On June 2, 2024 Astrazeneca reported positive results from the ADRIATIC Phase III trial showed ​Imfinzi (durvalumab) ​demonstrated statistically significant and clinically meaningful improvements in the dual primary endpoints of overall survival (OS) and progression-free survival (PFS) compared to placebo for patients with limited-stage small cell lung cancer (LS-SCLC) who had not progressed following standard-of-care concurrent chemoradiotherapy (cCRT) (Press release, AstraZeneca, JUN 2, 2024, View Source [SID1234643933]).

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These results will be presented today during the Plenary Session at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (abstract #LBA5).

Results from the planned interim analysis showed Imfinzi reduced the risk of death by 27% versus placebo (based on an OS hazard ratio [HR] of 0.73; 95% confidence interval [CI] 0.57-0.93; p=0.0104). Estimated median OS was 55.9 months for Imfinzi versus 33.4 months for placebo. An estimated 57% of patients treated with Imfinzi were alive at three years compared to 48% on placebo. Imfinzi also reduced the risk of disease progression or death by 24% (based on a PFS HR of 0.76; 95% CI 0.61-0.95; p=0.0161) versus placebo. Median PFS was 16.6 months for Imfinzi versus 9.2 months for placebo. An estimated 46% of patients treated with Imfinzi had not experienced disease progression at two years compared to 34% on placebo.

The OS and PFS benefits observed were generally consistent across key prespecified patient subgroups including age, sex, race, disease stage1 at diagnosis, prior radiation and whether patients received prophylactic cranial irradiation.

David R. Spigel, MD, Chief Scientific Officer at Sarah Cannon Research Institute and investigator in the trial, said: "The ADRIATIC results represent a breakthrough in limited-stage small cell lung cancer, a highly aggressive disease where recurrence rates are high and only 15 to 30 per cent of patients survive five years. Durvalumab is the first systemic treatment to show improved survival for these patients in decades and should become a new standard of care in this setting."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "The strong improvement in overall survival seen with Imfinzi after concurrent chemoradiotherapy is transformative in the treatment of limited-stage small cell lung cancer. These tremendous results underscore our ambition to drive up survival rates in this earlier-stage lung cancer setting, and we look forward to working with regulatory authorities to bring Imfinzi to these patients as quickly as possible."

Summary of results: ADRIATIC

​

​Imfinzi

​(n=264)

​Placebo

​(n=266)

OS

Median OS, in months (95% CI)

55.9

(37.3-NEi)

33.4

(25.5-39.9)

Hazard ratio (95% CI)

0.73 (0.57-0.93)

p-value

0.0104

OS rate at 24 months (%)

68.0

58.5

OS rate at 36 months (%)

56.5

47.6

PFS

Median PFS, in months (95% CI)

16.6

(10.2-28.2)

9.2

(7.4-12.9)

Hazard ratio (95% CI)

0.76 (0.61-0.95)

p-value

0.0161

PFS rate at 18 months (%)

48.8

36.1

PFS rate at 24 months (%)

46.2

34.2

​i Not estimable

The safety profile for Imfinzi was generally manageable and consistent with the known profile of this medicine. No new safety signals were observed. Grade 3 and 4 adverse events due to any cause occurred in 24.4% of patients treated with Imfinzi and 24.2% of patients treated on placebo.

Notes

Small cell lung cancer
Lung cancer is the leading cause of cancer death among men and women and accounts for about one-fifth of all cancer deaths.2 Lung cancer is broadly split into non-small cell lung cancer and SCLC, with about 15% of cases classified as SCLC, a highly aggressive form of the disease.3-4

LS-SCLC (Stage I-III), which accounts for approximately 30% of SCLC diagnoses, is classified as SCLC that is generally only in one lung or one side of the chest.5-6 LS-SCLC typically recurs and progresses rapidly despite initial response to standard-of-care chemotherapy and radiotherapy.4,7 The prognosis for LS-SCLC is particularly poor, as only 15-30% of patients will be alive five years after diagnosis.8

ADRIATIC
The ADRIATIC trial is a randomised, double-blind, placebo-controlled, multi-centre global Phase III trial evaluating Imfinzi monotherapy and Imfinzi plus Imjudo (tremelimumab) versus placebo in the treatment of 730 patients with LS-SCLC who had not progressed following cCRT. In the experimental arms, patients were randomised to receive a 1500mg fixed dose of Imfinzi with or without Imjudo 75mg every four weeks for up to four doses/cycles each, followed by Imfinzi every four weeks for up to 24 months.

