On September 9, 2024 SystImmune, Inc. (SystImmune), a clinical-stage biotechnology company, reported that three abstracts on BL-B01D1, a potentially first-in-class EGFRxHER3 bispecific antibody drug conjugate (ADC) will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 taking place on September 13–17 in Barcelona, Spain (Press release, SystImmune, SEP 9, 2024, View Source [SID1234646452]). BL-B01D1 is being jointly developed by SystImmune and Bristol Myers Squibb under an exclusive license and collaboration agreement.

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Expanded results from clinical trials of BL-B01D1 will include data from patients with advanced stages of Urothelial Carcinoma, Biliary Tract Carcinoma, and Esophageal Squamous Cell Carcinoma and having multiple cycles of prior therapies. The data to be presented at ESMO (Free ESMO Whitepaper) highlights continued progress in BL-B01D01 clinical development and builds upon the previously reported clinical data in lung and breast cancer patients at ASCO (Free ASCO Whitepaper), ESMO (Free ESMO Whitepaper) and SABCS in 2023.

"These data support our continued conviction that BL-B01D1 has a manageable safety profile and add to the body of evidence that shows encouraging signals of efficacy across a wide variety of tumors" said Jonathan Cheng, M.D., CMO of SystImmune. "This positions BL-B01D1 as a versatile therapeutic option that may address the unmet medical needs of patients with limited treatment options. We are committed to advancing this therapy through clinical trials, exploring its potential not only as a monotherapy but also in combination with other agents, to improve outcomes for cancer patients globally."

Details on the presentations at ESMO (Free ESMO Whitepaper) are below:

BL-B01D1, an EGFR x HER3 Bispecific Antibody-drug Conjugate (ADC), in Patients with Locally Advanced or Metastatic Urothelial Carcinoma (UC)
Session Title: Proffered paper session 1: GU tumours, non-prostate
Presentation Number: 19590
Speaker: Dingwei Ye (Shanghai, China)
Session Date & Time: Friday, September 13th, 2024, 2:00 PM-3:30 PM CEST

BL-B01D1, an EGFR x HER3 Bispecific Antibody-drug Conjugate (ADC), in Patients with Locally Advanced or Metastatic Biliary Tract Carcinoma (BTC)
Presentation Number: 54P
Speaker: Zhihao Lu (Beijing, China)
Onsite Poster display date: Monday, September 16th, 2024

BL-B01D1, an EGFR x HER3 Bispecific Antibody-drug Conjugate (ADC), in Patients with Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)
Presentation Number: 1426P
Speaker: Liu Chang (Beijing, China)
Onsite Poster display date: Monday, September 16th, 2024

About BL-B01D1
The company is developing BL-B01D1, a bispecific antibody-drug conjugate (ADC) that targets both EGFR and HER3. These proteins are highly expressed in most epithelial tumors. The tetravalent BL-B01D1 has two binding domains for distinct Growth Factor Receptors that drive cancer cell proliferation and survival. Inheriting the SI-B001 mechanisms of action, BL-B01D1 blocks EGFR and HER3 signals to cancer cells, reducing proliferation and survival signals. Upon antibody mediated internalization, BL-B01D1 is trafficked to cancer cell lysosomes and liberates its therapeutic payload that induces genotoxic stress activating pathways leading to cancer cell death.

On September 9, 2024 ArriVent BioPharma, Inc. (Company or ArriVent) (Nasdaq: AVBP), a clinical-stage company dedicated to accelerating the global development of innovative biopharmaceutical therapeutics, reported positive proof-of-concept randomized global Phase 1b FURTHER interim data for first-line firmonertinib monotherapy in patients with non-small cell lung cancer (NSCLC) harboring EGFR PACC mutations at a Presidential Symposium Presentation at the IASCLC 2024 annual World Conference on Lung Cancer (WCLC), in San Diego, California (Press release, ArriVent Biopharma, SEP 9, 2024, View Source [SID1234646422]). ArriVent plans to host a virtual webinar on September 9, 2024 at 4:30 pm ET.

