On September 11, 2022 Amgen (NASDAQ: AMGN) reported detailed results from the global Phase 3 CodeBreaK 200 trial, which showed once-daily oral LUMAKRAS/LUMYKRAS (sotorasib) led to significantly superior progression-free survival (PFS; primary endpoint) and a significantly higher objective response rate (ORR; a key secondary endpoint) in patients with KRAS G12C-mutated non small cell lung cancer (NSCLC), compared with intravenous chemotherapy, docetaxel (Press release, Amgen, SEP 11, 2022, View Source [SID1234619382]). These data will be presented Monday, Sept. 12 at 5:20 p.m. CEST at the Presidential Symposium III session as a late-breaker oral presentation (#LBA5812) during the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris.

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"The totality of evidence from this study supports LUMAKRAS as an important targeted treatment option for patients with non-small cell lung cancer who harbor the KRAS G12C mutation, and reinforces the critical need for comprehensive biomarker testing for all patients with advanced disease," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We plan to submit this data to health authorities around the world where LUMAKRAS/LUMYKRAS is conditionally approved, and we look forward to our discussions with regulators."

LUMAKRAS significantly improved PFS as determined by Blinded Independent Central Review (BICR) compared to docetaxel in heavily pre-treated patients (HR, 0.66 [95% CI: 0.51, 0.86]; P = 0.002), and PFS favored LUMAKRAS across all clinically relevant subgroups. The proportion of patients with PFS at one year was 25% for LUMAKRAS versus 10% for docetaxel. LUMAKRAS demonstrated a significantly higher ORR than docetaxel with double the response rates in the LUMAKRAS arm (28% versus 13%, respectively; P < 0.001) and showed consistent benefit across other efficacy secondary endpoints, including improved disease control rate (DCR; 83% versus 60%, respectively). Overall survival (OS; a key secondary endpoint) was not significantly different between treatment arms. The study was not powered to detect a statistical difference in OS, and cross-over from docetaxel to LUMAKRAS was permitted after disease progression.

There were fewer treatment-related adverse events (TRAEs) for LUMAKRAS versus docetaxel. Grade ≥ 3 TRAEs (33% LUMAKRAS; 40% docetaxel) and serious TRAEs (11% LUMAKRAS; 23% docetaxel) were lower with LUMAKRAS compared to docetaxel. The most common TRAEs reported by at least 15% of patients in either treatment group were diarrhea (34% LUMKRAS; 19% docetaxel), fatigue (7% LUMAKRAS; 25% docetaxel), alopecia (1% LUMKARAS; 21% docetaxel), nausea (14% LUMAKRAS; 20% docetaxel) and anemia (3% LUMAKRAS; 18% docetaxel).

"This is the first Phase 3 randomized clinical trial for a KRASG12C inhibitor to show benefit in heavily pre-treated patients who have limited treatment options," said Melissa L. Johnson, M.D., director of Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology and presenting author. "It is encouraging that progression-free survival benefits were consistent across all clinically relevant subgroups, and that sotorasib response rates were more than double compared to docetaxel response rates. This data represents a major advance for the treatment of patients with KRAS G12C-mutated non-small cell lung cancer."

Data from CodeBreaK 200 will be submitted to global regulatory authorities where LUMAKRAS/LUMYKRAS has accelerated approval or conditional marketing authorization. LUMAKRAS is the only KRASG12C inhibitor approved anywhere in the world with approval in 44 markets, including the United States, the European Union, the United Kingdrom and Japan. CodeBreaK 200 is the first randomized, controlled clinical trial for a KRASG12C inhibitor.

About LUMAKRAS/LUMYKRAS (sotorasib)
Amgen took on one of the toughest challenges of the last 40 years in cancer research by developing LUMAKRAS/LUMYKRAS, a KRASG12C inhibitor.1 LUMAKRAS/LUMYKRAS has demonstrated a positive benefit-risk profile with rapid, deep, and durable anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation with a once daily oral formulation.2

Amgen is progressing the largest and broadest global KRASG12C inhibitor development program with unparalleled speed and exploring more than 10 sotorasib combination regimens, with clinical trial sites spanning five continents. To date, over 6,500 patients around the world have received LUMAKRAS/LUMYKRAS through the clinical development program and commercial use.

In May 2021, LUMAKRAS was the first KRASG12C inhibitor to receive regulatory approval with its approval in the U.S., under accelerated approval. LUMAKRAS/LUMYKRAS is also approved in the European Union, Japan, United Arab Emirates, South Korea, Hong Kong, Switzerland, Taiwan, Qatar, and in Australia, Brazil, Canada, Great Britain, Singapore, and Israel under the FDA’s Project Orbis. Additionally, Amgen has submitted MAAs in Argentina, Colombia, Kuwait, Macao, Malaysia, Mexico, Russia, Saudi Arabia, Thailand and Turkey.

LUMAKRAS/LUMYKRAS is also being studied in multiple other solid tumors.3

About Non-Small Cell Lung Cancer and the KRAS G12C Mutation
Lung cancer is the leading cause of cancer-related deaths worldwide, and it accounts for more deaths worldwide than colon cancer, breast cancer and prostate cancer combined.4 Overall survival rates for NSCLC are improving but remain poor for patients with advanced disease, and 5-year survival is only 8% for those with metastatic disease.5

KRAS G12C is the most common KRAS mutation in NSCLC.6 About 13% of patients with NSCLC harbor the KRAS G12C mutation.7 Unmet medical need remains high and treatment options are limited for NSCLC patients with the KRAS G12C mutation whose first-line treatment has failed to work or has stopped working. The outcomes with other approved therapies are suboptimal, with a median progression-free survival of approximately four months following second-line treatment of KRAS G12C-mutated NSCLC.8

About CodeBreaK
The CodeBreaK clinical development program for Amgen’s drug sotorasib is designed to study patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers.

CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors.9 Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 124 of whom had centrally evaluable lesions by RECIST at baseline.2 The Phase 2 trial in colorectal cancer (CRC) enrolled 62 patients and results have been published.10

CodeBreaK 200, the global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC completed enrollment of 345 patients. Eligible patients had previously treated, locally advanced and unresectable or metastatic KRAS G12C-mutated NSCLC. The primary endpoint is progression-free survival and key secondary endpoints include overall survival, objective response rate, and patient-reported outcomes.11

Amgen also has several Phase 1b studies investigating sotorasib monotherapy and sotorasib combination therapy across various advanced solid tumors (CodeBreaK 101) open for enrollment.12 A Phase 2 randomized study will evaluate sotorasib in patients with stage IV KRAS G12C-mutated NSCLC in need of first-line treatment (CodeBreaK 201).13

For information, please visit www.hcp.codebreaktrials.com.

LUMAKRAS (sotorasib) U.S. Indication
LUMAKRAS is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

LUMAKRAS (sotorasib) Important U.S. Safety Information

Hepatotoxicity

LUMAKRAS can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
Among 357 patients who received LUMAKRAS in CodeBreaK 100, hepatotoxicity occurred in 1.7% (all grades) and 1.4% (Grade 3). A total of 18% of patients who received LUMAKRAS had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 6% were Grade 3 and 0.6% were Grade 4. In addition to dose interruption or reduction, 5% of patients received corticosteroids for the treatment of hepatotoxicity.
Monitor liver function tests (ALT, AST and total bilirubin) prior to the start of LUMAKRAS every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations.
Withhold, dose reduce or permanently discontinue LUMAKRAS based on severity of adverse reaction.
Interstitial Lung Disease (ILD)/Pneumonitis

LUMAKRAS can cause ILD/pneumonitis that can be fatal. Among 357 patients who received LUMAKRAS in CodeBreaK 100, ILD/pneumonitis occurred in 0.8% of patients, all cases were Grade 3 or 4 at onset, and 1 case was fatal. LUMAKRAS was discontinued due to ILD/pneumonitis in 0.6% of patients.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified.
Most Common Adverse Reactions

The most common adverse reactions ≥ 20% were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity and cough.
Drug Interactions

Advise patients to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, dietary and herbal products.
Inform patients to avoid proton pump inhibitors and H2 receptor antagonists while taking LUMAKRAS.
If coadministration with an acid-reducing agent cannot be avoided, inform patients to take LUMAKRAS 4 hours before or 10 hours after a locally acting antacid.
Please see LUMAKRAS full Prescribing Information.

About Amgen Oncology
At Amgen Oncology, our mission to serve patients drives all that we do. That’s why we’re relentlessly focused on accelerating the delivery of medicines that have the potential to empower all angles of care and transform lives of people with cancer.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company’s history, moving with great speed to advance those innovations for the patients who need them.

On September 11, 2022 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported the presentation of updated findings from the Phase II SUMMIT basket trial of neratinib for HER2 (ERBB2)-mutant, metastatic cervical cancer at the 2022 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, currently taking place in Paris, France (Press release, Puma Biotechnology, SEP 11, 2022, View Source [SID1234619381]). The poster (#559P) entitled, "Neratinib in HER2-mutant, recurrent/metastatic cervical cancer: updated findings from the phase 2 SUMMIT basket trial," was presented by Claire F. Friedman, M.D., Melanoma and Immunotherapy Service, Memorial Sloan Kettering Cancer Center, on September 11 at 11:10 a.m. CEST.

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The Phase II SUMMIT ‘basket’ trial is an open-label, multicenter, multi-national study evaluating the safety and efficacy of neratinib administered daily to patients who have solid tumors with activating, somatic HER2 mutations. The cervical cancer cohort was comprised of 22 patients with persistent, recurrent, or metastatic cervical cancer and a HER2 mutation, as documented by institutional testing at a CLIA/CAP- (or regionally equivalent) certified laboratory. Patients were treated with neratinib monotherapy (240 mg/day); 22 patients (100%) had previously received platinum-based chemotherapy, 16 patients (73%) had prior bevacizumab, and 4 patients (18%) received prior pembrolizumab. Overall, the objective response rate was 18.2% (95% CI: 5.2–40.3%) and the clinical benefit rate was 45.5% (95% CI: 24.4–67.8%), which included 1 patient with a confirmed complete response, 3 patients with confirmed partial responses, and 6 patients with stable disease at equal or greater than 16 weeks. The median progression-free survival was 5.1 months (95% CI: 1.7–7.2 months). Among the 13 patients (59.1%) who had tumors with a highly activating HER2 S310F/Y mutation, 4 had confirmed responses.

The safety profile observed in the neratinib-treated cervical cancer patients was consistent with that reported for neratinib monotherapy in HER2-amplified breast cancer. The most frequently observed treatment-related adverse event was any-grade diarrhea (n=18; 81.8%), which included 5 (22.7%) Grade 3 or higher diarrhea events. Diarrhea was manageable with anti-diarrheal prophylaxis and none of the diarrhea events resulted in dose reduction or treatment discontinuation.