The dual primary endpoints were PFS and OS for Imfinzi monotherapy versus placebo. Key secondary endpoints included OS and PFS for Imfinzi plus Imjudo versus placebo, safety and quality of life measures. The trial included 164 centres in 19 countries across North and South America, Europe and Asia.

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 currently approved in a number of countries across multiple types of lung cancer. Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiation therapy. Imfinzi is also approved for the treatment of extensive-stage SCLC and in combination with a short course of Imjudo and chemotherapy for the treatment of metastatic NSCLC.

In addition to its indications in lung cancers, Imfinzi is approved in a number of countries in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma (HCC). Imfinzi is also approved as a monotherapy in unresectable HCC in Japan and the EU and in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 220,000 patients have been treated with Imfinzi. 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, breast cancer, several gastrointestinal cancers and other solid tumours.

On June 2, 2024 Astrazeneca reported detailed positive results from the DESTINY-Breast06 Phase III trial showed that Enhertu (trastuzumab deruxtecan) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care chemotherapy in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) metastatic breast cancer and the overall trial population (patients with HR-positive, HER2-low and HER2-ultralow [defined as IHC 0 with membrane staining] expression) following one or more lines of endocrine therapy (Press release, AstraZeneca, JUN 2, 2024, View Source [SID1234643932]).

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These results will be presented today as a late-breaking oral presentation during the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (abstract #LBA1000).

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

In the primary analysis of DESTINY-Breast06, results showed Enhertu reduced the risk of disease progression or death by 38% by blinded independent central review (BICR) versus chemotherapy in patients with HER2-low expression (hazard ratio [HR] 0.62; 95% confidence interval [CI]: 0.51-0.74; p<0.0001). Median PFS was 13.2 months in the Enhertu arm compared to 8.1 months for chemotherapy.

PFS results by BICR in the overall trial population were similar and showed Enhertu achieved a 37% reduction in the risk of disease progression or death compared to chemotherapy, with a median PFS of 13.2 months with Enhertu versus 8.1 months for chemotherapy (HR 0.63; 95% CI: 0.53-0.75; p<0.0001).

A prespecified exploratory analysis showed the clinically meaningful improvement in PFS was consistent between patients with HER2-low and HER2-ultralow expression. In patients with HER2-ultralow expression, Enhertu reduced the risk of disease progression or death by 22% compared to chemotherapy with a median PFS of 13.2 months versus 8.3 months, respectively (HR 0.78; 95% CI: 0.50-1.21).

Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at the University of Milan and Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy and principal investigator for the trial, said: "Endocrine therapies are widely used early in the treatment of HR-positive metastatic breast cancer, but following one or more lines of treatment, patients often derive limited efficacy from further endocrine-based therapy. With a median progression-free survival of more than a year, the results from DESTINY-Breast06 show that Enhertu could become a new standard of care for patients with HER2-low- and HER2-ultralow-expressing tumours following endocrine therapy in the metastatic setting."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "DESTINY-Breast06 represents another potential paradigm shift in how we treat patients across the spectrum of HR-positive metastatic breast cancer. The results reinforce the potential for Enhertu to improve outcomes earlier in the treatment landscape and in a broader population of patients with HER2-expressing breast cancer who have never before been eligible for a HER2-directed therapy."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "Enhertu continues to deliver pioneering results for a HER2-directed medicine across many different types of cancer. These latest results from DESTINY-Breast06 demonstrate clinically meaningful results with Enhertu even in tumours with very low levels of HER2 expression, suggesting that it may have an important role in treating a wide range of HER2-expressing metastatic breast cancer."

In patients with HER2-low expression, confirmed objective response rate (ORR) was 56.5% for Enhertu versus 32.2% with chemotherapy. In the overall trial population, confirmed ORR was 57.3% for Enhertu versus 31.2% with chemotherapy and in patients with HER2-ultralow expression the confirmed ORR was 61.8% versus 26.3%, respectively. Complete responses were seen in 13 patients from the Enhertu arm, including nine patients with HER2-low expression. In the HER2-ultralow subgroup, four patients in the Enhertu arm had complete responses. No complete responses were seen in the chemotherapy arm.