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"These compelling dose-dependent interim data are the first to demonstrate robust systemic and CNS anti-tumor activity for firmonertinib in a PACC mutant population," said Bing Yao, Chairman and Chief Executive Officer of ArriVent. "We believe that the generally well-tolerated safety profile and response duration seen to date reinforce the therapeutic potential of firmonertinib to be an effective oral, chemotherapy-free treatment for this underserved patient population. Importantly, these data add to the clinical body of evidence supporting firmonertinib as a potentially effective option across EGFR mutation types and lines of non-small cell lung cancer therapy."

Presidential Symposium Presentation Highlights

Current standards of care have improved outcomes for classical EGFR mutations but have been less effective against uncommon EGFR mutation types including PACC and exon 20 insertion mutations which represent approximately 12% and 9% of NSCLC EGFR mutations, respectively. Firmonertinib, an oral, once-daily, highly brain-penetrant EGFR inhibitor with broad activity across EGFR mutations, was evaluated for interim clinical proof-of-concept data in first-line EGFR PACC mutant NSCLC as part of the Phase 1b FURTHER trial. Select clinical activity and safety results from FURTHER interim data analysis include:

· First clinical dataset from an EGFR inhibitor being tested in a randomized defined population of EGFR PACC mutant NSCLC

· Robust systemic and central nervous system (CNS) responses across patients observed as of June 20, 2024 (data cut):

o 81.8% at 240mg and 47.8% at 160mg overall response rate (ORR) by blinded independent central review (BICR)

o 63.6% and 34.8% confirmed ORR by BICR at 240mg and 160mg dose levels, respectively. One unconfirmed partial response pending confirmation at each of the 160mg and 240mg dose levels.

o Median duration of response had not yet been reached; 90.9% (n = 20/22) patients with confirmed responses remain on study

o 46.2% (n = 6/13) CNS confirmed ORR by modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by BICR in first-line patients with brain metastases at baseline

· Generally well-tolerated with a profile consistent with prior firmonertinib data

o Most frequent treatment-related adverse events (TRAEs) were diarrhea, rash, dry skin, stomatitis, and hepatic enzyme elevation

o No treatment discontinuation due to TRAEs was observed

· Firmonertinib showed promising dose-dependent activity in NSCLC patients across a broad range of EGFR PACC mutations in the first-line metastatic setting and includes CNS antitumor activity consistent with its high brain penetrance.

Dr. Xiuning Le, Associate Professor of Thoracic Head and Neck Medical Oncology at MD Anderson Cancer Center and the lead Principal Investigator added, "Treating lung cancer patients with EGFR uncommon mutation lung cancer, including PACC mutations and exon 20 insertion mutations, remains a clinical challenge, as we need more potent and better tolerated EGFR inhibitors. These encouraging randomized data for firmonertinib suggest rapid and robust anti-tumor activity across PACC mutations which is similar to that observed for firmonertinib in exon 20 insertion mutations. Moreover, the apparent high CNS activity points to firmonertinib as a promising potential new therapy for frontline patients with PACC mutations including those with CNS disease.

On September 9, 2024 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported data from abstracts to be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 in Barcelona, Spain, including updates from the Phase 1 portions of the ongoing ALKOVE-1 Phase 1/2 clinical trial of ALK-selective inhibitor NVL-655 and ARROS-1 Phase 1/2 clinical trial of ROS1-selective inhibitor zidesamtinib, and new preclinical data further characterizing the intracranial activity of zidesamtinib accepted for a poster session (Press release, Nuvalent, SEP 9, 2024, View Source [SID1234646453]).

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The Phase 1 data described in the abstracts will be updated in two oral presentations at ESMO (Free ESMO Whitepaper) and discussed during a live webcast and conference call with management on Saturday, September 14, 2024, at 8:30 a.m. ET/2:30 p.m. CEST, along with updates on the status of the global Phase 2 portions of both studies which are designed with registrational intent.