"HER2 mutations are present in 5% of cervical cancers, most commonly in endocervical adenocarcinomas, and HER2 targeted therapy is a potential treatment option for patients whose cancer has grown after standard first lines of treatment, including platinum-based chemotherapy," said Dr. Friedman, an investigator of the study from Memorial Sloan Kettering Cancer Center. "Neratinib treatment has been effective against several HER2-mutant cancers and the observed durable responses and disease control in metastatic patients with HER2-mutant cervical cancer are extremely promising for patients."

Alan H. Auerbach, CEO and President of Puma Biotechnology, added, "We are very pleased to observe that treatment with neratinib led to durable response and effective disease control in patients with aggressive HER2-mutant cervical cancer and that the adverse event of diarrhea could be managed with prophylaxis. Improving the lives of our cancer patients is our foremost goal, and we are pleased to see the benefit that was provided to these patients in the SUMMIT trial."

About Puma Biotechnology

Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licenses the global development and commercialization rights to PB272 (neratinib, oral), PB272 (neratinib, intravenous) and PB357. Neratinib, oral was approved by the U.S. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets. In February 2020, NERLYNX was also approved by the FDA in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. NERLYNX was granted marketing authorization by the European Commission in 2018 for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy. NERLYNX is a registered trademark of Puma Biotechnology, Inc.

Further information about Puma Biotechnology may be found at View Source

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at View Source or 1-855-816-5421.

INDICATIONS:

NERLYNX (neratinib) tablets, for oral use, is a kinase inhibitor indicated:

As a single agent, for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.
In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2 based regimens in the metastatic setting.
IMPORTANT SAFETY INFORMATION Regarding NERLYNX (neratinib) U.S. Indication:

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Manage diarrhea through either NERLYNX dose escalation or loperamide prophylaxis. If diarrhea occurs despite recommended prophylaxis, treat with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS: The most common adverse reactions (reported in ≥ 5% of patients) were as follows:

NERLYNX as a single agent: Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection.
NERLYNX in combination with capecitabine: Diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms.
To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) or FDA at 1-800-FDA-1088 or View Source

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors. Separate NERLYNX by at least 2 hours before or 10 hours after H2-receptor antagonists. Or separate NERLYNX by at least 3 hours with antacids.
Strong CYP3A4 inhibitors: Avoid concomitant use.
P-gp and moderate CYP3A4 dual inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
Certain P-gp substrates: Monitor for adverse reactions of P-gp substrates for which minimal concentration change may lead to serious adverse reactions when used concomitantly with NERLYNX.

On September 11, 2022 Daiichi Sankyo (TSE: 4568) and Sarah Cannon Research Institute (SCRI) reported that extended follow-up data from a phase 1/2 trial of DS-7300, a specifically designed potential first-in-class B7-H3 directed DXd antibody drug conjugate (ADC), continues to show promising durable tumor response in patients with several types of heavily pretreated cancers including lung, prostate or esophageal cancer (Press release, Daiichi Sankyo, SEP 11, 2022, View Source [SID1234619377]). These data were presented today in a Proffered Paper session (Abstract #453O) at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) (#ESMO22) Congress.

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B7-H3 is overexpressed in a wide range of cancer types, including lung, prostate and esophageal, and its overexpression has been shown to correlate with poor prognosis in some cancers, making B7-H3 a promising therapeutic target.1,2,3,4,5,6

A response rate of 32% (95% CI: 24-41) was observed with 38 responses (33 confirmed; 28%; 95% CI: 20-37) in 118 patients with various solid tumors including small cell lung cancer (SCLC), squamous non-small cell lung cancer (NSCLC), metastatic castration-resistant prostate cancer (CRPC), esophageal squamous cell carcinoma (ESCC), head and neck squamous cell carcinoma (HNSCC) or endometrial cancer receiving doses of DS-7300 ranging from 4.8 mg/kg to 16.0 mg/kg.

"These results represent important progress in the development of DS-7300, which is continuing to show promising durable efficacy in patients with several different types of advanced cancers, including lung, prostate or esophageal cancer," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "Based on these results, we are evaluating next steps for the clinical development of DS-7300 beyond the phase 2 trial recently initiated in patients with extensive-stage small cell lung cancer."

Lung Cancer Subset Efficacy Analyses

In two subsets of patients with advanced lung cancer, response rates of 58% (95% CI: 33-80) and 40% (95% CI: 5-85) were observed in patients with SCLC (n=19) and squamous NSCLC (n=5), respectively. Eleven responses (10 confirmed; 53%; 95% CI: 29-76) were seen in patients with SCLC and two confirmed responses (40%; 95% CI: 5-85) were seen in patients with squamous NSCLC. Median duration of response (DOR) was 5.5 months (95% CI: 2.8-NR) in patients with SCLC and 4.3 months (95% CI: 3.1-NR) in patients with squamous NSCLC. Median follow-up was 4.9 months (95% CI: 3.3-8.8) in patients with SCLC and 1.7 months (95% CI: 0.3-5.2) in patients with squamous NSCLC.

"All lung cancer patients except for one with squamous non-small cell lung cancer experienced a reduction in tumor size with DS-7300, which is potentially promising for patients looking beyond standard chemotherapy and immunotherapy options," said Melissa L. Johnson, MD, Director, Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology. "We are eager to confirm the encouraging efficacy and safety results in patients with small cell lung cancer in an ongoing phase 2 trial currently enrolling patients with extensive-stage disease."

Prostate Subset Efficacy Analysis

A response rate of 33% (95% CI: 21-47) was observed in a subset of patients in the dose escalation and expansion cohorts with metastatic CRPC (n=54). Eighteen responses (15 confirmed; 28%; 95% CI: 17-42) were seen in patients with metastatic CRPC and median DOR was 4.4 months (95% CI: 2.7-NR). Median follow-up was 9.3 months (95% CI: 7.5-10.6). For metastatic CRPC, 46% of patients had baseline liver metastases of which 40% of patients had a response.