Summary of results: DESTINY-Breast06

HER2-low
(IHC 1+ or IHC 2+/ISH-)i

Overall trial population
(HER2-low and HER2-ultralow)

HER2-ultralow (defined as IHC 0 with membrane staining)i

Enhertu

(n=359)

Chemo

(n=354)

Enhertu

(n=436)

Chemo

(n=430)

Enhertu

(n=76)

Chemo

(n=76)

PFSii

Median PFS in months

13.2

8.1

13.2

8.1

13.2

8.3

HR (95% CI)

0.62 (0.51-0.74)

0.63 (0.53-0.75)

0.78 (0.50-1.21)

p-value

p<0.0001

p<0.0001

—

OSiii

HR (95% CI)

0.83 (0.66-1.05)

0.81 (0.65-1.00)

0.75 (0.43-1.29)

p-value

p=0.1181iv

Not testedv

—

12-month OS rate (%)

87.6

81.7

87.0

81.1

84.0

78.7

ORRii,vi

Confirmed ORR (%) (n)vii

56.5

(203)

32.2

(114)

57.3

(250)

31.2

(134)

61.8

(47)

26.3

(20)

CR (%) (n)

2.5 (9)

0

3.0 (13)

0

5.3 (4)

0

PR (%) (n)

54.0 (194)

32.2 (114)

54.4 (237)

31.2 (134)

56.6 (43)

26.3 (20)

SD (%) (n)

34.8 (125)

48.0 (170)

33.9 (148)

49.3 (212)

28.9 (22)

55.3 (42)

Median DOR in months

14.1

8.6

14.3

8.6

14.3

14.1

PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival; ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; DOR, duration of response

i HER2-low status determined per IRT data, and HER2-ultralow status determined per central laboratory data

ii As assessed by BICR

iii Less than 40% maturity for interim OS analysis

iv P-value of <0.0046 required for statistical significance

v No test of significance was performed in line with the multiple testing procedure

vi ORR is (CR + PR); ORR based on RECIST v1.1

vii Response required confirmation after 4 weeks

Patients in the trial received a median of two prior lines of endocrine therapy in each treatment arm. In the overall trial population, 14.9% of patients (n=65) in the Enhertu arm and 19.2% of patients (n=82) in the chemotherapy arm had received one prior line of endocrine therapy. No patients in the trial had received prior chemotherapy treatment in the metastatic setting. Median duration of follow-up was 18.2 months. As of the data cut-off of 18 March 2024, a total of 119 patients (14%) remained on treatment, 89 patients receiving Enhertu and 30 receiving chemotherapy.

The safety profile of Enhertu was consistent with previous breast cancer clinical trials with no new safety concerns identified. The most common Grade 3 or higher treatment-related treatment-emergent adverse events occurring in 5% or more of patients treated with Enhertu were neutropenia (20.7%), leukopenia (6.9%) and anaemia (5.8%). Interstitial lung disease (ILD)/pneumonitis, adjudicated as drug-related by an independent committee, occurred in 11.3% of patients treated with Enhertu. The majority of ILD events were low Grade (Grade 1 [n=7; 1.6%]; Grade 2 [n=36; 8.3%]). There were three Grade 3 ILD events (0.7%), no Grade 4 events and three Grade 5 events (0.7%).

Additional Enhertu data at ASCO (Free ASCO Whitepaper)

DESTINY-Breast03 updated results
Updated overall survival (OS) results from the DESTINY-Breast03 Phase III trial showed Enhertu continued to demonstrate a clinically meaningful survival improvement over trastuzumab emtansine (T-DM1) after more than three years of follow up in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab.

Results showed median OS was 52.6 months in the Enhertu arm compared to 42.7 months for T-DM1 (HR 0.73; 95% CI: 0.56-0.94).

The safety profile of Enhertu continues to be generally manageable and no cumulative toxicities were observed with longer follow-up. Results will be presented during the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting (abstract #1025).

