited RET at lower concentrations than other pharmacologically relevant kinases, including VEGFR2, FGFR2 and JAK2. For more information, visit GAVRETO.com.

Blueprint Medicines and Roche are co-developing GAVRETO globally (excluding Greater China) for the treatment of patients with RET-altered NSCLC, various types of thyroid cancer and other solid tumors. The European Medicines Agency validated a marketing authorization application for GAVRETO for the treatment of RET fusion-positive NSCLC. The FDA granted breakthrough therapy designation to GAVRETO for the treatment of RET fusion-positive NSCLC that has progressed following platinum-based chemotherapy and for RET mutation-positive MTC that requires systemic treatment and for which there are no acceptable alternative treatments.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of GAVRETO in Greater China, which encompasses Mainland China, Hong Kong, Macau and Taiwan.

Enrollment is ongoing in the Phase 1/2 ARROW trial, including for patients with various RET fusion-positive solid tumors, and in the Phase 3 AcceleRET Lung trial for treatment-naïve patients with RET fusion-positive NSCLC. For more information about GAVRETO clinical trials, visit www.clinicaltrials.gov or www.blueprintclinicaltrials.com.

About RET-Altered Solid Tumors

RET activating fusions and mutations are key disease drivers in many cancer types, including NSCLC and multiple types of thyroid cancer. RET fusions are implicated in approximately 1 to 2 percent of patients with NSCLC and approximately 10 to 20 percent of patients with papillary thyroid cancer, while RET mutations are implicated in approximately 90 percent of patients with advanced MTC. In addition, oncogenic RET fusions are observed at low frequencies in colorectal, breast, pancreatic and other cancers, as well as in patients with treatment-resistant EGFR-mutant NSCLC.

On May 19, 2021 BioRay Pharmaceutical, a Taizhou biotech, reported that in-licensed rights to pritumumab, a potential treatment for brain cancer, from Nascent Biotech of San Diego (Press release, Shanghai Bioray Laboratory, MAY 19, 2021, View Source [SID1234580461]). BioRay will pay up to $5 million for global pritumumab rights except for North America and Central America. Pritumumab is a natural human antibody that binds to vimentin, a protein expressed on the surface of epithelial cancers but not healthy cells. BioRay is the biologics subsidiary of China’s Hisun Pharma. In 2019, PAG, a Hong Kong private equity firm, paid $540 million to acquire a 58% stake in BioRay.

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On May 19, 2021 AstraZeneca reported that it will present new data underscoring its ambition to redefine cancer care at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, 4 to 8 June 2021 (Press release, AstraZeneca, MAY 19, 2021, View Source [SID1234580250]).

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More than 100 abstracts will feature 21 approved and potential new medicines across the Company’s industry-leading oncology portfolio, with four abstracts selected as late-breakers, 12 oral presentations and one plenary presentation.

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "Our data at ASCO (Free ASCO Whitepaper) this year show our unwavering resolve to revolutionise cancer care and strengthen our leading portfolio in lung and breast cancers as well as haematology. New results for Lynparza and Imfinzi continue to validate our strategy of treating cancer early in settings with curative intent, and data for Calquence deliver on our commitment to improve the patient experience by demonstrating efficacy with safe, tolerable medicines."

Cristian Massacesi, Senior Vice President, Head of late-stage development, Oncology R&D said: "Over the past few years, the outlook for breast cancer patients with BRCA mutations has radically changed, and the OlympiA data at ASCO (Free ASCO Whitepaper) will represent another critical step forward. We have an opportunity to fundamentally change the prognosis for women with high-risk early disease and usher in a potential new standard of care in the adjuvant setting. Additionally, promising data in triple-negative breast cancer will challenge current treatment expectations and bring hope for new approaches in this aggressive form of the disease."