Esophageal Subset Efficacy Analysis

A response rate of 23% (95% CI: 8-45) was observed in a subset of patients in the dose escalation and expansion cohorts with ESCC (n=22). Five responses (four confirmed; 18%; 95% CI: 5-40) were seen in patients with ESCC and median DOR was 2.8 months (95% CI: 2.6-NR). Median follow-up was 7.7 months (95% CI: 3.3-10.9).

Overall Safety

The safety and tolerability of DS-7300 was consistent with that previously reported from the trial. The most common treatment emergent adverse events (TEAEs) reported in >10% of all patients (n=147) were nausea (63%), anemia (33%), infusion-related reaction (32%), decreased appetite (31%), fatigue (30%), vomiting (30%), diarrhea (16%), pyrexia (16%), constipation (14%), chills (13%) and dehydration (11%). Grade ≥ 3 TEAEs occurred in 66 patients (45%), the most common of which were anemia (19%), neutropenia (4%), nausea (3%), pneumonia (3%) and decreased neutrophil count (3%). Two grade 1 and four grade 2 treatment-related interstitial lung disease (ILD)/pneumonitis events were reported at the 12.0 mg/kg dose and one grade 5 ILD event previously reported at the 16.0 mg/kg dose, which was discontinued due to safety concerns. These ILD events were adjudicated as drug-related by an independent adjudication committee. Two ILD/pneumonitis events are currently pending adjudication. Treatment discontinuations due to TEAEs occurred in 8% of patients.

"Prostate and esophageal cancer are two types of cancer that remain difficult to treat in advanced stages, where many patients experience repeated disease recurrence," said Toshihiko Doi, MD, PhD, Director of Exploratory Oncology Research, Director of Clinical Trial Center and Center of Promotion of Translational Research, and Chief of Department of Experimental Therapeutics, National Cancer Center Hospital East. "Targeting the B7-H3 protein in both prostate and esophageal cancer with DS-7300 may be an encouraging treatment strategy for these patients who have limited treatment options in the metastatic setting."

Patients enrolled in both the dose escalation and dose expansion parts of the trial across the 4.8 mg/kg to 16.0 mg/kg doses of DS-7300 received a median of five prior lines of therapies (range, 0-14). As of the data cut-off on June 30, 2022, 35 patients (24%) were still being treated with DS-7300 including eight patients (40%) with SCLC, 17 patients (23%) with metastatic CRPC, four patients (15%) with ESCC and five patients (56%) with squamous NSCLC. The expansion cohort in patients with squamous NSCLC remains open for enrollment.

About the DS-7300 Phase 1/2 Trial

This first-in-human, open-label phase 1/2 trial is evaluating the safety, tolerability and preliminary activity of DS-7300 in adult patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerable to standard treatment or for whom no standard treatment exists.

The phase 1 part of the trial (dose escalation) is assessing the safety and tolerability of increasing doses of DS-7300 to determine the maximum tolerated dose (MTD) or recommended dose for expansion (RDE). This portion of the trial enrolled 81 patients with advanced/unresectable or metastatic SCLC, squamous NSCLC, metastatic CRPC, ESCC, HNSCC, bladder cancer, sarcoma, endometrial cancer, melanoma or breast cancer.

The phase 2 part of the trial (dose expansion) is evaluating the safety, tolerability and preliminary activity of DS-7300 at the RDE of 12.0 mg/kg in patients with squamous NSCLC, metastatic CRPC or ESCC.

The dose escalation part of the trial is evaluating dose-limiting toxicity and safety. The dose expansion part of the trial is evaluating ORR, DOR, disease control rate, progression-free survival, overall survival and safety. Pharmacokinetic endpoints, exploratory biomarker and immunogenicity endpoints also will be assessed.

Patient enrollment into the squamous NSCLC cohort of the dose expansion part of the trial remains underway in Asia and North America. For more information, please visit ClinicalTrials.gov.

About B7-H3

B7-H3 is a transmembrane protein that belongs to the B7 family, which also includes PD-L1.6 B7-H3 is overexpressed in a wide range of cancer types, including lung, prostate and esophageal, and its overexpression has been shown to correlate with poor prognosis in some cancers, making B7-H3 a promising therapeutic target.1,2,3,4,5,6 Currently, no B7-H3 directed medicines are approved for the treatment of any cancer.

About Lung, Prostate and Esophageal Cancer

Lung cancer is the second most common cancer and the leading cause of cancer-related mortality worldwide with more than 2.2 million new cases and 1.7 million deaths in 2020.7 The two main types of lung cancer include NSCLC, which represents more than 80 to 85% of all cases, and SCLC, which comprises about 15% of cases.8 NSCLC is further divided into three subtypes including squamous cell carcinoma, which represents about 25% of cases and originates in squamous cells that line the inside of the airways in the lungs.8 More than half of patients with lung cancer are diagnosed in the metastatic stage.9 The five-year survival rate is only 8% and 3% for patients diagnosed with advanced NSCLC and SCLC, respectively.10,11

Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men with an estimated 1.4 million new cases and 375,000 deaths worldwide in 2020.7 The five-year survival rate is only 32.3% for patients with metastatic prostate cancer.12,13

Esophageal cancer is the tenth most common cancer worldwide and the sixth leading cause of cancer mortality with an estimated 604,000 new cases and 544,000 deaths reported in 2020.7 The majority of patients with esophageal cancer are diagnosed at advanced stage where the five-year survival rate is only 5.7%.14, 15

About DS-7300

DS-7300 is an investigational B7-H3 directed ADC and is one of five ADCs currently in clinical development in the oncology pipeline of Daiichi Sankyo. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, DS-7300 is comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

In addition to the phase 1/2 trial in collaboration with Sarah Cannon Research Institute, DS-7300 also is being evaluated by Daiichi Sankyo in a phase 2 trial in patients with extensive-stage SCLC.

