On June 5, 2023 Astrazeneca reported Positive results from an interim analysis of the ongoing DESTINY-PanTumor02 Phase II trial showed that Enhertu (trastuzumab deruxtecan) demonstrated clinically meaningful and durable responses across a broad range of HER2-expressing advanced solid tumours in previously treated patients (Press release, AstraZeneca, JUN 5, 2023, View Source [SID1234632486]).

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These results will be presented today as a late-breaking oral presentation at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (abstract #LBA3000).

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

In the trial, previously treated patients (2 median prior lines of therapy) with HER2-expressing advanced solid tumours including either biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers or other tumours treated with Enhertu showed a confirmed objective response rate (ORR) of 37.1%, as assessed by investigator at an interim analysis. A greater response was observed in patients with the highest level of HER2 expression (immunohistochemistry (IHC) 3+), where Enhertu demonstrated a confirmed ORR of 61.3% as confirmed by central testing. A complete response (CR) was observed in 15 (5.6%) patients in the overall trial population, with 84 (31.5%) partial responses (PR) observed, and 123 (46.1%) patients achieving stable disease. The disease control rate (DCR) in the overall trial population was 68.2%, as assessed by investigator.

Nearly half (49.6%) of all patients in DESTINY-PanTumor02 who achieved a response remained in response at one year. Median duration of response (DoR) was 11.8 months (95% confidence interval [CI] 9.8-NE) in the overall trial population and 22.1 months (CI 9.3-NE) in patients with IHC 3+ expression.

Funda Meric-Bernstam, MD, Chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, US and principal investigator for the trial, said: "The DESTINY-PanTumor02 data showed encouraging and durable response rates across a broad range of HER2-expressing solid tumours where there are currently no approved HER2-targeted treatments. Based on these results, Enhertu has the potential to benefit specific patients with HER2-expressing advanced disease who currently have limited options and may face a poor prognosis."

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: "While HER2 is an established biomarker in breast, gastric, lung and colorectal cancers, data from the DESTINY-PanTumor02 trial validate HER2 as an actionable biomarker across a broad range of tumour types. Enhertu is the first treatment to demonstrate broad activity across HER2-expressing solid tumours where there are currently no approved HER2-directed therapies. These data will support our ongoing conversations with global health authorities as we look to bring Enhertu to as many patients as possible."

Mark Rutstein, MD, Global Head, Oncology Development, Daiichi Sankyo, said: "Nearly half of patients who achieved a response with Enhertu as a late-line treatment for HER2-expressing advanced solid tumours in DESTINY-PanTumor02 remained in response at one year, demonstrating the potential of this important medicine to provide benefit to patients with hard-to-treat cancers in need of new options. The results further reinforce the important role of antibody drug conjugates like Enhertu to provide potential new solutions to advance current standards of care in areas of high unmet need and improve the outcomes of patients."

Summary of results: DESTINY-PanTumor02

Efficacy Measure

Cervical

Endometrial

Ovarian

BTC

Pancreatic

Bladder

Otheri

All Patients

All IHC Expression Levelsii

(n)

40

40

40

41

25

41

40

267

Confirmed ORR (%)

50.0%

57.5%

45.0%

22.0%

4.0%

39.0%

30.0%

37.1%

Complete response (%)

5.0%

17.5%

10.0%

2.4%

0%

2.4%

0%

5.6%

Partial response (%)

45.0%

40.0%

35.0%

19.5%

4.0%

36.6%

30.0%

31.5%

Stable disease (%)

30.0%

32.5%

35.0%

61.0%

68.0%

43.9%

60.0%

46.1%

Progressive disease (%)

17.5%

10.0%

17.5%

17.1%

28.0%

17.1%

7.5%

15.7%

Not evaluable (%)

2.5%

0%

2.5%

0%

0%

0%

2.5%

1.1%

DCRiii at 12 weeks (%)

67.5%

80.0%

70.0%

65.9%

36.0%

70.7%

75.0%

68.2%

Median DoR (months) (95% CI)

9.8

(4.2-NE)

NR

(9.9-NE)

11.3

(4.1-NE)

8.6

(2.1-NE)

NR

8.7

(4.3-11.8)

NR

(4.1-NE)

11.8

(9.8-NE)

IHC 3+ii

(n)

8

13

11

16

2

16

9

75

Confirmed ORR (%)

75.0%

84.6%

63.6%

56.3%

0.0%

56.3%

44.4%

61.3%

IHC 2+ii

(n)

20

17

19

14

19

20

16

125

Confirmed ORR (%)

40.0%

47.1%

36.8%

0.0%

5.3%

35.0%

18.8%

27.2%

BTC, biliary tract cancer; CI, confidence interval; DCR, disease control rate; DoR, duration of response; IHC, immunohistochemistry; NE, not estimable; NR, not reached; ORR, objective response rate iResponses in extramammary Paget disease, head and neck cancer, oropharyngeal neoplasm, and salivary gland cancer. iiIHC based on central HER2 testing; 67 patients had IHC 1+ (n=25), IHC 0 (n=30) or unknown IHC status (n=12) by central testing iii Confirmed complete response, confirmed partial response or stable disease.