Redefining survival by treating cancer earlier
A plenary presentation of results from the OlympiA Phase III trial in early breast cancer will highlight the impact of Lynparza (olaparib) on the risk of disease recurrence versus placebo in the adjuvant treatment of patients with germline BRCA-mutated (gBRCAm) high-risk human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. Lynparza is the first PARP inhibitor to demonstrate clinical benefit as an adjuvant treatment in early breast cancer. In February 2021, the trial’s Independent Data Monitoring Committee recommended moving to early primary analysis based on a planned interim analysis showing a sustainable and clinically relevant treatment effect in the primary endpoint of invasive disease-free survival.

Five-year overall survival data from the PACIFIC Phase III trial will continue to support the unprecedented and sustained survival benefits of Imfinzi (durvalumab) for patients with unresectable, Stage III non-small cell lung cancer (NSCLC) who have not progressed following concurrent chemoradiation therapy. These data represent the longest-ever survival reported in a Phase III trial of immunotherapy in this treatment setting.

Additionally, an oral presentation of Phase II data from the externally sponsored GeparNuevo trial conducted by the German Breast Group will show initial potential of Imfinzi to improve outcomes in patients with early triple-negative breast cancer (TNBC) when added to standard neoadjuvant chemotherapy.

Transforming the patient experience
Four-year follow-up data from the ELEVATE-TN trial will confirm the sustained clinical benefit of either Calquence monotherapy or Calquence in combination with obinutuzumab, providing flexibility to tailor treatment for adults with treatment-naïve chronic lymphocytic leukaemia (CLL).

In addition, an oral presentation of detailed results from the ELEVATE-RR Phase III trial will demonstrate significantly lower atrial fibrillation, fewer cardiac events and fewer discontinuations with Calquence (acalabrutinib) versus ibrutinib in adults with previously treated CLL at high risk for progression. ELEVATE-RR is the first head-to-head Phase III trial of two Bruton’s tyrosine kinase inhibitors in CLL, confirming the favourable benefit-risk profile of Calquence for patients with CLL.

Updated data from DESTINY-Gastric01 and DESTINY-CRC01 will further support the potential role of Enhertu (trastuzumab deruxtecan) across HER2-targetable cancers. Additionally, data from a subgroup analysis of previously treated HER2-positive breast cancer patients with brain metastases in the DESTINY-Breast01 trial will reinforce the commitment to understanding the potential benefit of Enhertu in hard-to-treat patient populations.

Initial results will be shared from the BEGONIA Phase Ib/II trial testing Imfinzi combinations in metastatic TNBC, including with Enhertu. Also, data will be shared from a Phase II trial with ceralasertib, an ataxia telangiectasia and rad3-related (ATR) kinase inhibitor, in combination with Imfinzi showing that this combination demonstrated promising anti-tumour activity in melanoma patients for whom prior anti-PD1 treatment had failed.

Additional evidence will underscore the need for improved central nervous system control and the role of next-generation tyrosine kinase inhibitors (TKIs) such as Tagrisso (osimertinib) in the treatment of advanced epidermal growth factor (EGFR)-mutated NSCLC, as shown in the REFLECT retrospective real-world analysis of first- and second-generation TKIs.

Advancing an industry-leading clinical development programme
In all, AstraZeneca will share 18 posters at ASCO (Free ASCO Whitepaper) describing trials-in-progress exploring novel medicines and combinations across multiple types and stages of cancer. These posters include:

Datopotamab deruxtecan (Dato-DXd) – the TROPION-Lung01 Phase III trial testing datopotamab deruxtecan in patients with previously treated metastatic NSCLC, and the BEGONIA trial testing Imfinzi in combination with datopotamab deruxtecan in metastatic TNBC
Enhertu – trials testing Enhertu alone or in various combinations, including: DESTINY-Breast07, DESTINY-PanTumor01, and DESTINY-CRC02
Imfinzi – the MATTERHORN Phase III trial of neoadjuvant-adjuvant Imfinzi and chemotherapy in resectable gastric and gastroesophageal junction cancer, and the BEGONIA Phase I/II trial testing Imfinzi in novel combinations for 1st-line treatment of patients with TNBC, including with Enhertu and datopotamab deruxtecan.
Calquence – the ESCALADE Phase III trial of Calquence in combination with standard chemotherapy for patients age 65 and younger newly diagnosed with diffuse large B-cell lymphoma, the most common type of non-Hodgkin lymphoma
Camizestrant (AZD9833) – the SERENA-4 Phase III trial comparing camizestrant, a next-generation oral selective oestrogen receptor degrader (SERD), plus palbociclib, versus anastrozole plus palbociclib, in patients with oestrogen receptor-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease
Adavosertib – the ADAGIO Phase II multicentre trial of the WEE1 inhibitor adavosertib as a treatment for recurrent or persistent uterine serous carcinoma, a highly aggressive form of endometrial cancer
Collaboration in the scientific community is critical to improving outcomes for patients. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. in the US and Canada). AstraZeneca is collaborating with Daiichi Sankyo Company, Limited (Daiichi Sankyo) to develop and commercialise Enhertu and datopotamab deruxtecan globally.

Key AstraZeneca presentations during the 2021 ASCO (Free ASCO Whitepaper) Annual Meeting1

Lead author

Abstract title

Presentation details2

Immuno-Oncology

Spigel, D

Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: An update from the PACIFIC trial.

Abstract #8511

Poster Discussion Session

Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers

4 June 2021

Janjigian, Y

MATTERHORN: Efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer—A randomized, double-blind, placebo-controlled, phase 3 study.

Abstract #TPS4151

Poster Session

Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary

4 June 2021

McCoon, P

T-cell receptor pharmacodynamics associated with survival and response to tremelimumab (T) in combination with durvalumab (D) in patients (pts) with unresectable hepatocellular carcinoma (uHCC).

Abstract #4087

Poster Session

Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary

4 June 2021

Schmid, P

BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC)—Initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd).

Abstract #1023

Poster Discussion Session

Breast Cancer—Metastatic

4 June 2021

Schmid, P

BEGONIA: Phase 1b/2, open-label, platform study of the safety and efficacy of durvalumab (D) ± paclitaxel (P) with novel oncology therapies for first line metastatic triple-negative breast cancer (mTNBC): Addition of Arm 7, D + datopotamab deruxtecan (Dato-DXd; DS-1062).

Abstract #TPS1105

Poster Session

Breast Cancer—Metastatic

4 June 2021

Kwon, M

Phase II study of ceralasertib (AZD6738), in combination with durvalumab in patients with metastatic melanoma who have failed prior anti-PD-1 therapy.

Abstract #9514

Poster Discussion Session

Melanoma/Skin Cancers

4 June 2021

Suárez, C

Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer.

Abstract #4511

Poster Discussion Session

Genitourinary Cancer—Kidney and Bladder

4 June 2021

Tumour drivers and resistance

Janzic, U

Real-world outcomes and clinical characteristics of patients with brain metastases from EGFR mutated non-small cell lung cancer: Data from a large retrospective study (REFLECT).

Abstract #9086

Poster Session

Lung Cancer—Non-Small Cell Metastatic

4 June 2021

Im, S-A

SERENA-4: A phase 3 comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease.

Abstract #TPS1101

Poster Session

Breast Cancer—Metastatic

4 June 2021

Tada, H

Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): A randomized phase 3 trial.

Abstract #8501

Oral Abstract Session

Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers

6 June 2021

Antibody drug conjugates

Yoh, K

A randomized, phase 3 study of datopotamab deruxtecan (Dato-DXd; DS-1062) versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (TROPION-Lung01).

Abstract #TPS9127

Poster Session

Lung Cancer – Non-small Cell Metastatic

4 June 2021

Andre, F

Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07).

Abstract #TPS1096

Poster Session

Breast Cancer—Metastatic

4 June 2021

Li, BT

A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of solid tumors harboring specific HER2-activating mutations (DESTINY-PanTumor01).

Abstract #TPS3162

Poster Session

Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

4 June 2021

Yoshino, T

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01).