"Our development strategy has been anchored around our guiding hypothesis: that we could drive deep and durable responses for patients by creating precisely targeted therapies that address the limitations of currently available options. We believe the data from the fully enrolled Phase 1 portions of our ALKOVE-1 and ARROS-1 clinical trials continue to support the potential for our parallel lead programs to achieve this goal through addressing the combined challenges of treatment-emergent resistance, brain metastases, and off-target central nervous system (CNS) adverse events," said Christopher Turner, M.D., Chief Medical Officer of Nuvalent. "We are particularly encouraged by the durability of responses seen with both NVL-655 and zidesamtinib in these heavily pre-treated patient populations, which we believe has the potential to be differentiated and to translate into meaningful improvements in earlier lines of treatment."

"Complementary to our clinical updates at ESMO (Free ESMO Whitepaper), we are pleased to also share new preclinical data that characterize the intracranial activity of our ROS1-selective inhibitor zidesamtinib in comparison to FDA-approved or investigational dual TRK/ROS1 inhibitors, which we believe supports the potential for zidesamtinib to deliver more durable intracranial responses while avoiding TRK inhibition," said Henry Pelish, Ph.D., Chief Scientific Officer at Nuvalent. "These data further add to the body of evidence that we believe supports the differentiated profile of zidesamtinib for patients with ROS1-positive NSCLC."

"At the outset of these programs, we set out to design best-in-class molecules that could deliver clinically meaningful outcomes for patients with ALK- or ROS1-positive NSCLC and eventually become the front-line standard of care. Our Phase 1 updates at ESMO (Free ESMO Whitepaper) are a critical milestone towards achieving our goal, with longer follow-up demonstrating that NVL-655 and zidesamtinib can drive deep and durable responses even in heavily pre-treated patients that have exhausted all other treatment options," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "These data support the ongoing Phase 2 investigation of NVL-655 and zidesamtinib in both TKI pre-treated and TKI naïve patients, and we look forward to providing further program updates during our conference call later this week."

Updated ALKOVE-1 Phase 1 Data

Title: Phase 1/2 ALKOVE-1 study of NVL-655 in ALK-positive solid tumors
Presentation Number: 1253O
Session Category: Proffered paper session
Session Title: NSCLC metastatic
Updated Presentation Date and Time: Saturday September 14, 2024, 9:30 – 9:40 a.m. CEST
Location: Barcelona Auditorium – Hall 2
Presenter: Alexander Drilon, M.D. (Memorial Sloan Kettering Cancer Center, New York, USA)

Background: NVL-655 is a potent, brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to address key limitations of prior generation ALK TKIs (first generation (1G), second generation (2G) and third generation (3G)); it demonstrates preclinical activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations, while avoiding tropomyosin receptor kinase (TRK) inhibition, which is associated with neurologic toxicities.

Methods: The global ALKOVE-1 Phase 1 (NCT05384626) enrolled patients with pretreated advanced ALK-positive solid tumors. Key objectives were selection of a recommended Phase 2 dose (RP2D), safety, and efficacy (RECIST 1.1, investigator assessment).

Results: As of the data cut-off date of March 23, 2024, 133 patients (131 NSCLC, 2 other) received NVL-655 (15-200 mg orally once daily (QD)) in Phase 1. Patients were heavily pre-treated with a median of 3 (range: 1-8) prior anticancer therapies and included:

patients treated with a 2G ALK TKI (alectinib, brigatinib, ceritinib) or the 3G ALK TKI lorlatinib (100%);
patients who had received ≥1 2G ALK TKI and the 3G ALK TKI lorlatinib (79%);
patients who had received ≥3 prior ALK TKIs (46%);
patients who had also received prior chemotherapy (56%); and,
patients with a history of treated/untreated CNS metastases (56%).
A maximum tolerated dose was not reached. 150 mg QD was selected as the RP2D, providing favorable safety, activity and exposure exceeding targeted efficacy thresholds for ALK resistance mutations. The most common treatment-related adverse events (TRAEs) were ALT increase (33%), AST increase (29%), constipation (15%), nausea (12%) and dysgeusia (11%); 2% discontinued due to TRAEs.