The safety profile of Enhertu was consistent with previous clinical trials, with no new safety concerns identified. The most common Grade 3 or higher treatment-related treatment-emergent adverse events (TEAEs) were neutropenia (19.1%), anaemia (8.6%), fatigue (6.0%) and thrombocytopenia (5.2%).

In DESTINY-PanTumor02, 20 patients (7.5%) experienced interstitial lung disease (ILD) or pneumonitis related to treatment with Enhertu as determined by an independent adjudication committee. The majority (6.7%) were low Grade (Grade 1 or 2) with one (0.4%) Grade 3 event, no Grade 4 events and one (0.4%) Grade 5 event observed.

DESTINY-CRC02 primary results support 5.4mg/kg as optimal dose of Enhertu in patients with HER2-positive metastatic colorectal cancer

Primary results from the DESTINY-CRC02 Phase II trial, which evaluated Enhertu at the 5.4mg/kg and 6.4mg/kg doses in patients with previously treated locally advanced, unresectable or metastatic HER2-positive (IHC 3+ or IHC 2+/in-situ hybridisation [ISH]+) colorectal cancer of BRAF wild-type, RAS wild-type or RAS mutant tumour types, were also presented at ASCO (Free ASCO Whitepaper).

In the primary endpoint analysis, a confirmed ORR of 37.8% (95% CI 27.3-49.2) and 27.5% (95% CI 14.6-43.9) was seen in patients in the 5.4mg/kg and 6.4mg/kg arms respectively, as assessed by blinded independent central review (BICR). All responses (n=42) were partial, with 40 (48.8%) patients in the 5.4mg/kg arm and 23 (57.5%) patients in the 6.4mg/kg arm achieving stable disease. Greater efficacy (46.9% ORR (95% CI 34.3-59.8)) was observed in patients with the highest levels of HER2 expression (IHC 3+) compared to those with IHC 2+/ISH+ HER2 status in the 5.4mg/kg treatment arm (5.6% ORR (95% CI 0.1-27.3)). Anti-tumour efficacy was observed regardless of RAS mutation status (39.7% with RAS mutations; 28.6% without RAS mutations) and in those with prior HER2-directed therapy (41.2%) in the 5.4mg/kg arm.

Enhertu also demonstrated a median DoR of 5.5 months in both the 5.4mg/kg (95% CI 4.2-8.1) and 6.4mg/kg (95% CI 3.7-NE) arms with a median duration of follow-up of 8.9 months and 10.3 months in the two arms respectively. Median progression-free survival (PFS) was 5.8 months (95% CI 4.6-7.0) in the 5.4mg/kg arm and 5.5 months (95% CI 4.2-7.0) in the 6.4mg/kg arm. Median overall survival (OS) was 13.4 months (95% CI 12.5-16.8) in the 5.4mg/kg arm and not reached (95% CI 9.9-NE) in the 6.4mg/kg arm.

The safety profile observed in DESTINY-CRC02 at the 5.4mg/kg and 6.4mg/kg dose levels was consistent with other clinical trials of Enhertu, with no new safety signals identified at either dose. A more favourable benefit-risk profile was observed in patients treated with Enhertu 5.4mg/kg, resulting in its selection as the recommended dose. Grade 3 or higher treatment related TEAEs were numerically higher with Enhertu 6.4mg/kg versus 5.4mg/kg. Grade 3 or higher treatment related TEAEs occurred in 41.0% and 48.7% of 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 (16.9% (5.4mg/kg), 28.2% (6.4mg/kg)), anaemia (9.6% (5.4mg/kg), 23.1% (6.4mg/kg)) and thrombocytopenia (6.0% (5.4mg/kg); 12.8% (6.4mg/kg)). There were 12 cases (8.4% in the 5.4mg/kg arm and 12.8% in the 6.4mg/kg arm) of treatment related ILD or pneumonitis reported, as determined by an independent adjudication committee. The majority (5.4mg/kg: 8.4%, 6.4mg/kg: 10.2%) were low Grade (Grade 1 or 2) with no Grade 3, no Grade 4 and one Grade 5 event observed (6.4mg/kg: 2.6%).