DS-7300 is an investigational medicine that has not been approved for any indication in any country. Safety and efficacy have not been established.

On September 11, 2022 AstraZeneca reported that Updated results after approximately four years of follow-up of the POSEIDON Phase III trial showed a limited course of tremelimumab when added to it’s Imfinzi (durvalumab) plus four cycles of chemotherapy demonstrated a sustained improvement in overall survival (OS) compared to chemotherapy alone in the 1st-line treatment of patients with Stage IV (metastatic) non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, SEP 11, 2022, View Source [SID1234619376]). Additional post-hoc, exploratory analyses continued to show a trend for OS improvement with this combination in patients with STK11, KEAP1 and KRAS-mutated NSCLC, as well as in patients whose tumours were PD-L1-negative (less than 1% tumour cell expression).

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These late-breaking results were presented today at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 (Abstract #LBA59).

KRAS mutations are the most common tumour growth driver in NSCLC, occurring in approximately 25% of patients. NSCLC tumours with STK11 and KEAP1 mutations are often associated with poor outcomes and classified as immunologically "cold." KRAS-mutated NSCLC can be responsive to immunotherapy but also can have poor outcomes, particularly when associated with STK11 or KEAP1 co-mutations.1-6

Melissa Johnson, MD, Director of Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology in Nashville, Tennessee, and a lead investigator in the POSEIDON Phase III trial, said: "Metastatic non-small cell lung cancer is a devastating diagnosis, particularly for patients whose cancers are less responsive to standard treatments such as chemotherapy and immune therapy. These results support the addition of a limited course of tremelimumab to durvalumab plus chemotherapy as a potential new treatment option for patients with these harder-to-treat forms of lung cancer."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "These updated POSEIDON results at nearly four years of follow-up show further evidence that the addition of a limited course of tremelimumab to Imfinzi plus chemotherapy improves outcomes for metastatic non-small cell lung cancer patients, including those with specific tumour mutations where a high unmet need for effective, well tolerated treatments remains. We look forward to bringing this potential new treatment option to patients as quickly as possible."

These latest data show that a limited course of five cycles of tremelimumab added to Imfinzi plus platinum-based chemotherapy improved overall survival by 25% compared to chemotherapy alone (hazard ratio [HR] 0.75; 95% CI 0.63-0.88). Updated median OS was 14 months for the combination versus 11.7 for chemotherapy alone. An estimated 25% of patients treated with the combination were alive at three years versus 13.6% for those treated with chemotherapy alone.

A trend for OS improvement continued to be observed in patients with STK11, KEAP1, and KRAS-mutated mNSCLC when treated with the combination, which reduced the risk of death by 38% (based on a HR of 0.62; 95% CI 0.34-1.12), 57% (based on a HR of 0.43; 95% CI 0.16-1.25), and 45% (based on a HR of 0.55; 95% CI 0.36-0.85), respectively. The combination also extended sustained OS benefit to patients with less than 1% PD-L1 tumour cell expression. These post hoc, exploratory subgroup analyses should be interpreted with caution due to the small sample sizes.

Consistent with previous POSEIDON Phase III trial readouts, OS benefit in these updated results appeared more pronounced with tremelimumab plus Imfinzi and chemotherapy in patients with non-squamous NSCLC histology. A 32% improvement in OS compared to chemotherapy alone (HR 0.68; 95% CI 0.55–0.85) was reported for patients with non-squamous histology, with an updated median OS of 17.2 months for the combination versus 13.1 months for chemotherapy. An estimated 31.4% of patients with non-squamous NSCLC treated with the combination were alive at three years versus 17.3% for those receiving chemotherapy alone.

Summary of efficacy resultsi, ii

Tremelimumab + Imfinzi + chemotherapy

Chemotherapy

Intention-To-Treat (ITT)

n=338

n=337

Median OS (in months)

14.0

11.7

Hazard ratio (95% CI)iii

0.75 (0.63, 0.88)

OS rate at 3 years (%)

25.0

13.6

STK11 mutation

n=31

n=22

Median OS (in months)

15.0

10.7

Hazard ratio (95% CI)iv

0.62 (0.34, 1.12)

OS rate at 3 years (%)

25.8

4.5

KEAP1 mutation

n=22

n=6

Median OS (in months)

13.7

8.7

Hazard ratio (95% CI)iv

0.43 (0.16, 1.25)

OS rate at 3 years (%)

30.0

0.0

KRAS mutation

n=60

n=53

Median OS (in months)

25.7

10.4

Hazard ratio (95% CI)iv

0.55 (0.36, 0.85)

OS rate at 3 years (%)

40.0

15.8

i. STK11 and KRAS subgroup analyses were presented for patients with non-squamous histology; while the KEAP1 subgroup analysis was presented for all mutation-evaluable patients irrespective of tumour histology, due to a small sample size.
ii. Data cut-off (DCO) date: 11 March 2022. Median follow-up in censored patients at DCO: 46.5 months (range 0.0–56.5)
iii. Stratified analysis by PD-L1 expression (TC ≥50% vs <50%), disease stage (IVA vs IVB) and histology
iv. Unstratified analysis

Tremelimumab plus Imfinzi and chemotherapy continued to be well-tolerated, with no new safety signals identified based on the collection of serious adverse events (AEs) during the approximately four years of follow-up. Serious treatment-related AEs of any grade occurred in 27.6% of patients in the Imfinzi, tremelimumab and chemotherapy arm versus 17.7% in the chemotherapy alone arm as assessed by investigators. Treatment-related AEs leading to death occurred in 3.3% of patients in the combination arm versus 2.4% in the chemotherapy arm.