ALK+ NSCLC response-
evaluable (± chemo)

ORR at all
doses, % (n/n)

Median DOR,
months (m),

(95% CI)

% DOR > 6 m

(95% CI)

ORR at

150 mg, % (n/n)

All

38% (39/103)

9.2 (6.9, NE)

79 %(56, 91)

39% (15/38) *

≥3 prior ALK TKI inc. 2G and lorlatinib

37% (16/43)

7.7 (5.6, NE)

79 %(37, 95)

38% (6/16)

lorlatinib-naïve (≥1 2G ± 1G)

53% (9/17)

NR (3.5, NE)

83 %(27, 97)

57% (4/7)

ALK mutation

55% (30/55)

14.4 (6.9, NE)

86 %(63, 95)

57% (12/21)

G1202R

76% (22/29)

14.4 (6.9, NE)

88 %(60, 97)

83% (10/12)

prior lorlatinib

49% (23/47)

14.4 (6.9, NE)

83 %(56, 94)

50% (8/16)

compound (≥2) mut.

58% (15/26)

14.4 (5.1, NE)

80 %(50, 93)

78% (7/9)

lorlatinib-naïve (≥1 2G ± 1G)

88% (7/8)

NR (NE, NE)

100 %(100, 100)

80% (4/5)

NE, not estimable; NR, not reached

*13/15 responses ongoing (DOR range 1.1 – 9.0 m)

CNS activity, including complete resolution of CNS metastases in lorlatinib-experienced patients, was observed.

Conclusions: NVL-655 demonstrated encouraging efficacy and durability in heavily pretreated ALK-positive NSCLC patients, including patients who exhausted available therapies (including lorlatinib), with ALK single and compound resistance mutations, and with CNS metastases. Safety was favorable, consistent with the ALK-selective, TRK-sparing design. Phase 2 enrollment is ongoing with registrational intent for previously treated patients.

Updated ARROS-1 Phase 1 Data

Title: Phase 1/2 ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumors
Presentation Number: 1256MO
Session Category: Mini oral session
Session Title: NSCLC metastatic
Updated Presentation Date and Time: Saturday September 14, 2024, 10:25 – 10:30 a.m. CEST
Location: Santander Auditorium – Hall 5
Presenter: Benjamin Besse, M.D., Ph.D. (Institut Gustav Roussy, Villejuif, France)

Background: Zidesamtinib is a brain-penetrant, TRK-sparing, highly selective ROS1 TKI with activity against diverse ROS1 fusions and resistance mutations including G2032R.

Methods: The global ARROS-1 Phase 1 (NCT05118789) enrolled patients with heavily pretreated advanced/metastatic ROS1-positive solid tumors. Key objectives were selection of the RP2D and evaluation of safety and efficacy (RECIST 1.1, investigator assessment).

Results: As of the data cut-off date of March 12, 2024, 104 patients (99 NSCLC, 5 other) received zidesamtinib (25-150 mg orally QD) in Phase 1. Patients were heavily pre-treated with a median of 3 (range: 1-11) prior anticancer therapies including any ROS1 TKI (99%), and included:

the most heavily pre-treated of patients, receiving two or more prior ROS1 TKIs (69%) and one or more prior lines of chemotherapy (66%);
patients previously treated with lorlatinib (55%), repotrectinib (repo; 21%), or either (67%); and,
patients with a history of treated/untreated CNS metastases (53%).
100 mg QD was selected as the RP2D with no observed dose relationships for safety or efficacy. No dose-limiting toxicity or discontinuation due to TRAE occurred. TRAE led to dose reduction in 5.8%. Most common TRAEs were peripheral edema (18%) and transaminase increase (12%); TRAEs were grade ≥3 in 7.7%.

73 patients with ROS1-positive NSCLC were response-evaluable:

# Prior ROS1 TKIs ±
Chemo

ORR

Median DOR,
months (m)

(95% CI)

% DOR

> 6m

(95% CI)

% DOR

> 12m

(95% CI)

Any prior ROS1 TKI (range: 1-4)

38% (28/73*)

NR (10.2, NE)

85 %(64, 94)

69 %(45, 84)

Repo-naïve

45% (25/55*)

NR (10.2, NE)

91 %(69, 98)

74 %(48, 89)

≥2

36% (19/53*)

15.8 (6, NE)

79 %(53, 92)

62 %(35, 80)

Repo-naïve

42% (16/38*)

NR (6.4, NE)

88 %(59, 97)

68 %(38, 85)

1 (crizotinib)

64% (7/11)

NR (NE, NE)

All ongoing (range, 1.8+ – 22.8+m)

NE, not estimable; NR, not reached.

