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 .

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

On September 11, 2022 AstraZeneca reported that Updated results from the pivotal ADAURA Phase III trial showed that AstraZeneca’s Tagrisso (osimertinib) demonstrated a sustained, clinically meaningful improvement in disease-free survival (DFS) compared to placebo in the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumour resection with curative intent (Press release, AstraZeneca, SEP 11, 2022, View Source [SID1234619374]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

These late-breaking results will be presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris (abstract #LBA47).

With an additional two years of follow-up from the 2020 readout, allowing all patients the opportunity to complete three years of adjuvant treatment, Tagrisso reduced the risk of disease recurrence or death by 77% (based on a hazard ratio [HR] of 0.23; 95% confidence interval [CI] 0.18-0.30) in the primary analysis population (Stages II-IIIA) and by 73% (HR 0.27; 95% CI 0.21-0.34) in the overall trial population (Stages IB-IIIA). A median DFS of nearly five and a half years (65.8 months) was seen in both the primary and overall populations treated with Tagrisso, compared to 21.9 and 28.1 months in the primary and overall populations, respectively, treated with placebo.

While up to 30% of all patients with NSCLC may be diagnosed early enough to have surgery with curative intent, recurrence is still common in early-stage disease.1,2 Historically, approximately half of patients diagnosed in Stages I-II, and three quarters of patients diagnosed in Stage III, have experienced recurrence within five years of resection.3,4

Results from an additional, prespecified exploratory analysis showed Tagrisso reduced the risk of central nervous system (CNS) disease recurrence by 76% in patients with Stage II-IIIA disease (HR: 0.24; 95% CI 0.14-0.42). At four years, 90% of patients in the Tagrisso arm were disease-free in the brain and spinal cord (95% CI 85-94%) compared to 75% of patients in the placebo arm (95% CI 67-81%). CNS disease recurrence refers to the spread of tumours to the brain or spinal cord, a frequent complication of EGFRm NSCLC associated with an especially poor prognosis.

Masahiro Tsuboi, MD, PhD, Chief and Director, Department of Thoracic Surgery & Oncology, National Cancer Center Hospital East, Japan, and principal investigator in the ADAURA trial, said: "The updated ADAURA results show us that adjuvant osimertinib not only continues to strikingly prolong the time patients with early-stage EGFR-mutated lung cancer are living cancer-free after surgery, but also continues to reduce the risk of tumours recurring in the central nervous system over time. These results reinforce adjuvant osimertinib as a standard-of-care treatment for these early-stage lung cancer patients who previously had no targeted treatment options after surgery, and who otherwise face high rates of disease recurrence."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: "It is remarkable that just two years ago, patients with early-stage EGFR-mutated lung cancer had no targeted treatment options after surgery. Now, around the world, patients have access to Tagrisso and its added benefit of protecting the brain and spinal cord. We look forward to mature overall survival results for ADAURA in due time, but our research and commitment to early-stage lung cancer patients continue through our broader Tagrisso programme, which is investigating a prolonged duration of post-surgery treatment and the potential role of adjuvant Tagrisso in even earlier stages of disease."

i. Data cut-off: April 11, 2022
ii. NC: Not calculable
iii. Defined as the probability of observing a CNS recurrence event, conditional on the patient not experiencing a competing risk event (non-CNS recurrence and death by any cause)

The safety and tolerability of Tagrisso in this trial were consistent with its established profile. No new safety concerns were reported with an extended treatment duration. Adverse events at Grade 3 or higher from all causes occurred in 23% of patients in the Tagrisso arm versus 14% in the placebo arm.

Notes

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.5 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.6 The majority of all NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.1,2

Among patients with resectable tumours (Stage IB-IIIA), the majority of patients eventually develop recurrence despite complete tumour resection and adjuvant chemotherapy.3 In the absence of organised screening efforts, early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.7,8

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.9-11 These patients are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which block the cell-signalling pathways that drive the growth of tumour cells.12

ADAURA
ADAURA is a randomised, double-blind, placebo-controlled, global Phase III trial in the adjuvant treatment of 682 patients with Stage IB, II, IIIA EGFRm NSCLC following complete tumour resection and, at physicians’ and patients’ discretion, adjuvant chemotherapy. Patients were treated with Tagrisso 80mg once-daily oral tablets or placebo for three years or until disease recurrence.