DESTINY-Breast07 results
Interim results from the DESTINY-Breast07 Phase Ib/II trial of Enhertu alone or in combination with other anticancer therapies as a 1st-line treatment for HER2-positive metastatic breast cancer demonstrated promising clinical activity for Enhertu as a monotherapy (n=75) and in combination with pertuzumab (n=50). Results were presented as an oral presentation at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting (abstract #1009).

Results showed a confirmed ORR of 76.0% with Enhertu and 84.0% with Enhertu in combination with pertuzumab. The 12-month PFS rate was 80.8% with Enhertu monotherapy and 89.4% with Enhertu and pertuzumab.

The safety of Enhertu as a monotherapy and in combination with pertuzumab was consistent with the known safety profiles of each therapy. ILD/pneumonitis was reported in seven patients (9.3%) in the Enhertu monotherapy arm and seven patients (14.0%) in the combination arm. All ILD events were Grade 3 or lower.

These are the first data presented for Enhertu as a 1st-line treatment in HER2-positive metastatic breast cancer. Analyses from the ongoing DESTINY-Breast09 Phase III trial will provide further insights regarding the efficacy and safety of Enhertu in this HER2-positive patient population.

Notes

Breast cancer and HER2 expression
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.1 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.1 While survival rates are high for those diagnosed with early breast cancer, only approximately 30% of patients who are diagnosed with or who progress to metastatic disease are expected to live five years after their diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours, including breast cancer.3 Patients with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and treated with HER2-directed therapies, representing approximately 15-20% of all breast cancers.4 Historically, tumours that were not classified as HER2-positive were classified as HER2-negative.5

HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.2 Despite being classified as HER2-negative, many of these tumours still carry some level of HER2 expression.5 It is estimated that approximately 60-65% of HR-positive, HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow.6,7

Endocrine therapies are widely used in the early lines of treatment for HR-positive metastatic breast cancer; however, after two lines of treatment, further efficacy from endocrine therapy is often limited.8 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes.8-11

Prior to the approval of Enhertu in HER2-low metastatic breast cancer post chemotherapy based on the DESTINY-Breast04 trial, there were no targeted therapies approved specifically for patients with HER2-low expression. There are no targeted therapies specifically approved for patients with HER2-low expression prior to chemotherapy or for patients with HER2-ultralow expression.12

DESTINY-Breast06
DESTINY-Breast06 is a global, randomised, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (defined as IHC 0 with membrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months.

The primary endpoint is PFS in the HR-positive, HER2-low patient population as measured by BICR. Key secondary endpoints include PFS by BICR in the overall trial population (HER2-low and HER2-ultralow), OS in the HER2-low patient population and OS in the overall trial population. Other secondary endpoints include ORR, DOR, time to first subsequent treatment or death, time to second subsequent treatment or death and safety.

DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow) randomised at multiple sites in Asia, Europe, Australia, North America and South America. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-Breast03
DESTINY-Breast03 is a global, head-to-head, randomised, open-label, pivotal Phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus T-DM1 in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The primary efficacy endpoint of DESTINY-Breast03 is PFS based on BICR. OS is the key secondary efficacy outcome measure. Other secondary endpoints include ORR, DOR, PFS based on investigator assessment and safety.

DESTINY-Breast03 enrolled 524 patients at multiple sites in Asia, Europe, North America, Australia and South America. Primary results from DESTINY-Breast03 were published in The New England Journal of Medicine, with updated OS results published in The Lancet. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-Breast07
DESTINY-Breast07 is a global, randomised, open-label Phase Ib/II dose-finding and dose-expansion trial to explore the safety, tolerability and anti-tumour activity of Enhertu alone or in combination with other anticancer agents in patients with HER2-positive metastatic breast cancer.

The study consists of two phases: a dose escalation phase and a dose expansion phase. The dose escalation phase enrolled patients with locally assessed HER2-positive or advanced metastatic breast cancer in 2nd-line or later treatment. The dose expansion phase enrolled patients with previously untreated for HER2-positive advanced or metastatic breast cancer.

The primary endpoints of DESTINY-Breast07 are safety and tolerability. Secondary endpoints include ORR and PFS based on investigator assessment.