*2 complete responses (CRs), ongoing with DOR 16.6+ and 23.5+m

Median follow-up for response evaluable patients 9.4m (range, 0.8 – 25.8m)

In patients with known ROS1 G2032R, ORR was 65% (11/17) with a median duration of response (mDOR) of 15.8m (6, NE) among repo-naïve patients and ORR was 38% (3/8) among repo-pretreated patients. In patients with measurable intracranial (IC) metastases and ≥2 prior ROS1 TKIs (all with prior lorlatinib and/or repo), IC-ORR was 57% (4/7), and IC-DOR range was 1.9+ – 17.3+m with no IC progression.

Conclusions: Zidesamtinib demonstrated encouraging efficacy and durability in patients with pretreated ROS1-positive NSCLC, including those who had exhausted available therapies, with ROS1 resistance mutations including G2032R, and/or with CNS metastases. Safety was favorable and consistent with the highly ROS1-selective and TRK-sparing design. Phase 2 enrollment is ongoing with registrational intent in patients with TKI-naïve and pre-treated ROS1-positive NSCLC.

Preclinical Intracranial Activity of Zidesamtinib

Title: Profiling of Zidesamtinib and Other ROS1 Inhibitors in an Intracranial CD74-ROS1 G2032R Preclinical Model

Presentation Number: 8P
Abstract Number: 4811

Onsite Poster Display Date: Sunday September 15, 2024
Presenter: Anupong Tangpeerachaikul (Nuvalent, Inc., Cambridge, Massachusetts, United States)

Introduction. TKIs crizotinib, entrectinib, and repotrectinib (US only) are approved for the treatment of ROS1-positive non-small cell lung cancer. Depth and durability of responses can be limited by the ROS1 G2032R resistance mutation and brain metastases, identified in ~40% and ~50% of patients, respectively, after disease progression on crizotinib. ROS1-selective TKI zidesamtinib and dual-TRK/ROS1 TKIs repotrectinib and taletrectinib have reported clinical activity against ROS1 G2032R and intracranial activity, with different adverse event profiles. In this study, we compared these three TKIs in a preclinical ROS1 G2032R brain tumor model.

Methods. Ba/F3 CD74-ROS1 G2032R luciferase cells were implanted in the brain of Balb/c nude mice. Mice were orally treated with TKIs for 25 days QD or twice daily (BID). Brain tumors were monitored 1 – 2 times per week by bioluminescence imaging (BLI). At the endpoint, plasma and brain samples were collected for pharmacokinetics analyses.

Results. Zidesamtinib (3 mg/kg BID) suppressed CD74-ROS1 G2032R brain tumors to <5% of initial BLI signal through day 25. Brain tumors were suppressed by repotrectinib (15 or 75 mg/kg BID) and taletrectinib (100 mg/kg QD) up to day 8 but regrew and eventually exceeded the initial BLI signal by 300 – 3,000%. Switching from repotrectinib (15 mg/kg BID) to zidesamtinib (3 mg/kg BID) on day 8 kept brain tumors to <15% of initial BLI signal. In this study, all TKIs achieved plasma exposures near or above their reported clinical plasma exposures. Zidesamtinib brain exposure exceeded its in vitro ROS1 G2032R IC50 but not TRKB IC50; by contrast, repotrectinib brain exposure exceeded its TRKB IC50 but not ROS1 G2032R IC50.

Conclusion. In this preclinical model, zidesamtinib demonstrated more durable intracranial activity than repotrectinib and taletrectinib at clinically relevant plasma concentrations. Switching treatment from repotrectinib to zidesamtinib resulted in improved preclinical intracranial activity. Preclinical activity against ROS1 G2032R, including in the brain, together with a TRK-sparing design supports zidesamtinib as a potential best-in-class ROS1-selective therapy.