These updated results build on the primary progression-free survival (PFS) and OS results presented at the 2021 World Conference on Lung Cancer (WCLC) in September 2021 as well as post-hoc exploratory results in patients with STK11, KEAP1 or KRAS-mutated metastatic NSCLC recently presented at WCLC 2022 in August.

Tremelimumab is under review by global regulatory authorities in combination with Imfinzi and chemotherapy in 1st-line metastatic NSCLC based on the results of the POSEIDON trial.

Notes

Stage IV NSCLC
Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC), with 80-85% classified as NSCLC. 7-9 Within NSCLC, patients are classified as squamous, representing 25-30% of patients, or non-squamous, the most common type representing approximately 70-75% of NSCLC patients.7 Stage IV is the most advanced form of lung cancer and is often referred to as metastatic disease.10 Approximately 5% of patients with metastatic NSCLC will survive 5 years after diagnosis.11

POSEIDON
The POSEIDON trial was a randomised, open-label, multi-centre, global, Phase III trial of Imfinzi plus platinum-based chemotherapy or Imfinzi, tremelimumab and chemotherapy versus chemotherapy alone in the 1st-line treatment of 1,013 patients with metastatic NSCLC. The trial population included patients with either non-squamous or squamous disease and the full range of PD-L1 expression levels. POSEIDON excluded patients with certain epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions.

In the experimental arms, patients were treated with a flat dose of 1,500mg of Imfinzi, or Imfinzi and 75mg of tremelimumab with up to four cycles of chemotherapy every three weeks, followed by maintenance treatment with Imfinzi once every four weeks, or Imfinzi and a fifth dose of 75mg of tremelimumab given at week 16. In comparison, the control arm allowed up to six cycles of chemotherapy. Pemetrexed maintenance treatment was allowed in all arms in patients with non-squamous disease if given during the induction phase. Nearly all patients with non-squamous disease (95.5%) had pemetrexed and platinum, while the majority of patients with squamous disease receiving chemotherapy (88.3%) received gemcitabine and platinum.

Primary endpoints included PFS and OS for the Imfinzi plus chemotherapy arm. Key secondary endpoints included PFS and OS in the Imfinzi plus tremelimumab and chemotherapy arm. As both PFS endpoints were met for Imfinzi plus chemotherapy and Imfinzi, tremelimumab and chemotherapy, the prespecified statistical analysis plan allowed for testing OS in the Imfinzi plus tremelimumab and chemotherapy arm. The trial was conducted in more than 150 centres across 18 countries, including the US, Europe, South America, Asia and South Africa.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy, and is the global standard of care in this setting based on the PACIFIC Phase III trial.

Imfinzi is currently approved in a number of countries in multiple tumour types including for the treatment of extensive-stage small cell lung cancer (ES-SCLC); for previously treated patients with advanced bladder cancer and for locally advanced or metastatic BTC in combination with chemotherapy (gemcitabine plus cisplatin).

Since the first approval in May 2017, more than 100,000 patients have been treated with Imfinzi.

Imfinzi combinations have demonstrated clinical benefit in multiple additional cancer settings with positive Phase III trials in unresectable advanced liver cancer (HIMALAYA), metastatic NSCLC (POSEIDON) and resectable NSCLC (AEGEAN). The data from HIMALAYA and POSEIDON are under review with global health authorities.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several GI cancers, ovarian cancer, endometrial cancer and other solid tumours. 

Tremelimumab
Tremelimumab is a human monoclonal antibody and potential new medicine that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.

Beyond POSEIDON, tremelimumab is being tested in combination with Imfinzi across multiple tumour types including in bladder cancer (VOLGA and NILE), locoregional HCC (EMERALD-3) and SCLC (ADRIATIC).

Tremelimumab is also under review by global regulatory authorities in combination with Imfinzi in unresectable advanced liver cancer based on the results of the HIMALAYA Phase III trial.

AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and tremelimumab; Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

AstraZeneca in immuno-oncology (IO)
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s Immuno-Oncology (IO) portfolio is anchored in immunotherapies that have been designed to overcome evasion of the anti-tumour immune response. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a single treatment and in combination with tremelimumab and other novel antibodies in multiple tumour types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.

In addition, the ability to combine the IO portfolio with radiation, chemotherapy, and targeted small molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

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 September 11, 2022 AstraZeneca reported that Detailed positive results from an interim analysis of the DESTINY-Lung02 Phase II trial showed Enhertu (trastuzumab deruxtecan) demonstrated clinically meaningful tumour responses in previously-treated patients with HER2-mutant (HER2m) unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, SEP 11, 2022, View Source [SID1234619375]). Results will be presented today as a late-breaking presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 .

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Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

At a pre-specified interim analysis of DESTINY-Lung02, patients receiving Enhertu at a dose of 5.4mg/kg or 6.4mg/kg demonstrated clinically meaningful activity. The safety profile for both doses was also consistent with the overall safety profile of Enhertu, with the 5.4mg/kg dose demonstrating a favourable safety profile in this patient population. A confirmed objective response rate (ORR) of 53.8% (95% confidence interval [CI] 39.5-67.8) and 42.9% (95% CI 24.5-62.8) was seen in the 5.4mg/kg and 6.4mg/kg arms respectively, as assessed by blinded independent central review (BICR). One complete response (CR) was observed in each arm (5.4mg/kg: 1.9%, 6.4mg/kg: 3.6%), with 27 (51.9%) partial responses (PR) observed in the 5.4mg/kg arm and 11 (39.3%) PRs observed in the 6.4mg/kg arm.