The trial enrolled in more than 200 centres across more than 20 countries, including the US, in Europe, South America, Asia and the Middle East. The primary endpoint was DFS in Stage II and IIIA patients and a key secondary endpoint was DFS in Stage IB, II and IIIA patients.

Though the primary data readout was originally anticipated in 2022, data from the trial were first reported early in 2020, following a recommendation from an Independent Data Monitoring Committee (IDMC) based on its determination of overwhelming efficacy. The trial is ongoing and will continue to assess the secondary endpoint of OS.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat more than 600,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

In Phase III trials, Tagrisso is being tested in the neoadjuvant resectable setting (NeoADAURA), in the Stage IA2-IA3 adjuvant resectable setting (ADAURA2), in the Stage III locally advanced unresectable setting (LAURA), and in combination with chemotherapy (FLAURA2). AstraZeneca is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso given concomitantly with savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines.

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 assessing 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.

On September 11, 2022 Relay Therapeutics, Inc. (Nasdaq: RLAY) reported late breaking interim clinical data in an oral presentation for RLY-4008, an investigational, potent, selective and oral small molecule inhibitor of fibroblast growth factor receptor 2 (FGFR2), in a global phase 1/2 clinical trial in patients with FGFR2-altered CCA and multiple other solid tumors (Press release, Relay Therapeutics, SEP 11, 2022, View Source [SID1234619369]). The interim data presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress demonstrate an 88% overall response rate (ORR) at the pivotal dose of RLY-4008, 70 mg once daily (QD), as of August 1, 2022, and further support our hypothesis that selective inhibition of FGFR2 can improve the treatment for patients with FGFR2-driven tumors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are thrilled to be sharing interim RLY-4008 data from patients treated at the pivotal dose with the ESMO (Free ESMO Whitepaper) community," said Don Bergstrom, M.D., Ph.D., President of R&D at Relay Therapeutics. "We believe the interim ORR of 88% for these patients helps to demonstrate the potential power of our Dynamo platform to build transformative therapies for patients. Additionally, we continue to generate clinical data outside of CCA and anticipate sharing them in 2023. Beyond RLY-4008, we have a robust pipeline of precision medicine candidates, and we look forward to next presenting initial clinical data on our pan-mutant-selective PI3Kα inhibitor, RLY-2608, expected in the first half of 2023. Thank you to the patients, investigators and clinical trial teams who participate in clinical trials of our investigational therapies."

Key Data Presented at ESMO (Free ESMO Whitepaper) Congress 2022

The data presented at the ESMO (Free ESMO Whitepaper) Congress were based on an August 1, 2022 data cut-off date from both the dose escalation and dose expansion phases of the trial. The interim data included a safety database of 195 patients, with 89 patients treated at the pivotal dose of 70 mg QD, of which 17 were FGFRi-naïve FGFR2-fusion CCA patients eligible for efficacy evaluation (patients with measurable disease who had opportunity for ≥2 tumor assessments to confirm response or discontinued treatment with <2 tumor assessments).

15 out of 17 of the efficacy evaluable patients at the pivotal dose experienced a partial response resulting in an 88% interim ORR (14 confirmed, 1 unconfirmed in an ongoing patient).
13 out of 15 responders remain on treatment; 1 responder came off study to be resected with curative intent.
The two patients with best response of stable disease remain on treatment.
More broadly across all dose levels and schedules, 38 FGFRi-naïve FGFR2-fusion CCA patients were eligible for efficacy evaluation, of which 24 experienced a partial response resulting in a 63% interim ORR (22 confirmed, 2 unconfirmed).
The interim safety analysis as of the August 1, 2022 cut-off date was generally consistent with the analysis from the June 2022 data disclosure:

Most treatment emergent adverse events were expected FGFR2 on-target, low-grade, monitorable, manageable and largely reversible.
There were no observed Grade 4 or 5 adverse events.
Off-target toxicities of hyperphosphatemia and diarrhea continued to be clinically insignificant.
The oral presentation from the ESMO (Free ESMO Whitepaper) Congress is available on the Relay Therapeutics website under Publications: View Source

Key Upcoming RLY-4008 Milestones

The pivotal cohort of FGFRi-naïve FGFR2-fusion CCA patients is anticipated to be fully enrolled in the second half of 2023.
Initial data from the non-CCA expansion cohorts are expected to be presented in 2023.
The entirety of the dose escalation data is expected to be presented at a medical meeting or published by the end of the first half of 2023.
Conference Call Information

Relay Therapeutics will host a conference call and live webcast on September 12, 2022 at 8:00 am E.T. Registration and dial-in for the conference call may be accessed through Relay Therapeutics’ website under Events in the News & Events section through the following link: View Source An archived replay of the webcast will be available following the event.