Abstract #3505

Oral Abstract Session

Gastrointestinal Cancer—Colorectal and Anal

7 June 2021

Raghav, K

Trastuzumab deruxtecan in patients with HER2-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC): A randomized, multicenter, phase 2 study (DESTINY-CRC02).

Abstract #TPS3620

Poster Session

Gastrointestinal Cancer—Colorectal and Anal

4 June 2021

Jerusalem, G

Trastuzumab deruxtecan (T-DXd) in patients with HER2+ metastatic breast cancer with brain metastases: a subgroup analysis of the DESTINY-Breast01 trial.

Abstract #526

Poster Session

Breast Cancer— Local/Regional/Adjuvant

4 June 2021

Yamaguchi, K

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: Final overall survival (OS) results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01).

Abstract #4048

Poster Session

Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary

4 June 2021

DNA damage response

Tutt, A

OlympiA: A phase 3, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high risk HER2-negative early breast cancer.

Abstract #LBA1

Plenary Session

6 June 2021, 1:00pm EDT

Liu, JF

ADAGIO: A phase IIb, open-label, single-arm, multicenter study assessing the efficacy and safety of adavosertib (AZD1775) as treatment for recurrent or persistent uterine serous carcinoma.

Abstract #TPS5612

Poster Session

Gynecologic Cancer

4 June 2021

Poveda, A

Olaparib maintenance monotherapy for non-germline BRCA1/2-mutated (non-gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase IIIb OPINION primary analysis.

Abstract #5545

Poster Session

Gynecologic Cancer

4 June 2021

Matthews, CA

Olaparib treatment (Tx) in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSR OC) by BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: Overall survival (OS) results from the phase II LIGHT study.

Abstract #5515

Poster Discussion Session

Gynecologic Cancer

4 June 2021

Pautier, P

Progression-free survival (PFS) and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab (bev) with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial.

Abstract #5514

Poster Discussion Session

Gynecologic Cancer

4 June 2021

Haematology

Byrd, J

First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia.

Abstract #7500

Oral Abstract Session

Hematologic Malignancies

7 June 2021

Sharman, JP

Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: Elevate-TN four-year follow up.

Abstract #7509

Poster Discussion Session

Hematologic Malignancies

4 June 2021

Sehn, L

ESCALADE: A phase 3 study of acalabrutinib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for patients ≤65y with untreated non-germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).

Abstract #TPS7572

Poster Session

Hematologic Malignancies

4 June 2021

174 company-sponsored or supported abstracts will be presented at ASCO (Free ASCO Whitepaper) 2021.
2Beginning Friday 4 June 2021 09:00 EDT oral presentations, poster discussions and poster sessions will be available on demand for 180 days including video and slide presentations and discussant commentary.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On May 19, 2021 Seagen Inc.(Nasdaq:SGEN) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported updated results from two clinical trials examining PADCEV (enfortumab vedotin-ejfv) alone (EV-201 Cohort 2) and PADCEV in combination with Merck’s (known as MSD outside the United States and Canada) KEYTRUDA (pembrolizumab) (EV-103 Cohort A) in patients with locally advanced or metastatic urothelial cancer who are not able to receive cisplatin chemotherapy (Press release, Seagen, MAY 19, 2021, View Source [SID1234580267]).

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"EV-201 Cohort 2 is the first study to report objective responses in patients with advanced urothelial cancer that progressed following immunotherapy and who have medical conditions that prevent them from receiving cisplatin chemotherapy," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas. "The analysis that will be presented at ASCO (Free ASCO Whitepaper) showed that after a median follow-up of 16 months, many patients continued to benefit from PADCEV – an important finding for these patients, who have very limited treatment options."

"EV-103 is the first clinical trial to combine the antibody-drug conjugate PADCEV with Merck’s anti-PD-1 therapy KEYTRUDA in patients newly diagnosed with locally advanced or metastatic urothelial cancer," said Roger Dansey, M.D., Chief Medical Officer, Seagen. "The updated data from EV-103 Cohort A, with two years of follow-up, build upon findings from the initial analysis, showing continued durability for this platinum-free combination."

Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors: An updated analysis of EV-201 Cohort 2(Abstract 4524)

Patients in Cohort 2 of EV-201 received prior treatment with an immunotherapy but had not received a platinum-containing chemotherapy in the locally advanced or metastatic setting and were ineligible for cisplatin chemotherapy.

With a median follow-up of 16 months, 51 percent of patients who received PADCEV had a confirmed objective response [95% Confidence Interval (CI): 39.8, 61.3] per blinded independent central review (the primary endpoint), with 22 percent of patients experiencing a complete response (CR). Median duration of response (DOR) was 13.8 months [95% CI: 6.4, not reached]. Patients lived a median of 6.7 months without cancer progression [progression-free survival (PFS) (95% CI: 5.0-8.3)] and had a median overall survival (OS) of 16.1 months (95% CI: 11.3, 24.1).

The most common all-grade treatment-related adverse events (TRAEs) were alopecia (51%), peripheral sensory neuropathy (49%) and fatigue (34%), and the most common Grade 3 or greater TRAEs were neutropenia (9%), maculopapular rash (8%) and fatigue (7%). Grade 3 or greater TRAEs of special interest included skin reactions (17%), peripheral neuropathy (8%) and hyperglycemia (6%). Four deaths were previously reported as treatment-related by investigators in patients age 75 years and older with multiple comorbidities.

The U.S. Food and Drug Administration (FDA) recently granted Priority Review to a supplemental application for PADCEV based on the primary analysis from EV-201 Cohort 2, which was published this month inThe Lancet Oncology.

Study EV-103: Update on durability results and long-term outcome of enfortumab vedotin + pembrolizumab in first-line locally advanced or metastatic urothelial carcinoma (la/mUC)(Abstract 4528)

In the dose-escalation cohort and expansion Cohort A in EV-103, patients were treated with a combination of PADCEV and the anti-PD-1 therapy KEYTRUDA as a first-line treatment for locally advanced or metastatic disease. Participants were ineligible for cisplatin-based chemotherapy, had no prior systemic treatment for locally advanced or metastatic disease, and did not receive adjuvant/neoadjuvant platinum-based therapy within 12 months prior to enrollment.

The primary outcome measure in this analysis was safety. With a median follow-up of 24.9 months, the longer-term analysis demonstrated a safety profile generally consistent with previous findings with no new safety signals observed. The most common TRAEs were peripheral sensory neuropathy (55.6%), fatigue (51.1%) and alopecia (48.9%), and the most common Grade 3 or greater TRAEs were increased lipase (17.8%), maculopapular rash (11.1%) and fatigue (11.1%). Grade 3 or greater TRAEs of interest included skin reactions (20%), hyperglycemia (8.9%) and peripheral neuropathy (4.4%). There was one death previously reported as possibly related to study treatment (multiple organ dysfunction syndrome).

As previously reported, results demonstrated an objective response rate of 73.3 percent (95% CI: 58.1, 85.4) per investigator assessment, with 15.6 percent of patients experiencing a CR. The median PFS was 12.3 months (95% CI: 8.0, not reached). With longer-term follow-up, the study showed a median DOR of 25.6 months (95% CI: 8.3, not reached) and median OS of 26.1 months (95% CI: 15.7, not reached).

The FDA granted Breakthrough Therapy designation last year for the PADCEV and KEYTRUDA combination for patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting.

About Urothelial Cancer

Urothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.1 Globally, approximately 573,000 new cases of bladder cancer and more than 212,000 deaths are reported annually.2

About the EV-201 Trial

The EV-201 trial (NCT03219333) is a single-arm, dual-cohort, pivotal phase 2 clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (Cohort 1) and those who have not received a platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (Cohort 2). The trial enrolled 128 patients in Cohort 1 and 91 patients in Cohort 2 at multiple centers internationally.1 The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety and tolerability.