Notes

HER2 expression in solid tumours
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth.1,2 In some cancers, HER2 expression is amplified or the cells have activating mutations.1,3 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.4

While HER2-directed therapies have been used to treat breast, gastric, lung and colorectal cancers, more research is needed evaluating their potential role in treating other HER2-expressing tumour types.2,5,6

HER2 is an emerging biomarker in biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers.3 Testing is not routinely performed in these additional tumour types and as a result, available literature is limited. HER2 overexpression (IHC3+) has been observed at rates from 1% to 28% in these solid tumours.7,8 There is an unmet need for effective therapies for certain HER2-expressing solid tumours, particularly for those who have progressed on or are refractory to standard of care therapies as there are currently no approved HER2-directed therapies for these cancers.2,9

Colorectal cancer is the third most common cancer and second most common cause of cancer deaths worldwide, with more than 1.9 million patients diagnosed and more than 935,000 deaths globally in 2020.10 Approximately 25% of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs and about 50% of patients with colorectal cancer will eventually develop metastases.11 For patients with metastatic disease, approximately 2 to 3% are HER2 overexpressing.6,12

DESTINY-PanTumor02
DESTINY-PanTumor02 is a global, multicentre, multi-cohort, open-label Phase II trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) for the treatment of previously treated HER2-expressing tumours, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer and other tumours.

The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DoR, DCR, PFS, OS, safety, tolerability and pharmacokinetics.

DESTINY-PanTumor02 has enrolled 267 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-CRC02
DESTINY-CRC02 is a global, randomised, two arm, parallel, multicentre Phase II trial evaluating the efficacy and safety of two doses (5.4mg/kg or 6.4mg/kg) of Enhertu in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumour types previously treated with standard therapy.

The trial was conducted in two stages. In the first stage, patients (n=80) were randomised 1:1 to receive either 5.4mg/kg or 6.4mg/kg of Enhertu. In the second stage, additional patients (n=42) were enrolled in the 5.4mg/kg arm.

The primary endpoint is confirmed ORR as assessed by BICR. Secondary endpoints include DoR, DCR, investigator-assessed confirmed ORR, clinical benefit ratio, PFS, OS and safety.

DESTINY-CRC02 enrolled 122 patients at multiple sites in 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 50 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 more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridisation [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 (5.4mg/kg) is approved in Israel and under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumours have activating HER2 (ERBB2) mutations, as detected by an FDA-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 (6.4mg/kg) is approved in more than 30 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 and/or DESTINY-Gastric02 trial.

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

On June 5, 2023 Astrazeneca reported Updated results from the TROPION-Lung02 Phase Ib trial showed that, with additional enrolment and follow-up from the initial presentation, datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum-based chemotherapy demonstrated promising clinical activity and no new safety signals in both previously untreated or pretreated patients with advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs) (Press release, AstraZeneca, JUN 5, 2023, View Source [SID1234632485]).

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Results will be presented on 6 June in an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (#9004).

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

More than one million people are diagnosed with advanced stage NSCLC each year.1,2 While 1st-line treatment with immune checkpoint inhibitors with or without chemotherapy has improved outcomes for patients with NSCLC without AGAs, like EGFR or ALK, most patients eventually experience disease progression.3-5 TROP2 is a protein expressed in more than 90% of NSCLC tumours; there are currently no TROP2-directed ADCs approved for the treatment of lung cancer.6-8

Across previously untreated and pretreated patients, an objective response rate (ORR) of 38% was observed (95% confidence interval [CI], 26-51) in patients receiving doublet datopotamab deruxtecan plus pembrolizumab (Merck & Co., Inc., Rahway, NJ, USA), an anti-PD-1 therapy. In patients receiving triplet datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy, an ORR of 49% was observed (95% CI, 37-61). Disease control rates (DCR) of 84% and 87% were observed in the doublet and triplet cohorts, respectively. Median duration of response (DoR) was not reached across cohorts. Although immature, median progression-free survival (PFS) was 8.3 months (95% CI, 6.8-11.8) in the doublet cohort and 7.8 months (95% CI, 5.6-11.1) in the triplet cohort. Response rates were highest in previously untreated patients with ORRs of 50% (95% CI, 32-68) and 57% (95% CI, 42-70) observed in the doublet and triplet cohorts, respectively, with a consistent DCR of 91% observed across cohorts.

Yasushi Goto, MD, Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan, and investigator in the trial, said: "Nearly all patients with advanced non-small cell lung cancer experience disease progression following initial therapy, underscoring the need for novel therapeutic approaches across treatment lines. The updated results from TROPION-Lung02 signal the potential for datopotamab deruxtecan combinations to improve outcomes for patients with non-small cell lung cancer and are a promising development in the pursuit of a new standard treatment option beyond immunotherapy."