About RLY-4008

RLY-4008 is a potent, selective and oral small molecule inhibitor of FGFR2, a receptor tyrosine kinase that is frequently altered in certain cancers. FGFR2 is one of four members of the FGFR family, a set of closely related proteins with highly similar protein sequences and properties. Preclinically, RLY-4008 demonstrated FGFR2-dependent killing in cancer cell lines and induced regression in in vivo models, while minimal inhibition of other targets was observed, including other members of the FGFR family. In addition, RLY-4008 demonstrated strong activity against known clinical on-target resistance mutations in cellular and in vivo preclinical models. RLY-4008 is currently being evaluated in a clinical trial in patients with advanced or metastatic FGFR2-altered solid tumors with a single arm, potentially registration-enabling cohort for FGFRi-naïve FGFR2-fusion CCA. To learn more about the clinical trial of RLY-4008, please visit here.

ReFocus Trial Background

RLY-4008 is currently being evaluated in a global phase 1/2 clinical trial (ReFocus) in patients with FGFR2-altered CCA and multiple other solid tumors including a single arm, potentially registration-enabling cohort for FGFRi-naïve FGFR2-fusion CCA. The phase 1 dose escalation has been completed, and 70 mg QD has been selected as the registrational dose. The expansion cohorts were initiated in December 2021 and now consist of seven different cohorts based on FGFR2 alteration and tumor type. Of the seven cohorts, the potential pivotal cohort consists of approximately 100 previously treated, FGFRi-naïve FGFR2-fusion CCA patients.

On September 11, 2022 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a biopharmaceutical company focused on discovering, developing, and commercializing important new medicines to improve the lives of people with cancer, reported updated results from the ongoing Phase 1/2 study of vimseltinib, an orally administered, potent, and highly selective switch-control kinase inhibitor of CSF1R, for the treatment of patients with tenosynovial giant cell tumor (TGCT) not amenable to surgery (Press release, Deciphera Pharmaceuticals, SEP 11, 2022, View Source [SID1234619368]). Results from the Phase 1 and Phase 2 portions of the study are being presented as separate posters, titled "Efficacy and safety of vimseltinib in tenosynovial giant cell tumour (TGCT): Phase 2 expansion" and "Safety and efficacy of vimseltinib in tenosynovial giant cell tumour (TGCT): Long-term phase 1 update" at the ESMO (Free ESMO Whitepaper) Congress 2022 on September 11 and September 12, respectively.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The updated data presented at ESMO (Free ESMO Whitepaper) underscore the best-in-class potential of vimseltinib for patients with TGCT. Additionally, preliminary patient-reported outcome results found a clinically meaningful symptomatic benefit at week 25 compared with baseline for both pain and stiffness, highlighting the important impact that vimseltinib can have on a patient’s quality of life," said Matthew L. Sherman, M.D., Chief Medical Officer of Deciphera. "These results support vimseltinib’s evaluation in the Phase 3 MOTION study, a two-part, randomized, double-blind, placebo-controlled study, which is currently enrolling patients. We believe vimseltinib has the potential to become a best-in-class therapy for TGCT patients who are not amenable to surgery."

Jean-Yves Blay, M.D., Ph.D., General Director of the Centre Léon Bérard Lyon said, "There remains a substantial unmet medical need for a highly effective and well-tolerated drug for patients with TGCT whose disease is not amenable to surgery. These updated Phase 1/2 data demonstrate not only the strong clinical activity of vimseltinib, but also the favorable safety and tolerability profile that is essential for TGCT patients. Vimseltinib has the potential to address this unmet need and offer a new option for patients around the world."