About the EV-103 Trial

EV-103 (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter phase 1b/2 trial of PADCEV alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive urothelial cancer, and in locally advanced or metastatic urothelial cancer in first- or second-line settings.

The dose-escalation cohort and expansion Cohort A include locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. Patients were dosed in a 21-day cycle, receiving an intravenous (IV) infusion of enfortumab vedotin on Days 1 and 8 and pembrolizumab on Day 1. At the time of the initial analysis, 45 patients (5 from the dose-escalation cohort and 40 from the dose-expansion Cohort A) with locally advanced and/or metastatic urothelial cancer had been treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in the first-line setting.

The primary outcome measure of the cohorts included in this analysis is safety. Key secondary objectives related to efficacy include objective response rate, disease control rate, duration of response, progression-free survival and overall survival.

Additional enrolling cohorts in the EV-103 study include:

PADCEV as monotherapy or in combination with pembrolizumab in a first-line setting for locally advanced or metastatic disease, in patients ineligible for cisplatin-based chemotherapy (Cohort K)
PADCEV as a monotherapy in muscle-invasive disease (Cohort L)
About PADCEV (enfortumab vedotin-ejfv)

PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA’s Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.3

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.3,4 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).4 PADCEV is co-developed by Astellas and Seagen.

PADCEV (enfortumab vedotin-ejfv) U.S. Important Safety Information

Warnings and Precautions

Skin reactions: Severe cutaneous adverse reactions, including fatal cases of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later.

Skin reactions occurred in 54% of the 310 patients treated with PADCEV in clinical trials. Twenty-six percent (26%) of patients had maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In one clinical trial, the median time to onset of severe skin reactions was 0.8 months (range: 0.2 to 5.3). Of the patients who experienced rash, 65% had complete resolution and 22% had partial improvement. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines as clinically indicated. Withhold PADCEV and consider referral for specialized care for severe (Grade 3) skin reactions, suspected SJS, or TEN. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia occurred in patients treated with PADCEV, including death and diabetic ketoacidosis, in those with and without pre-existing diabetes mellitus. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. In one clinical trial, 8% of patients developed Grade 3-4 hyperglycemia. Patients with baseline hemoglobin A1C ≥8% were excluded. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.

Peripheral neuropathy (PN), predominantly sensory, occurred in 49% of the 310 patients treated with PADCEV in clinical trials; 2% experienced Grade 3 reactions. In one clinical trial, peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy. The median time to onset of Grade ≥2 was 3.8 months (range: 0.6 to 9.2). Neuropathy led to treatment discontinuation in 6% of patients. At the time of their last evaluation, 19% had complete resolution, and 26% had partial improvement. Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs. Permanently discontinue PADCEV in patients that develop Grade ≥3 peripheral neuropathy.

Ocular disorders occurred in 46% of the 310 patients treated with PADCEV. The majority of these events involved the cornea and included keratitis, blurred vision, limbal stem cell deficiency and other events associated with dry eyes. Dry eye symptoms occurred in 36% of patients, and blurred vision occurred in 14% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.9 months (range: 0.3 to 6.2). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion site extravasation: Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 310 patients, 1.3% of patients experienced skin and soft tissue reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. One percent (1%) of patients developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicity: PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

Adverse Reactions

Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (≥20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade ≥3 adverse reactions (≥5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab Abnormalities

In one clinical trial, Grade 3-4 laboratory abnormalities reported in ≥5% were: lymphocytes decreased (10%), hemoglobin decreased (10%), phosphate decreased (10%), lipase increased (9%), sodium decreased (8%), glucose increased (8%), urate increased (7%), neutrophils decreased (5%).

Drug Interactions

Effects of other drugs on PADCEV Concomitant use with a strong CYP3A4 inhibitor may increase free MMAE exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with strong CYP3A4 inhibitors.

Specific Populations

Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.