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: "With more patients and nearly a year of additional follow-up, the updated TROPION-Lung02 results show that datopotamab deruxtecan continues to elicit promising and durable responses in a diverse subset of patients with non-small cell lung cancer. These early data give us confidence in the ongoing Phase III development programme evaluating datopotamab deruxtecan combinations as potential first-line treatment options for patients with advanced lung cancer across tumour histologies and PD-L1 expression levels."

Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo said: "We continue to be encouraged by the findings from TROPION-Lung02, the first trial to evaluate the combination of a TROP2-directed antibody-drug conjugate and an immune checkpoint inhibitor with or without platinum chemotherapy in patients with advanced non-small cell lung cancer. These data, alongside previous results for datopotamab deruxtecan combined with an immune checkpoint inhibitor, reinforce the potential of these combinations to improve outcomes for patients with different advanced cancers."

The safety profiles of datopotamab deruxtecan-based combinations were consistent with previous data with no new safety signals observed. Grade 3 or greater treatment-related adverse events (TRAEs) occurred in 31% of patients receiving doublet therapy and 58% of patients receiving triplet therapy. The most frequent adverse events of any Grade in the doublet and triplet cohorts, respectively, were stomatitis (56% and 35%), nausea (41% and 47%), anaemia (21% and 48%) and fatigue (31% and 37%). Across treatment cohorts, there were 27 interstitial lung disease (ILD) or pneumonitis events adjudicated as drug-related by an independent committee. The percentage of ILD events was similar across cohorts. The majority of ILD events were low grade with 23 Grade 1 or Grade 2 and four Grade 3 events. No Grade 4 or Grade 5 ILD events or Grade 5 TRAEs were observed.

In the doublet cohort of TROPION-Lung02, 58% of patients were previously untreated and 42% were previously treated with platinum chemotherapy (38%) or immunotherapy (19%). In the triplet cohort, 75% of patients were previously untreated and 25% were previously treated with platinum chemotherapy (24%) or immunotherapy (25%). Eighty percent of patients in the doublet cohort and 73% of patients in the triplet cohort had PD-L1 tumour proportion scores of less than 50%, including 36% and 40% of patients who had PD-L1 tumour proportion scores of less than 1% in the doublet and triplet cohorts, respectively. As of the April 7, 2023 data cut-off, 36% and 46% of patients remained on the doublet and triplet therapy, respectively.

Summary of Results

Overall Population

Doublet (n=64)

Triplet (n=72)

Study Duration (range)

14.8 months (1-30.2)

12.9 months (2.6-23.4)

Efficacy Measure

Doublet (n=61)

Triplet (n=71)

ORR, %i (confirmed and pending) (95% CI)

38% (n=23) (26-51)

49% (n=35) (37-61)

CR, % (confirmed)

0% (n=0)

1% (n=1)

CR, % (pending confirmation)

0% (n=0)

0% (n=0)

PR, % (confirmed)

34% (n=21)

48% (n=34)

PR, % (pending confirmation)

3% (n=2)

0% (n=0)

SD, %

49% (n=30)

38% (n=27)

Median DoR (months) (95% CI)

NR (8.8-NR)

NR (5.8-NR)

Median PFS (months) (95% CI)

8.3 months (6.8-11.8)

7.8 months (5.6-11.1)

DCR, % ii

84% (n=51)

87% (n=62)

1st-Line Therapy

Efficacy Measure

Doublet (n=34)

Triplet (n=53)

ORR, %i (confirmed and pending) (95% CI)

50% (n=17) (32-68)

57% (n=30) (42-70)

CR, % (confirmed)

0% (n=0)

2% (n=1)

CR, % (pending confirmation)

0% (n=0)

0% (n=0)

PR, % (confirmed)

44% (n=15)

55% (n=29)

PR, % (pending confirmation)

6% (n=2)

0% (n=0)

SD, %

47% (n=16)

34% (n=18)

Median DoR (months) (95% CI)

NR (5.5-NR)

NR (5.7-NR)

DCR, %ii

91% (n=31)

91% (n=48)

CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; NR, not reached; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease iORR is CR + PR iiDCR is best overall response of confirmed CR + confirmed PR + SD

AstraZeneca and Daiichi Sankyo have three Phase III trials evaluating datopotamab deruxtecan as a potential 1st-line treatment option for patients with advanced or metastatic NSCLC without AGAs compared to the respective standard of care for the patient population of each study:

· TROPION-Lung07 is evaluating datopotamab deruxtecan plus pembrolizumab with or without chemotherapy in patients with non-squamous disease and PD-L1 expression less than 50%.