Summary of Data and Findings from Phase 1/2 Studies

Results from the Phase 2 portion of the study are being presented today in a poster presentation, summarized below. Updated results from the Phase 1 study are being presented in a poster presentation tomorrow, Monday, September 12. The Phase 1 data summarized below are based on the previously released abstract with a data cutoff date of February 18, 2022. The Phase 1 poster presentation remains under embargo until tomorrow and will include updated data based on a May 6, 2022 data cutoff date.

Safety and Efficacy of Vimseltinib in Tenosynovial Giant Cell Tumour (TGCT): Long-term Phase 1 Update

The Phase 1/2 study of vimseltinib is an open-label, multicenter study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of vimseltinib in patients with solid tumors and TGCT. The data presented from the Phase 1 update include long-term safety and efficacy for patients with TGCT from the dose escalation portion of the study.

Dose Cohorts and Demographics

As of the February 18, 2022 cutoff date, 32 patients were enrolled in three dose cohorts:
Phase 1 Cohort 5 (n=8): 30 mg loading dose daily for five days followed by a maintenance dose of 30 mg twice a week.
Phase 1 Cohort 8 (n=12): 30 mg loading dose daily for three days followed by a maintenance dose of 10 mg daily.
Phase 1 Cohort 9 (n=12): 20 mg loading dose daily for three days followed by a maintenance dose of 6 mg daily.
32 patients were evaluable for efficacy by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at the data cutoff; response data is based on independent radiological review (IRR) except for one patient that did not have an IRR.
Antitumor Activity and Treatment Duration

Clinical Benefit Rate: 100% of patients demonstrated clinical benefit, defined as patients with complete response, partial response, or stable disease, without disease progression.
Objective Response Rate: 69% ORR (CR=1, PR=21).
Most responses were achieved within six months.
Treatment Duration: The median duration of treatment was 16.4 months with 59% of patients remaining on treatment as of the data cutoff date in February 2022.
Safety and Tolerability

Treatment with vimseltinib was generally well-tolerated in patients with TGCT and consistent with previously disclosed data.
Grade 3 or 4 treatment-emergent adverse events (TEAEs) (>5%) included increases in creatine phosphokinase, aspartate aminotransferase, lipase, amylase, and hypertension.
Observed transaminase, lipase, amylase, and creatine phosphokinase enzyme elevations were mostly low grade, asymptomatic, and consistent with mechanism of action of CSF1R inhibitors.
No postbaseline bilirubin elevations observed.
There were no new treatment-related serious adverse events since the June 7, 2021 data cutoff date.
Safety and Efficacy of Vimseltinib in Tenosynovial Giant Cell Tumour (TGCT): Phase 2 Expansion

The data presented from the Phase 2 expansion portion of the ongoing Phase 1/2 study includes safety, efficacy, and preliminary patient-reported outcome data in patients with TGCT treated with vimseltinib at the recommended Phase 2 dose (RP2D; 30 mg twice weekly) enrolled in two cohorts. Cohort A includes TGCT patients with no prior anti-CSF1/CSF1R (previous therapy with imatinib or nilotinib is allowed) and Cohort B includes patients with prior anti-CSF1/CSF1R (previous therapy with only imatinib or nilotinib are not eligible).

Dose Cohorts and Demographics

As of the May 6, 2022 cutoff date, 58 TGCT patients treated with vimseltinib were included in the safety population, including 46 patients enrolled in Cohort A and 12 patients enrolled in Cohort B.
56 patients were evaluable for efficacy by RECIST version 1.1 at the data cutoff in the Phase 2 across both cohorts; response data is based on independent radiological review.
Antitumor Activity, Treatment Duration, and Preliminary Patient-Reported Outcomes