DESTINY-Breast07 enrolled 244 patients at multiple sites in Asia, Europe, North America and South 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 number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Enhertu (5.4 mg/kg) is approved in more than 60 countries for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or in-situ hybridisation [ISH]+) 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 (5.4 mg/kg) is approved in more than 60 countries for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or 2+/ISH-) breast cancer who have received a prior systemic therapy 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 (5.4 mg/kg) is approved in more than 35 countries for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.

Enhertu (5.4 mg/kg) is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours who have received prior systemic treatment and who have no satisfactory alternative treatment options based on results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials.

Enhertu development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anti-cancer treatments, such as immunotherapy, also are underway.

On June 2, 2024 GSK plc (LSE/NYSE: GSK) reported positive results from an interim analysis of the DREAMM-8 phase III head-to-head trial evaluating Blenrep (belantamab mafodotin), in combination with pomalidomide plus dexamethasone (PomDex), versus a standard of care, bortezomib plus PomDex, as a second line and later treatment for relapsed or refractory multiple myeloma (Press release, GlaxoSmithKline, JUN 2, 2024, View Source [SID1234643926]). These late-breaking data, being presented today at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (31 May – 4 June) in Chicago, IL, were featured in the official ASCO (Free ASCO Whitepaper) press programme and simultaneously published in the New England Journal of Medicine.

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On the primary endpoint of progression-free survival (PFS), a statistically significant and clinically meaningful improvement (hazard ratio [HR]: 0.52 [95% confidence interval (CI): 0.37-0.73], p-value<0.001) was observed with the belantamab mafodotin combination (n=155) compared to the bortezomib combination (n=147). At a median follow-up of 21.8 months, the median PFS was not yet reached (95% CI: 20.6-not yet reached [NR]) with the belantamab mafodotin combination compared to 12.7 months (95% CI: 9.1-18.5) in the bortezomib combination. At the end of one year, 71% (95% CI: 63-78) of patients in the belantamab mafodotin combination group compared to 51% (95% CI: 42-60) in the bortezomib combination group were alive and had not progressed. A benefit for belantamab mafodotin plus PomDex was observed across all pre-specified subgroups including those with poor prognostic features, such as patients who were refractory to lenalidomide and patients with high-risk cytogenetics.

Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK, said: "With the robust results from the DREAMM-8 phase III head-to-head trial, we now have consistent data from two phase III trials supporting the potential for Blenrep combinations to redefine the treatment of multiple myeloma at or after first relapse. This is exciting news given the high unmet need for new and efficacious combinations once patients relapse or stop responding to initial treatments. We continue to share data and discuss our path forward with regulators."

A positive overall survival (OS) trend was observed but not statistically significant (HR: 0.77 [95% CI: 0.53-1.14]) at the interim analysis. OS follow-up continues and further analyses are planned. At the end of one year, 83% (95% CI: 76-88) of patients were alive in the belantamab mafodotin combination group versus 76% (95% CI: 68-82) in the bortezomib combination group. The safety and tolerability profile of the belantamab mafodotin combination was broadly consistent with the known profile of the individual agents.

Suzanne Trudel, MD, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, said: "The profound progression-free survival benefit seen in DREAMM-8 highlights the potential for belantamab mafodotin, when used with pomalidomide and dexamethasone, to improve outcomes for patients with relapsed/refractory multiple myeloma. This combination may have potential to redefine treatment of multiple myeloma at or after first relapse, a setting where patients may benefit from novel therapies.

Similar to the results seen in the DREAMM-7 phase III head-to-head trial, in DREAMM-8 the belantamab mafodotin combination also resulted in clinically meaningful improvements consistently across secondary efficacy endpoints, showing that the belantamab mafodotin combination resulted in deeper and more durable responses compared to the bortezomib combination. Key improvements included rate of complete response (CR) or better (more than twofold improvement); minimal residual disease (MRD) negativity rate (nearly fivefold improvement); and duration of response (median not yet reached with the belantamab mafodotin combination versus 17.5 months with the bortezomib combination).

Key and other secondary endpoint summaries are listed below.