· TROPION-Lung08 is evaluating datopotamab deruxtecan plus pembrolizumab in patients with PD-L1 expression of 50% or greater.

· AVANZAR is evaluating datopotamab deruxtecan plus Imfinzi (durvalumab) and platinum chemotherapy in patients regardless of PD-L1 expression or tumour histology.

Notes
Non-small cell lung cancer
More than one million people are diagnosed with advanced stage NSCLC each year. 1,2 While targeted therapies and immune checkpoint inhibitors have improved patient outcomes, advanced NSCLC has a poor prognosis and is associated with worsening outcomes after each line of subsequent therapy.3-5

Most patients with NSCLC have tumours that do not express a known AGA (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET or MET).9-11 The current 1st-line standard of care for these patients is treatment with immune checkpoint inhibitors with or without platinum-based chemotherapy. Approximately 40-60% of tumours will not respond to this initial treatment and while these therapies may improve survival for patients whose tumours do respond, most will experience disease progression.5,7

TROP2, a transmembrane glycoprotein, is expressed in more than 90% of NSCLC tumours.6 There are currently no TROP2-directed ADCs approved for the treatment of lung cancer.7,8

TROPION-Lung02
TROPION-Lung02 is an ongoing global, open-label, six-cohort Phase Ib trial evaluating the safety and efficacy of datopotamab deruxtecan at two dose levels (4 mg/kg and 6 mg/kg) in combination with pembrolizumab (200 mg) with or without four cycles of platinum chemotherapy (carboplatin or cisplatin) in both previously untreated and pretreated patients with advanced or metastatic NSCLC without AGAs (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET, MET or other known AGAs).

The primary endpoints of TROPION-Lung02 are dose-limiting toxicities and treatment-emergent adverse events. Secondary endpoints include ORR, DoR, PFS as assessed by investigator, overall survival, pharmacokinetics and anti-drug antibodies for datopotamab deruxtecan and pembrolizumab.

TROPION-Lung02 is one of three clinical trials, alongside TROPION-Lung07 and TROPION-Lung08, in a collaboration and supply agreement between Daiichi Sankyo, AstraZeneca and a subsidiary of Merck & Co., Inc., Rahway, NJ., USA to evaluate the combination of datopotamab deruxtecan and pembrolizumab.

Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of the three lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads, an exatecan derivative, via tetrapeptide-based cleavable linkers.

A comprehensive development program called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumours, including NSCLC, triple-negative breast cancer and hormone-receptor positive, HER2-low or negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials.

On June 5, 2023 Morphogenesis, Inc. ("Morphogenesis"), a privately-held Phase 2/3 clinical-stage biotechnology company developing novel personalized cancer vaccines and tumor microenvironment modulators to overcome primary and acquired resistance to current immunotherapies, and CohBar, Inc. (NASDAQ: CWBR) ("CohBar"), reported positive initial results from an exploratory analysis of anti-tumor responses to rechallenge with an ICI following protocol directed IFx-Hu2.0 therapy among patients with advanced MCC or cSCC who exhibited primary resistance to ICIs (Press release, Morphogenesis, JUN 5, 2023, View Source [SID1234632484]).

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The abstract titled, "Phase 1b trial of IFx-Hu2.0, a novel personalized cancer vaccine, in checkpoint inhibitor resistant Merkel cell carcinoma and cutaneous squamous cell carcinoma," was presented by Andrew Brohl, MD, H. Lee Moffitt Cancer Center and Research Institute in a poster presentation as part of the Melanoma/Skin Cancers – Advanced/Metastatic Diseases session held at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, taking place June 2-6, 2023 in Chicago, IL.

"While patients with advanced Merkel cell carcinoma and cutaneous Squamous cell carcinoma exhibit high response rates to immune checkpoint inhibitor therapy, the approximately 50% of patients who fail to respond have limited treatment options. We are particularly encouraged by the results in patients with advanced Merkel cell who exhibited primary resistance to ICIs, where 4 of 5 (80%) achieved long lasting, major objective anti-tumor responses on rechallenge with an ICI within the same checkpoint axis," noted Dr. James Bianco, Chief Executive Officer of Morphogenesis. "The potential for IFx-Hu2.0 adjunctive therapy to pembrolizumab in the first line treatment of advanced MCC could overcome primary resistance, allowing higher response rates than pembrolizumab alone."

IFx-Hu2.0 is Morphogenesis’ lead personalized cancer vaccine candidate that is designed to overcome primary resistance to checkpoint inhibitors. In a Phase 1 study in advanced melanoma, biomarker analyses demonstrated robust immune priming effects of IFx administration. The ongoing Phase 1b study evaluates IFx-Hu2.0 in a two-stage study design to assess safety and to examine the effects of repeated weekly dosing up to 3 weeks on the magnitude of the ensuing systemic immune response to determine the optimal dose and schedule for the company’s planned Phase 2/3 registration directed trial.