Koichi Goto, MD, Medical Oncologist and Investigator at National Cancer Center Hospital East, Kashiwa, Japan, said: "DESTINY-Lung02 reinforces HER2 as an actionable mutation in patients with metastatic non-small cell lung cancer and further demonstrates that Enhertu provides a clinically meaningful tumour response for these patients who have historically had limited treatment options. The response seen in this trial, along with the disease control observed support Enhertu as a potential treatment option in this type of non-small cell lung cancer."

Cristian Massacesi, Chief Medical Officer & Oncology Chief Development Officer, AstraZeneca, said: "The clinically meaningful activity, together with the favourable safety profile seen in the DESTINY-Lung02 trial helps establish the optimal dose of Enhertu at 5.4 milligrams per kilogram in previously-treated HER2-mutant non-small cell lung cancer. As we continue to explore the potential of this important medicine across multiple HER2-targetable tumour types, these data reaffirm the need to undertake HER2 testing in patients diagnosed with lung cancer."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "The DESTINY-Lung02 results are consistent with the data previously seen with Enhertu in non-small cell lung cancer and the efficacy demonstrated in this interim analysis, which supported the recent US FDA accelerated approval of Enhertu in patients with HER2-mutant non-small cell lung cancer, reinforces the potential to establish this medicine as a treatment option for these patients. These data will help inform future regulatory submissions worldwide with the goal of continuing to offer this innovative medicine to as many patients as possible."

Summary of results: DESTINY-Lung02

Efficacy Measure

Enhertu

(5.4mg/kg)

n=52

Enhertu

(5.4mg/kg)

n=52

Additional 90-day follow-upi

Enhertu

(6.4mg/kg)

n=28

Confirmed ORR (%)

(95% CI)ii,iii

53.8% (39.5-67.8)

57.7% (43.2-71.3)

42.9% (24.5-62.8)

Complete Response (%)

1.9%

1.9%

3.6%

Partial Response (%)

51.9%

55.8%

39.3%

Stable Disease (%)

36.5%

50.0%

Progressive Disease (%)

3.8%

3.6%

Not Evaluable (%)iv

5.8%

3.6%

DCR (95% CI) ii,v

90.4% (79.0-96.8)

92.9% (76.5-99.1)

Median DoR (months)

(95% CI)ii

NE (4.2-NE)

8.7 (7.1-NE)

5.9 (2.8-NE)

Median TTIR (months)

(95% CI)

1.4 (1.2-5.8)

1.4 (1.2-3.0)

CI, confidence interval; DCR, disease control rate; DoR, duration of response; NE, not estimable; ORR, objective response rate; TTIR, time to initial response
Data from subset of patients randomized >=4.5 months prior to the data cut-off
i As the median DoR for the 5.4mg/kg dose arm was not reached at the March 24, 2022 cutoff, an additional 90-day follow-up response analysis was conducted; data cutoff for the 90-day follow-up was June 22, 2022
ii As assessed by blinded independent central review
iii ORR is Complete Response + Partial Response
iv Three patients were NE at 5.4mg/kg (one patient never received treatment due to COVID; two patients discontinued before first tumour assessment); one NE at 6.4mg/kg (discontinued due to adverse event before first tumour assessment.
v DCR is Complete Response + Patrial Response + Stable Disease

At the pre-specified interim analysis, a median duration of response (DoR) was not reached in the 5.4mg/kg arm and a median DoR of 5.9 months (95% CI 2.8-NE) was seen in the 6.4mg/kg arm. As median DoR was not reached in the 5.4mg/kg arm, an additional 90-day follow-up response analysis was conducted, where Enhertu demonstrated a confirmed ORR of 57.7% (95% CI 43.2-71.3) and a median DoR of 8.7 months (95% CI 7.1-NE), with CRs seen in 1.9% of patients and PRs in 55.8% of patients.

In DESTINY-Lung02, a favourable safety profile was observed in patients treated with Enhertu 5.4mg/kg, with no new safety signals identified at either dose. Grade 3 treatment-emergent adverse events (TEAEs) were higher with Enhertu 6.4mg/kg versus 5.4mg/kg, with Grade 3 or higher treatment-related TEAEs occurring in 31.7% and 58.0% of all patients receiving Enhertu 5.4mg/kg or 6.4mg/kg, respectively. The most common Grade 3 or higher TEAEs occurring in greater than 10% of patients were neutropenia (11.9% (5.4mg/kg), 34.0% (6.4mg/kg)), anaemia (8.9% (5.4mg/kg), 14.0% (6.4mg/kg)) and leukopenia (2.0% (5.4mg/kg), 14.0% (6.4mg/kg)). There were 13 cases (5.9% in the 5.4mg/kg arm and 14.0% in the 6.4mg/kg arm) of treatment-related interstitial lung disease (ILD) or pneumonitis reported, as determined by an independent adjudication committee. The majority (5.4mg/kg: 5.0%, 6.4mg/kg: 14.0%) were low Grade (Grade 1 or 2), with one Grade 3 event (5.4mg/kg: 1.0%) reported. No Grade 4 or Grade 5 ILD or pneumonitis events occurred.