Key and Other Secondary Endpoints
Endpoint belantamab mafodotin + pomalidomide and dexamethasone (BPd)
(n= 155) pomalidomide + bortezomib and dexamethasone (PVd)
(n=147)
ORR (overall response rate), % (95% CI)

77% (70.0-83.7)

72% (64.1-79.2)

sCR (stringent complete
response), %

9%

3%

CR (complete response),
%

31%

14%

VGPR (very good partial
response), %

24%

22%

PR (partial response), %

14%

34%

CR or better rate
(sCR+CR), % (95% CI)

40% (32.2-48.2)

16% (10.7-23.3)

VGPR or better rate
(sCR+CR+VGPR), %
(95% CI)

64% (55.8-71.4)

38% (30.2-46.5)

MRD negativity rate* %
(95% CI)

23.9% (17.4-31.4)

4.8% (1.9-9.6)

Duration of response
(months), median (95% CI)

NR (24.9-NR)

17.5 months (12.1-26.4)

Overall Survival**
HR (95% CI)  0.77 (0.53-1.14)
* Measured in patients with a sCR or CR.
** Follow-up for OS is ongoing.
NR: Not reached.

Grade 3 or higher non-ocular adverse events (AEs) of clinical interest in the belantamab mafodotin combination versus bortezomib combination arms, respectively, included neutropenia (57% versus 39%; 42 patients/100 person-years in both arms); thrombocytopenia (38% versus 29%; 28 versus 31 patients/100 person-years); and pneumonia (17% versus 8%; 13 versus 8 patients/100 person-years).

Eye-related side effects, a known risk of treatment with belantamab mafodotin, were generally reversible, manageable with dose modifications, and led to low (9%) treatment discontinuation rates. Grade 3 or higher ocular adverse events occurred in 43% of patients receiving the belantamab mafodotin combination (Grade 3: 42%; Grade 4: 1%). Most commonly reported grade 3 or higher ocular symptoms included blurred vision (Grade 3: 17%; Grade 4: 0), dry eye (Grade 3: 8%: Grade 4: 0), and foreign body sensation in the eyes (Grade 3: 6%; Grade 4: 0). Fifty-one patients (34%) with a best corrected visual acuity (BCVA) of 20/25 or better in at least one eye at baseline had a worsening in both eyes to 20/50 or worse. At the time of this analysis, the first occurrence of such events had improved in 92% of these patients, and resolved in 85%, with a median time to resolution of 57 days (range: 14-451 days).

Global health status quality of life (QOL), as measured by the EORTC-QLQ-C30 remained stable in both treatment arms over time, suggesting that treatment did not lead to any decline in overall health related QOL.

The DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) clinical development programme continues to evaluate the potential of belantamab mafodotin in early lines of treatment and in combination with novel therapies and standard of care treatments. DREAMM-8 is the second phase III head-to-head belantamab mafodotin combination trial in second line and later treatment for multiple myeloma to report positive results. Positive findings from DREAMM-7, a phase III head-to-head trial evaluating belantamab mafodotin in combination with bortezomib and dexamethasone (BorDex) versus daratumumab plus BorDex in the same treatment setting, were presented1 at the ASCO (Free ASCO Whitepaper) Plenary Series on 6 February 2024, shared in an encore presentation at the 2024 ASCO (Free ASCO Whitepaper) Annual Meeting, and published in the New England Journal of Medicine.

About DREAMM-8
The DREAMM-8 phase III clinical trial is a multicentre, open-label, randomised trial evaluating the efficacy and safety of belantamab mafodotin in combination with PomDex compared to a combination of bortezomib and PomDex in patients with relapsed/refractory multiple myeloma previously treated with at least one prior line of multiple myeloma therapy, including a lenalidomide-containing regimen, and who have documented disease progression during or after their most recent therapy. Compared to the patient population studied in the DREAMM-7 trial, patients in DREAMM-8 were more heavily pre-treated in that all had prior exposure to lenalidomide, 75% were refractory to lenalidomide, 25% had prior daratumumab exposure and of those most were daratumumab refractory.

A total of 302 participants were randomised at a 1:1 ratio to receive either belantamab mafodotin plus PomDex, or bortezomib plus PomDex.

The primary endpoint is PFS as per an independent review committee. Key secondary endpoints include OS, minimal residual disease negativity as assessed by next-generation sequencing, and duration of response. Other secondary endpoints include ORR, patient-reported quality of life outcomes, adverse events, eye exam findings, and laboratory investigations.