As reported at ASCO (Free ASCO Whitepaper), following completion of protocol directed therapy, 5 patients with advanced MCC and 2 patients with cSCC who, prior to study entry, failed anti-PD(L)1 therapy were re-treated with anti-PD(L)1 monotherapy: pembrolizumab (3) or avelumab (2) in MCC and cemiplimab (2) in cSCC. Four of 5 (80%) patients with advanced MCC and 1 of 2 (50%) patients with cSCC, or 5 of 7 total (71%), experienced objective anti-tumor responses to ICI rechallenge in this setting, with duration of response ongoing in 4 patients (7+, 8+, 9+, 20+ months) and one response lasting 23 months. All 4 patients with advanced MCC with post-protocol response to anti-PD(L1) therapy had previously experienced progression to this same drug class prior to treatment on protocol.

Based on the positive preliminary results seen to-date, an additional 11 patients are planned for enrollment in the expansion stage of the Phase 1b study using the weekly x 3 dosing schedule. Additional exploratory/biomarker analyses are planned.

For more information about the company’s ongoing Phase 1b IFx-Hu2.0 study, visit Clinicaltrials.gov and reference Identifier NCT04160065.

Morphogenesis and CohBar recently announced that they have entered into a definitive merger agreement for an all-stock transaction to form a company combining expertise and resources to advance a late-stage oncology pipeline. The combined company will focus on advancing Morphogenesis’ two technologies that seek to overcome the major obstacles that limit the effectiveness of current immunotherapies in treating cancer. The combined company is expected to operate under the name "TuHURA Biosciences, Inc." and to trade on The Nasdaq Capital Market ("Nasdaq"). The transaction is expected to close in the third quarter of 2023.

About Immune Fx (IFx) Personalized Cancer Vaccines

IFx-Hu2.0 administration involves a simple injection into the patient’s tumor of a proprietary gene that encodes for an immunogenic bacterial protein which is expressed on the surface of the tumor cell. Recognizing the bacterial protein as being foreign, the patient’s immune system is activated "ingesting" the tumor cell and educating the immune system to all of the patient’s tumor’s neoantigens resulting in the production of tumor specific antibodies and cytotoxic T cells. The presence of activated T cells overcomes resistance to checkpoint inhibitors allowing checkpoint released activated T cells to seek out and destroy the tumor.

Additionally, Morphogenesis is advancing its CD22 targeted, mRNA vaccine (IFx-Hu3.0), toward IND-enabling studies in 2024 for intravenous or autologous whole cell administration for the treatment of B cell malignancies like diffuse large B-cell lymphoma (DLBCL).

On June 5, 2023 NexImmune, Inc. (Nasdaq: NEXI), a biotechnology company developing a novel approach to immunotherapy designed to orchestrate a targeted immune response by directing the function of antigen-specific T cells for liquid and solid malignancies, reported results from its Phase 1/2 clinical trial of NEXI-001 in patients with relapsed/refractory acute myeloid leukemia (AML) post-allogeneic hemopoietic stem cell transplant (allo-HSCT) (Press release, NexImmune, JUN 5, 2023, View Source [SID1234632483]). In this clinical trial to date, NEXI-001 is well tolerated with a favorable safety profile while eliciting an immune response to target antigens and a clinical effect in some patients. The data describing two patients from the dose escalation study of NEXI-001 are being presented in a poster session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2023 Annual Meeting in Chicago on Monday, June 5 at 8 AM in Hall A.

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"We are pleased that NEXI-001, our donor derived multi-antigen-specific T cell product candidate, is demonstrating evidence of dose response and tolerability in the initial Phase 1 dose escalation portion of this clinical trial," said Kristi Jones, NexImmune’s Chief Executive Officer. "We have seen a clinical response maintained for seven months, which is an additional update from the data reported in our poster. These data have established the ability of our AIM nanoparticles to expand healthy, multi-antigen-specific T cells with anti-tumor activity. The data also show these T cells persist and maintain their memory phenotype at the site of tumor. We expect to provide an additional update on Cohort 3 later this year with more details from the patients in this study, and plan to apply learnings from this trial to inform future trials for NexImmune products in cancer.

"We believe that NexImmune’s multi-antigen-specific product candidates, alone or in combination with other immunotherapies, offer the potential to benefit patients with challenging cancers such as AML, for which treatment options with meaningful benefit and tolerability has remained elusive. The safety profile of our product candidate to date also presents the potential to investigate trials in patients with lower burden disease where significant unmet need remains," added Ms. Jones.