Clinical Benefit Rate: 100% of patients demonstrated clinical benefit, defined as patients with complete response, partial response, or stable disease, without disease progression.
Objective Response Rate: 53% ORR (PR=24) in Cohort A and 46% ORR (CR=1, PR=4) in Cohort B.
In Cohort B, responses were observed in patients who had not achieved a response to prior anti-CSF1/CSF1R therapy.
Median duration of response was not reached in both cohorts.
75% of responses and 80% of responses were achieved within six months in Cohorts A and B, respectively.
ORR at 25 weeks was 38% (PR=17) in Cohort A.
Treatment Duration: The median duration of treatment was 9.8 months in Cohort A and 5.9 months in Cohort B. As of the data cutoff date, 61% of patients remained on treatment in Cohort A and 67% of patients remained on treatment in Cohort B.
Preliminary Patient-reported Outcomes: Initial data demonstrate that patients achieved clinically meaningful symptomatic benefit as of week 25 by two measures of patient-reported outcomes.
Brief Pain Inventory (BPI): 48% (Cohort A) and 56% (Cohort B) of patients had a BPI worse pain response at week 25.
Worse Stiffness Numeric Rating Scale: Patients showed progressive improvements in stiffness from baseline to week 25, with mean changes from baseline of -2.0 (Cohort A) and -2.7 (Cohort B). Improvement observed is considered clinically meaningful change with a threshold for meaningful change is estimated to be 1.
Safety and Tolerability

Treatment with vimseltinib was generally well-tolerated in patients with TGCT at the recommended Phase 2 dose of 30 mg twice weekly.
Most non-laboratory TEAEs were Grade 2 or lower.
The only Grade 3/4 TEAE observed in >5% of patients was elevated creatine phosphokinase.
Phase 3 MOTION Study

The pivotal Phase 3 MOTION study of vimseltinib for the treatment of TGCT is ongoing. MOTION is a two-part, randomized, double-blind, placebo-controlled study of vimseltinib to assess the efficacy and safety in patients with TGCT who are not amenable to surgery. The primary endpoint of the study is objective response rate at week 25 as measured by RECIST version 1.1 by blinded independent radiologic review. View Source

Conference Call and Webcast

Deciphera will host a conference call and webcast to discuss data presentations from the Company’s DCC-3116 and vimseltinib clinical programs at the ESMO (Free ESMO Whitepaper) Congress 2022 on Sunday, September 11, 2022, at 7:30 AM ET/ 1:30 PM CEST. The event may be accessed by registering at View Source A webcast of the event will be available in the "Events and Presentations" page in the "Investors" section of the Company’s website at View Source The archived webcast will be available on the Company’s website within 24 hours after the event and will be available for 30 days following the event.

About Vimseltinib

Vimseltinib is an investigational, orally administered, potent and highly selective switch-control kinase inhibitor of CSF1R. It was discovered using Deciphera’s proprietary drug discovery platform and was designed to selectively bind to the CSF1R switch pocket. Vimseltinib has demonstrated encouraging preliminary efficacy and safety data in patients with TGCT and is currently being evaluated in a Phase 1/2 clinical study. The Phase 3 MOTION study, a two-part, randomized, double-blind, placebo-controlled study of vimseltinib to assess the efficacy and safety in patients with symptomatic TGCT who are not amenable to surgery, is currently enrolling.

On September 11, 2022 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported findings from an analysis of patient-reported outcomes (PROs) with mirvetuximab soravtansine (mirvetuximab) versus chemotherapy in the randomized Phase 3 FORWARD I study in platinum-resistant ovarian cancer (Press release, ImmunoGen, SEP 11, 2022, View Source [SID1234619367]). The Company also announced population pharmacokinetic (PK) and exposure response (ER) analyses across multiple clinical trials evaluating mirvetuximab monotherapy in folate receptor alpha (FRα)-positive ovarian cancer. These findings will be highlighted in three posters at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Paris, France.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The data presented at ESMO (Free ESMO Whitepaper) continue to support mirvetuximab’s potential to displace single-agent chemotherapy in FRα-positive ovarian cancer and will serve as a guide as we seek to advance the broader development program," said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen. "With our biologics license application for mirvetuximab under Priority Review with FDA, we look forward to potentially bringing this novel therapy to patients later this year."

ANALYSES OF PATIENT-REPORTED OUTCOMES WITH MIRVETUXIMAB SORAVTANSINE VERSUS STANDARD CHEMOTHERAPY IN THE RANDOMIZED PHASE 3 FORWARD I STUDY IN OVARIAN CANCER (GOG 3011)
Lead Author: Kathleen N. Moore, MD
Date/Time: September 11, 2022, 12:00 – 1:00 PM CEST / 6:00 – 7:00 AM ET
Poster: #532P

The Phase 3 FORWARD I trial enrolled 366 patients who were randomized 2:1 to receive either mirvetuximab or the physician’s choice of single-agent chemotherapy (pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel). Eligible patients were diagnosed with platinum-resistant ovarian cancer that expresses medium or high levels of FRα and were treated with up to three prior regimens. The primary endpoint was progression-free survival (PFS), which was assessed in the entire study population and in the subset of patients with high FRα expression. Patients completed PRO assessments during screening, on day 1 of cycle 1, every 9 weeks thereafter (±1 week) until disease progression, and at the end of treatment visit.