About multiple myeloma
Multiple myeloma is the third most common blood cancer globally and is generally considered treatable but not curable.2,3 There are approximately 176,000 new cases of multiple myeloma diagnosed globally each year.4 Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments.5

About Blenrep
Blenrep is an antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. The drug linker technology is licensed from Seagen Inc.; the monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa Inc., a member of the Kyowa Kirin Group.

Refer to the Blenrep UK Summary of Product Characteristics6 for a full list of adverse events and the complete important safety information in the United Kingdom.

On June 2, 2024 Flamingo Therapeutics ("Flamingo") reported the presentation of a Trial-in-Progress poster at the 2024 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (ASCO 2024) taking place in Chicago, Illinois (Press release, Flamingo Therapeutics, JUN 2, 2024, View Source;utm_medium=rss&utm_campaign=flamingo-therapeutics-presents-poster-at-asco-2024-on-phase-ii-pemda-hn-trial-for-head-and-neck-squamous-cell-carcinoma-hnscc [SID1234643925]).

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Flamingo’s lead oncology program, danvatirsen, is an oligonucleotide discovered by Ionis that selectively targets STAT3 and has shown clinical activity in HNSCC. PEMDA-HN (NCT05814666) is a multicenter, open-label, randomized study evaluating the efficacy and safety of danvatirsen in combination with pembrolizumab compared with pembrolizumab alone as first-line treatment of patients with recurrent/metastatic HNSCC whose tumor expresses PD-L1. Two-thirds of patients will be randomized to receive danvatirsen and pembrolizumab and one-third will be randomized to receive pembrolizumab alone. The primary endpoint of the study is overall response rate by RECIST 1.1 as assessed by the investigator. The secondary endpoints include safety, duration of response, disease control rate, progression free survival and overall survival. PEMDA-HN is being conducted at study centers in the United States, South Korea and the United Kingdom.

ASCO poster details are as follows:

Abstract#: TPS6113
Title: "PEMDA-HN, an open-label, phase II, randomized controlled study of danvatirsen plus pembrolizumab compared to pembrolizumab alone in first-line recurrent and/or metastatic head and neck squamous cell carcinoma (RM HNSCC)"
Session Title: Poster Session – Head and Neck Cancer
Session Date and Time: June 2, 2024, 9:00am CDT
Presenting Author: Marshall R. Posner, MD, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai

For more information, please visit the ASCO (Free ASCO Whitepaper) 2024 website.

On June 2, 2024 ALX Oncology Holdings Inc., ("ALX Oncology" or "the Company") (Nasdaq: ALXO), an immuno-oncology company developing therapies that block the CD47 immune checkpoint pathway, reported data from its Phase 1 ASPEN-07 clinical trial in a poster presentation (abstract #4575) at the 2024 American Society of Cancer Oncology ("ASCO") Annual Meeting being held in Chicago from May 31-June 4, 2024 (Press release, ALX Oncology, JUN 2, 2024, https://ir.alxoncology.com/news-releases/news-release-details/alx-oncology-presents-first-evorpacept-combination-data-antibody [SID1234643920]). These findings represent the first evorpacept combination data with an ADC from ASPEN-07’s ongoing, open-label, single-arm, clinical trial of evorpacept in combination with PADCEV (enfortumab vedotin or "EV") in patients with locally advanced or metastatic urothelial cancer ("la/m UC"). Evorpacept is a CD47 blocker with an inactivated Fc effector domain that is designed to minimize associated toxicity.

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Key results as of the data cut-off date of April 3, 2024:

Initial patient demographics

Twenty-eight EV-naïve patients were enrolled with 29% having received three or more prior lines of therapy.
All patients had disease that progressed after platinum chemotherapy and checkpoint inhibition.
Approximately 93% of patients had metastatic disease.
The combination was generally well-tolerated in a heavily pre-treated patient population

No maximum tolerated dose was reached, and the maximum administered evorpacept dose was 30 mg/kg Q2W.
There were no treatment-related deaths in the study.
The most frequent adverse events due to any cause were low-grade fatigue, dysgeusia, nausea, diarrhea, hyperglycemia, and pruritis.
Initial activity showed tumor reduction in the majority of evaluable patients