Study Design

The goals of the NEXI-001 Phase 1 clinical trial are to evaluate the safety, tolerability, immune response, and clinical activity of the antigen-specific CD8+ NEXI-001 T cells, as well as to inform the range of patient characteristics and to determine the recommended Phase 2 dose. The dose escalation phase of the study included patients who have relapsed acute myeloid leukemia (AML) post allo-HSCT and are refractory to salvage therapy. All patients in the study, except one, relapsed after, or were refractory to, subsequent salvage therapies (one to three prior therapies). A majority of patients had three-to-four adverse risk characteristics linked to poor prognosis in addition to poor prognostic patients with extramedullary disease.

Three dose-ascending cohorts of patients were enrolled in the study, with potential doses ranging from a single dose of 50 million NEXI-001 T cells to multiple doses of up to a total of 1.2 billion NEXI-001 T cells. To date, the maximum dose evaluated has been 600 million NEXI-001 T cells.

The study includes a lymphodepletion chemotherapy (Flu / Cy 30/300) following a baseline bone marrow biopsy. To date, 11 patients have completed the dose-limiting toxicity (DLT) period and one patient is currently ongoing in the first month of protocol treatment.

"I am very encouraged by the responses and the tolerability profile observed in these difficult-to-treat refractory patients," said Dr. Monzr M. Al Malki, MD, Associate Professor of Hematology, Director of BMT and Transplant, City of Hope and an investigator for NEXI-001. "These patients are frequently fragile and lack effective and tolerable options. Responses for these patients, if any, are typically short-lived and there is an urgent need for better options. As highlighted in the ASCO (Free ASCO Whitepaper) poster, achieving and maintaining a durable clinical response in extramedullary disease is clinically meaningful and supports the potential of NEXI-001 to provide significant benefit to these patients."

Key Data Highlights

Through all dose levels to date, NEXI-001 maintains a favorable tolerability profile with no grade 3 or greater treatment related SAEs. Two patients experienced grade 2 CRS which resolved within 24 hours with tocilizumab therapy. No cases of ICANS have occurred as of May 2023.
Patients treated with NEXI-001 experienced rapid reconstitution of both CD8+ and CD4+ T-cell subtypes after lymphodepletion chemotherapy.
Clinicians observed persistence of antigen-specific T cells in both peripheral blood and bone marrow with evidence of clinical activity including tumor burden reduction, increased chimerism and improved ECOG scores.
The antigen-specific T cells maintain less-differentiated immunophenotypes, including stem-cell-like T cells (Tscm) over time in both blood and bone marrow. Additionally, a marked increase in the antigen specificity of CD8+ T cells in the bone marrow resulted with increasing dose levels.
Six of 11 patients across all dose levels experienced stable disease for some period, including a stable clinical response (MRD+) in one patient and one CR (MRD-) for up to 9 months in cohort 2 (200 million NEXI-001 T cells, administered once), which was reported in the ASCO (Free ASCO Whitepaper) poster. Data continue to support potential dose response with 600 million total cells infused during Cycle 1 being the maximum dose evaluated as of May 2023. Additional cycles or dose increases are anticipated to offer benefit in the designed expansion phase of the study.
One patient in Cohort 3 with a poor prognostic extramedullary relapse of AML manifested by pericardial and bilateral pleural effusions (cytology positive for AML blasts) resulting in symptoms of moderate to severe dyspnea was enrolled in the highest dosing cohort (200 million NEXI-001 T cells administered weekly for three weeks). After one cycle of protocol therapy the patient became asymptomatic and repeat PET/CT scans document that the effusions regressed to minimal volumes. This extramedullary clinical response has been maintained for up to 7 months and is updated from the 3 months described in the ASCO (Free ASCO Whitepaper) poster.
These data indicating both immunologic and clinical dose responses and observed durability in the patient at the higher dose support further clinical study of NEXI-001.
Poster Presentation:

Title: An Analysis of a First-In-Human Study of NEXI-001 Donor-Derived Antigen-Specific CD8+ T-Cell Treatment of Relapsed AML after Allogeneic Hematopoietic Cell Transplantation (HCT)

Abstract #: 7043 (Poster Board #173)

Session Title: Hematologic Malignancies – Leukemia, Myelodysplastic Syndromes, and Allotransplant

Authors: Monzr M. Al Malki, MD1, Juan C. Varela MD, PhD2, Sumithira Vasu, MBBS3, Dipenkumar Modi, MD4, Suzanne Afonso-Smith, PhD5, Sojung Kim, PhD5, Emily Lu, PhD5, Robert D. Knight, MD5, and Mathias Oelke, PhD5