Conference Call Information

Following oral presentations at the ESMO (Free ESMO Whitepaper) Congress 2024 in Barcelona, Spain, management will host a live webcast and conference call on Saturday, September 14, 2024 at 8:30 a.m. ET/2:30 p.m. CEST.

To access the call, register online here for the live webcast or dial +1 (800) 836-8184 (domestic) or +1 (646) 357-8785 (international) at least 10 minutes prior to the start time and ask to be joined to the Nuvalent call. Accompanying slides and a live video webcast will be available in the Investors section of the Nuvalent website at https://investors.nuvalent.com/events. A replay and accompanying slides will be archived on the Nuvalent website for 30 days.

About NVL-655 and the ALKOVE-1 Phase 1/2 Clinical Trial

NVL-655 is a novel brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations such as G1202R. In addition, NVL-655 is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. NVL-655 has received breakthrough therapy designation for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC.

NVL-655 is currently being evaluated in the Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, a first-in-human study of NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors (NCT05384626). The completed Phase 1 portion enrolled ALK-positive NSCLC patients who previously received at least one ALK TKI and patients with other ALK-positive solid tumors who had been previously treated with at least one prior systemic anticancer therapy. The primary objectives were to determine the recommended Phase 2 dose (RP2D) and if applicable, the maximum tolerated dose (MTD) of NVL-655 in patients with ALK-positive solid tumors. Additional objectives included characterization of the overall safety, tolerability, and pharmacokinetic profile, and evaluation of the preliminary antitumor activity of NVL-655. The ongoing global, single arm, open label Phase 2 portion is designed with registrational intent for TKI pre-treated patients with ALK-positive NSCLC and to enable preliminary investigation for patients with ALK-positive NSCLC who are TKI naïve.

About Zidesamtinib and the ARROS-1 Phase 1/2 Clinical Trial

Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC.

Zidesamtinib is currently being investigated in the ARROS-1 trial (NCT05118789), a first-in-human Phase 1/2 clinical trial for patients with advanced ROS1-positive NSCLC and other solid tumors. The completed Phase 1 portion enrolled ROS1-positive NSCLC patients who previously received at least one ROS1 TKI, or patients with other ROS1-positive solid tumors who had been previously treated. The Phase 1 portion of the trial was designed to evaluate the overall safety and tolerability of NVL-520, with additional objectives including determination of the recommended Phase 2 dose (RP2D), characterization of the pharmacokinetic profile, and evaluation of preliminary anti-tumor activity. The ongoing global, single arm, open label Phase 2 portion is designed with registrational intent for TKI naïve and TKI pre-treated patients with ROS1-positive NSCLC.

On September 8, 2024 r Astrazeneca reported results from an exploratory analysis of the TROPION-Lung01 Phase III trial showed TROP2 as measured by it’s proprietary computational pathology platform, quantitative continuous scoring (QCS), was predictive of clinical outcomes in patients with advanced or metastatic non-small cell lung cancer (NSCLC) who were treated with datopotamab deruxtecan (Dato-DXd) (Press release, AstraZeneca, SEP 8, 2024, View Source [SID1234646406]). In patients with TROP2-QCS biomarker positive tumours, datopotamab deruxtecan demonstrated a meaningfully greater magnitude of efficacy versus docetaxel than in the overall trial population.

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These results will be featured in a Presidential Symposium (PL02.11) at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer.

TROP2 is a protein broadly expressed in NSCLC on the surface of and inside tumour cells.1,2 When assessed using conventional immunohistochemistry (IHC)-based pathology, TROP2 expression has not been predictive of patient responses to TROP2-directed antibody drug conjugates (ADC).3,4 QCS is a fully supervised computational pathology platform, developed by AstraZeneca, that analyses digitised images of patient tissue samples and precisely quantifies targets, like TROP2, on and inside a tumour cell.

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd ADC discovered by Daiichi Sankyo and being jointly developed by AstraZeneca and Daiichi Sankyo.