ASCO poster presentation data-cut reported an unconfirmed overall response rate ("ORR") of 59% (n=22) with evorpacept plus EV (EV single agent ORR benchmark is 41%1).
Following the April data cut-off, four additional response evaluable patients yielded an unconfirmed ORR of 61% (n=26) including two confirmed complete responses and six confirmed partial responses.
To date, 58% of evaluable patients remain in the study.
Continued follow-up for patients who are EV-naïve on ASPEN-07 is ongoing and, enrollment of a new cohort of patients who have received prior EV has begun.
"We are encouraged by the preliminary safety data and clinical activity of evorpacept combined with PADCEV in patients with advanced bladder cancer," said Sophia Randolph, M.D., Ph.D., Chief Medical Officer of ALX Oncology. "To our knowledge, these data are the first demonstration of anti-tumor activity with a CD47 blocker and an ADC in a heavily pre-treated patient population in the clinical setting. With these promising early results, we are evaluating clinical development options in both PADCEV-naïve and experienced patient populations."

"This emerging dataset reported favorable potential for evorpacept to be combined with an ADC in a patient population that has exhausted many treatments," said Jason Lettmann, Chief Executive Officer of ALX Oncology. "We are especially hopeful because of the two patients with confirmed complete responses, which further exhibited this combination is active and that responses could improve over time in more patients. Heading further into the year, we will continue the momentum for ASPEN-07 as we gear up to share multiple, randomized, Phase 2 clinical data readouts where evorpacept is combined with anti-cancer antibodies and checkpoint inhibitors."

The poster can be found on the Publications section of the ALX Oncology website here.

Company Event with ASPEN-07 Principal Investigator and ALX Oncology Management

The Company is hosting a virtual event with key opinion leaders on Friday, June 7, 2024, at 1:00 PM ET. The event will feature leading ASPEN-07 principal investigator and bladder cancer expect, Samuel A. Funt, M.D., from Memorial Sloan Kettering Cancer Center, along with the management team of ALX Oncology. The discussion will cover details of the first promising initial dose escalation data from the Phase 1 ASPEN-07 clinical trial of evorpacept in combination with EV in patients with la/m UC, and how ASPEN-07 could fit into the treatment paradigm of this indication.

Samuel A. Funt, M.D., is a genitourinary oncologist at Memorial Sloan Kettering Cancer Center in New York, NY, where he is also Director of the Inpatient Genitourinary Oncology Service, Director of Bladder Cancer Clinical Trials Operations, and member of the Data Safety Monitoring Committee. Dr. Funt has practiced medicine and been involved in clinical trials for over 10 years. His top areas of clinical expertise are Bladder and Testicular Cancers. Dr. Funt has co-authored over 60 peer-reviewed articles and been awarded research grants from the National Institutes Health, American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), and the American Cancer Society. His research focuses on the development of more personalized and effective treatments and novel biomarkers of therapeutic response and resistance.

The event will be webcast live and can be accessed by visiting the Investors section of ALX Oncology’s website at www.alxoncology.com and selecting Events under News and Events. To participate in the live event, please register using this link: View Source An archived webcast will be available following the event.

About the Phase 1 Clinical Trial Investigating Evorpacept plus EV in Advanced Bladder Cancer

The Phase 1 clinical trial is an ongoing, open-label, single arm is designed to evaluate the safety, tolerability, and efficacy of evorpacept in combination with EV in patients with la/m UC (NCT05524545). This dose escalation clinical trial has enrolled cohorts receiving 20 mg/kg Q2W or 30 mg/kg Q2W evorpacept plus standard EV treatment. The study is sponsored and conducted by ALX Oncology.

About Bladder Cancer and UC

As estimated by the National Cancer Institute, bladder cancer is the sixth most common cancer type in the United States. UC is the most common type of bladder cancer and accounts for approximately 90% of all bladder cancer cases. Roughly 83,000 new cases of bladder cancer will be diagnosed in the United States in 2024 with about 16,800 deaths. The five-year survival for patients with metastatic bladder cancer is less than 8%. Worldwide, over 614,000 new cases of bladder cancer and over 220,000 deaths occurred in 2022 according to The Global Cancer Observatory.