On May 19, 2021 Incyte (Nasdaq: INCY) reported that multiple abstracts highlighting data from its oncology portfolio will be presented during the upcoming 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, held virtually from June 4-8, 2021 (Press release, Incyte, MAY 19, 2021, View Source [SID1234580283]).

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"We look forward to presenting data from across Incyte’s oncology portfolio and partner programs at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting," said Steven Stein, M.D., Chief Medical Officer, Incyte. "Data being presented during this congress, including new three-year data from the L-MIND study of tafasitamab in relapsed or refractory diffuse large B-cell lymphoma as well as results of the OPTIC study of ponatinib in chronic phase-chronic myeloid leukemia, underscore our continued focus on advancing science to help meet patients’ needs."

Key abstracts accepted by ASCO (Free ASCO Whitepaper) include:

Oral Presentations

Ponatinib

OPTIC Primary Analysis: A Dose-Optimization Study of 3 Starting Doses of Ponatinib (PON)1(Abstract #7000. Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant.)

Poster Discussions

Tafasitamab

Long-Term Analyses from L-MIND, a Phase 2 Study of Tafasitamab (MOR208) Combined with Lenalidomide (LEN) in Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL)2 (Abstract #7513. Session: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia.)

Capmatinib

Capmatinib in MET Exon 14-Mutated, Advanced NSCLC: Updated Results from the GEOMETRY Mono-1 Study3(Abstract #9020. Session: Lung Cancer—Non-Small Cell Metastatic.)

ePosters

Capmatinib

Capmatinib Efficacy in Patients with NSCLC Identified as METex14 Using an NGS-Based Liquid Biopsy Assay: Results from the GEOMETRY Mono-1 Study3(Abstract #9111. Session: Lung Cancer—Non-Small Cell Metastatic.)

Patient-Reported Outcomes in Capmatinib-Treated Patients with METex14-Mutated Advanced NSCLC: Results from the Phase 2 GEOMETRY Mono-1 Study3(Abstract #9056. Session: Lung Cancer—Non-Small Cell Metastatic.)

Phase 1b/2 Study of Capmatinib Plus Gefitinib in Patients with EGFR-Mutated, MET-Dysregulated Non–Small Cell Lung Cancer who Received Prior Therapy: Final Overall Survival and Safety3(Abstract #9048. Session: Lung Cancer—Non-Small Cell Metastatic.)

Pemigatinib

Pemigatinib for Previously Treated Locally Advanced/Metastatic Cholangiocarcinoma (CCA): Update of FIGHT-202 (Abstract #4086. Session: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary.)

Retifanlimab

Phase 2 Study of Retifanlimab (INCMGA00012) in Patients (Pts) with Selected Solid Tumors (POD1UM-203) (Abstract #2571. Session: Developmental Therapeutics—Immunotherapy.)

Ruxolitinib-Parsaclisib Combination Studies

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ruxolitinib Plus Parsaclisib in Patients with JAK- and PI3K-Inhibitor Treatment–Naïve Myelofibrosis (Abstract #TPS7058. Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant.)

Tafasitamab

A Phase 3 Study to Evaluate the Efficacy and Safety of Tafasitamab Plus Lenalidomide and Rituximab Versus Placebo Plus Lenalidomide and Rituximab in Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) or Marginal Zone Lymphoma (MZL) (Abstract #TPS7568. Session: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia.)

First-MIND: A Phase 1b, Open-Label, Randomized Study to Assess Safety of Tafasitamab (tafa) or Tafa + Lenalidomide (LEN) in Addition to R‑CHOP in Patients with Newly Diagnosed DLBCL2(Abstract #7540. Session: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia.)

For full session details and data presentation listings, please see the ASCO (Free ASCO Whitepaper)21 online program at View Source Oral, poster discussion and poster sessions, as well as track-based clinical science symposia, accepted for presentation at ASCO (Free ASCO Whitepaper) will be available on demand beginning Friday, June 4, 2021 at 9:00 a.m. ET.