(1)Hematology/Hematopoietic Cell Transplant, City of Hope National Medical Center, Duarte, CA, (2)Advent Health Blood and Marrow Transplant Program, Orlando, FL, (3)Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus Ohio, (4)Division of Oncology, Karmanos Cancer Center/Wayne State University, Detroit, MI, (5)NexImmune, Inc., Gaithersburg, MD

On June 5, 2023 Vycellix, Inc., a transformational cell and gene engineering company with the mission to integrate its process-enhancing tools into the development and commercialization of next-generation, donor-derived medicines, including off-the-shelf T cell and natural killer (NK) cell-based cancer therapeutics, reported that its founding Chairman & CEO, Evren Alici, M.D., Ph.D., presented pre-clinical, proof-of-concept results for the Company’s single-step approach to engineer allogeneic cells (VY-UC) at the International Society for Cell & Gene Therapy (ISCT) Annual Meeting in Paris (Press release, Vycellix, JUN 5, 2023, View Source;utm_medium=rss&utm_campaign=vycellix-presents-proof-of-concept-data-for-vy-uc-allogeneic-cell-therapy-platform-at-the-international-society-for-cell-gene-therapy-isct-annual-meeting-paris [SID1234632482]).

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In an oral presentation during "Chief Scientific Officer Showcase", titled "Generation of Universal Cellular Grafts Utilizing Signaling Deficient Membrane-Bound CD45-Engagers", Dr. Alici debuted data showing that the insertion of a novel CD45-engager (VY-UC) into virtually any cell holds the potential to displace complex and costly gene-editing systems such as CRISPR-Cas9 to engineer fully immune privileged cells that in pre-clinical in vitro and in vivo models demonstrate persistence, retention of function, and avoidance of host immune rejection.

Dr. Alici’s studies, conducted by the Cell & Gene Therapy Group, which he leads at Karolinska Institutet (KI), Stockholm, Sweden, potentially position VY-UC as a preferred efficient and cost-effective off-the-shelf cell engineering strategy by focusing on the spatial abrogation of a functional immune synapse against the graft to avoid patient rejection responses towards cellular effector grafts (the donor-derived cells), while retaining the effector graft’s function. CD45-engagers were expressed on multiple cell types, including primary T cells, CAR-T cells, primary NK cells, CAR-NK cells, hepatocytes, and hematopoietic stem cells, and in each series of cell type evaluations, functional immune synapse formation was prevented, resulting in abrogation of cellular immune response, thus, eliminating the risk of graft rejection.

The VY-UC Abstract was recently published in a supplemental version of Cytotherapy (Volume 25, Issue 6 Supplement, S13-S14, May 2023) the official journal of ISCT: View Source(23)00148-2/fulltext

Dr. Alici fielded the following question at ISCT in summarizing the potential broad-reaching impact for VY-UC to redefine the paradigm for engineering "off-the-shelf" donor-derived medicines:

Q: There are multiple gene-editing strategies that claim to solve the challenges associated with engineering donor-sourced therapies, so why is VY-UC potentially disruptive?

A: "The goal for engineering any allogeneic cell is to overcome the risk that the patient’s immune system will recognize and eliminate the donor-sourced foreign cells. Unfortunately, allogeneic cell therapy studies to date do not appear to yet match up to the outcomes achieved by autologous products, especially when measuring cell persistence and durable outcomes. With our single-step CD45-engager program, we can completely avoid using any gene-editing system to ‘knock-out’ HLA Class I and II molecules, nor do we need to ‘knock-in’ any inhibitory ligands. We do not target to kill the host alloreactive population, either. We believe that Vycellix’s VY-UC platform has the potential to transform virtually any donor cell with a simple single transgene to become ‘stealth’ by preventing functional immune synapse formation in a single direction, and thus, avoid donor cell rejection. Our studies have shown complete escape from host-mediated rejection in many types of VY-UC engineered cells, including T cells and NK cells with these effector cells retaining their fitness and cytotoxicity, thus conserving viability, functionality and persistence. We are now preparing to advance the VY-UC platform into human clinical trials for off-the-shelf NK cell therapies targeting cancers, as well as preparing to partner and license our platform for T cell applications," explained Dr. Alici.

Vycellix’s platforms were all discovered by scientists at the world-renowned Karolinska Institutet (KI) in Stockholm, Sweden. The Company is also a collaborative partner in "NextGenNK", an international Competence Center for the development of next-generation NK cell-based cancer immunotherapies based at KI and funded by Sweden’s innovations agency, Vinnova. KI is globally recognized for its Nobel Assembly, which awards the Nobel Prize in Physiology or Medicine.