DESTINY-Lung01 updated results
Updated results from the DESTINY-Lung01 Phase II trial, which evaluated Enhertu in HER2m (cohort 2) or HER2-over-expressing (cohort 1 and cohort 1a) NSCLC, were also presented at ESMO (Free ESMO Whitepaper) and showed that Enhertu continues to demonstrate consistent efficacy, safety and survival with longer follow-up.

After a median follow-up of 16.7 months, results of previously treated patients with HER2m NSCLC (cohort 2) showed the median DoR for Enhertu in the overall patient population increased to 10.6 months (95% CI 5.6-18.3), with median overall survival (OS) increasing to 18.6 months (95% CI 13.8-25.8). Subgroup analyses of patients with or without a presence of baseline asymptomatic brain metastases showed that treatment with Enhertu resulted in a median PFS of 7.1 months (95% CI 5.5-9.8) and 9.7 months (95% CI 4.5-16.9) respectively, and a median OS of 14.0 months (95% CI: 9.8-19.5) and 27.0 months (95% CI: 15.3-NE), respectively. The subgroup analysis of patients who had received either two or fewer prior therapies or more than two prior therapies showed a median PFS of 8.3 months (95% CI: 5.8-15.2) and 6.8 months (95% CI: 4.4-9.8) respectively, and a median OS of 22.1 months (95% CI: 14.0-31.3) and 13.8 months (95% CI: 7.1-18.6), respectively.

Additionally, updated results from cohort 1 (Enhertu 6.4mg/kg) and cohort 1a (Enhertu 5.4mg/kg), which evaluated patients with previously-treated metastatic HER2-overexpressing NSCLC, highlight encouraging anti-tumour activity. In cohort 1, a confirmed ORR of 26.5% (95% CI 15.0-41.1) was seen in patients receiving Enhertu 6.4mg/kg, with a median progression-free survival (PFS) of 5.7 months (95% CI 2.8-7.2) and a median OS of 12.4 months (95% CI 7.8-17.2). In cohort 1a, a confirmed ORR of 34.1% (95% CI 20.1-50.6) was seen in patients receiving Enhertu 5.4mg/kg, with a median PFS of 6.7 months (95% CI 4.2-8.4), and a median OS of 11.2 months (95% CI 8.4-NE).

The overall safety profile of Enhertu in DESTINY-Lung01 was consistent with previous data, with no new safety signals identified with the longer follow-up. In the HER2m NSCLC patient cohort, there was one additional case of treatment-related ILD or pneumonitis observed, as determined by an independent adjudication committee. ILD has been observed in 27.5% of patients treated with Enhertu 6.4mg/kg in the HER2m cohort, with the majority identified as low Grade, and two Grade 5 events reported. In the HER2-overexpressing NSCLC patient cohorts, there were two additional cases of treatment-related ILD or pneumonitis observed in the 6.4mg/kg dose cohort, and two cases observed in the 5.4mg/kg dose cohort, as determined by an independent adjudication committee. ILD has been observed in 20.4% and 4.9% of patients treated with Enhertu at the 6.4mg/kg and 5.4mg/kg doses respectively in the HER2-overexpressing cohort, with the majority identified as low Grade, and four Grade 5 events (three in the 6.4mg/kg dose cohort and one in the 5.4mg/kg dose cohort) reported. Data from the DESTINY-Lung01 Phase II trial were previously published in The New England Journal of Medicine.1

Notes

HER2m and HER2-overexpressing NSCLC
Lung cancer is the second most common form of cancer globally, with more than two million patients diagnosed in 2020.2 For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.3

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including lung, breast, gastric and colorectal cancers. Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target and occur in approximately 2-4% of patients with this type of lung cancer.4,5

While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7

Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2-directed therapies in NSCLC prior to the accelerated US approval of Enhertu in unresectable or metastatic HER2m NSCLC.7,8 Next-generation sequencing has been utilised in the identification of HER2 (ERBB2) mutations.9

HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poorer prognosis.10 It has been reported in approximately 10-15% of patients with NSCLC, with an incidence as high as 30% in those with adenocarcinoma (a subtype of cancer that grows in the glands that line the insides of organs).11-14

DESTINY-Lung02
DESTINY-Lung02 is a global, randomised, Phase II trial evaluating the safety and efficacy of Enhertu in patients with HER2m metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. Patients were randomised 2:1 to receive Enhertu 5.4mg/kg (n=102) or Enhertu 6.4mg/kg (n=50).The primary endpoint of the trial is confirmed ORR as assessed by BICR. Secondary endpoints include confirmed disease control rate (DCR), DoR and PFS assessed by investigator and BICR, investigator-assessed OS and safety. DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-Lung01
DESTINY-Lung01 is a global Phase II, open-label, two-cohort trial evaluating the efficacy and safety of Enhertu (5.4mg/kg or 6.4mg/kg) in patients with HER2m (cohort 2, n=91) or HER2-overexpressing (defined as IHC 3+ or IHC 2+) [cohort 1 and 1a, n=90] unresectable or metastatic non-squamous NSCLC who had progressed after one or more systemic therapies. The primary endpoint is confirmed ORR by independent central review. Key secondary endpoints include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled 181 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Enhertu (5.4mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a (or one or more) prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is approved in several countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

Enhertu (5.4mg/kg) is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Enhertu (5.4mg/kg) is approved under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations, as detected by a FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

Enhertu development programme
A comprehensive development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for Enhertu in breast and gastric cancer are currently under review in several countries based on the DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Gastric01 and DESTINY-Gastric02 trials, respectively.

Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019 and datopotamab deruxtecan (a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.

The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and tremelimumab; Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.

AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment.

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.