Key findings:

In the intent-to-treat (ITT) population, a statistically significant improvement in the number of patients achieving a 15-point improvement in gastrointestinal (GI) symptoms was observed at week 8/9 in patients treated with mirvetuximab versus chemotherapy (31.7% vs 14.0% P = 0.0162).
The likelihood of GI symptom deterioration was 70% lower with mirvetuximab in the ITT population compared with chemotherapy (95% CI, 0.15–0.60; P=0.0007).
In the FRα-high population, the likelihood of GI symptom deterioration was 80% lower with mirvetuximab compared with chemotherapy (95% CI, 0.10–0.54; P=0.0007).
In both the ITT and FRα-high patient populations, improvements were seen with mirvetuximab compared with chemotherapy across multiple side effects, including sexuality, hair loss, pain severity, body image, and general improvement in ovarian cancer–specific symptoms.
In both the ITT and FRα-high patient populations, there were statistically significant benefits in physical functioning for mirvetuximab over chemotherapy.
"An unmet need remains for safe, effective, and well-tolerated therapeutic options for patients with platinum-resistant ovarian cancer, despite treatment advancements seen in this setting," said Kathleen Moore, Director of the Oklahoma TSET Phase I Program, Professor of the Section of Gynecologic Oncology at The University of Oklahoma College of Medicine and FORWARD I Co-Principal Investigator. "The improved PROs associated with mirvetuximab compared to chemotherapy reinforce the differentiated tolerability profile of mirvetuximab and, coupled with its compelling anti-tumor activity and favorable safety, support its potential to serve as a new standard of care for patients with FRα-positive ovarian cancer."

EXPOSURE RESPONSE ANALYSIS FOR EFFICACY AND SAFETY OF MIRVETUXIMAB SORAVTANSINE IN PATIENTS WITH FOLATE RECEPTOR ΑLPHA-POSITIVE CANCER
Lead Author: Ursula A. Matulonis, MD
Date/Time: September 11, 2022, 12:00 -1:00 PM CEST / 6:00 – 7:00 AM ET
Poster: #592P

An ER analysis was conducted across three studies – the Phase 1 IMGN853-0401 trial, the Phase 3 FORWARD I trial, and the Phase 3 SORAYA trial – to understand the relationship between exposure to single-agent mirvetuximab and the efficacy and safety responses observed in patients with FRα-positive tumors.

Key findings:

Both efficacy, in terms of objective response rate (ORR) and PFS, and ocular adverse events (AEs) were higher with increased exposure to mirvetuximab.
These data highlight the importance of adherence to recommended mirvetuximab dosing guidelines in clinical practice.
POPULATION PHARMACOKINETIC ANALYSIS OF MIRVETUXIMAB SORAVTANSINE IN PATIENTS WITH FOLATE RECEPTOR ALPHA-POSITIVE CANCER
Lead Author: Kathleen N. Moore, MD
Date/Time: September 11, 2022, 12:00 – 1:00 PM CEST / 6:00 – 7:00 AM ET
Poster: #605P

A PK analysis, taking into account patient demographics and clinical characteristics, was conducted across three studies – IMGN853-0401, FORWARD I, and SORAYA – to understand the efficacy and safety of mirvetuximab in patients with FRα-positive tumors.

Key findings:

Dosing adjustments do not appear to be necessary for patients with mild or moderate renal impairment or mild hepatic impairment.
The analyses support the final recommended dose of 6 mg/kg based on adjusted ideal body weight (AIBW) every 3 weeks with balanced efficacy and safety.
Additional information can be found at www.esmo.org.

ABOUT MIRVETUXIMAB SORAVTANSINE
Mirvetuximab soravtansine (IMGN853) is a first-in-class ADC comprising a folate receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, a potent tubulin-targeting agent, to kill the targeted cancer cells.