In this analysis, QCS was used to analyse tissue samples collected from patients in TROPION-Lung01. This produced a normalised membrane ratio for each tumour cell in each sample. Patients’ tumours were considered TROP2-QCS biomarker positive if the majority (≥75%) of tumour cells exhibited a ratio below a predetermined value (≤0.56), indicating a greater proportion of TROP2 in the cytoplasm.

The analysis showed a greater proportion of patients with nonsquamous NSCLC were considered TROP2-QCS biomarker positive than those with squamous NSCLC (66% versus 44%, respectively). The threshold for biomarker positivity was optimised for progression-free survival (PFS) in the subgroup of patients with nonsquamous NSCLC without actionable genomic alterations because it represents a population with significant unmet medical need and without actionable biomarkers.

In patients with TROP2-QCS biomarker positive tumours (60% of the biomarker evaluable population including patients with nonsquamous and squamous NSCLC), datopotamab deruxtecan reduced the risk of disease progression or death by 43% versus docetaxel (median PFS of 6.9 versus 4.1 months; hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41-0.79).

By comparison, in the primary analysis of the overall trial population, datopotamab deruxtecan reduced the risk of disease progression or death by 25% versus docetaxel (PFS of 4.4 versus 3.7 months; HR 0.75; 95% CI 0.62-0.91; p=0.004) as presented at the 2023 European Society for Medical Oncology Congress.5

In the subgroup of patients with nonsquamous NSCLC without actionable genomic alterations and with TROP2-QCS biomarker positive tumours, datopotamab deruxtecan reduced the risk of disease progression or death by 48% (PFS of 7.2 versus 4.1 months; HR 0.52; 95% CI 0.35-0.78).

Marina Garassino, MD, The University of Chicago, Professor of Medicine and investigator in the trial, said: "TROP2 is broadly expressed on solid tumour cells, including non-small cell lung cancer, but it has yet to be established as a predictive biomarker for any TROP2-directed antibody drug conjugate. We have shown with this analysis that the more precise quantitative measurement of TROP2 on and inside tumour cells, enabled by AstraZeneca’s computational pathology platform, can identify which patients with non-small cell lung cancer are most likely to benefit from treatment with datopotamab deruxtecan."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "This analysis demonstrates the power of our computational pathology platform to discover new predictive biomarkers and substantially improve patient selection for datopotamab deruxtecan. It also has great potential to help more precisely select patients across our broader antibody drug conjugate portfolio. ​We are excited to extend our collaboration with Roche Tissue Diagnostics with the aim of validating this exploratory approach for TROP2, developing the companion diagnostic and bringing it to the clinic as quickly as possible."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "The results from the QCS analysis support the potential of TROP2, as measured by quantitative continuous scoring, as a predictive biomarker for datopotamab deruxtecan and begin to answer the question of why certain patients with non-small cell lung cancer respond better to treatment. These insights are critical to advancing our understanding of how we can more precisely identify patients with non-small cell lung cancer who may benefit from treatment with our TROP2-directed antibody drug conjugate."

In the biomarker evaluable population, no new safety concerns were identified and rates of Grade 3 or higher treatment-related adverse events (TRAE) were similar regardless of TROP2 status. In patients with TROP2-QCS biomarker positive tumours, Grade 3 or higher TRAEs occurred in 30% and 46% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. The most common Grade 3 or higher TRAEs were stomatitis (7%, 3%) and ocular surface events (3%, 0%). Grade 3 or higher adjudicated drug-related interstitial lung disease events occurred in 3% and 1% of patients in the datopotamab deruxtecan and docetaxel arms, respectively.

AstraZeneca and Roche Tissue Diagnostics collaborate to co-develop and commercialise the TROP2-QCS biomarker companion diagnostic

AstraZeneca and Roche Tissue Diagnostics are extending their existing collaboration to co-develop a novel companion diagnostic incorporating AstraZeneca’s proprietary computational pathology platform, QCS, which will be deployed within Roche’s navify Digital Pathology image management system.

Jill German, Head, Roche Tissue Diagnostics, said: "Our collaboration with AstraZeneca continues to push the boundaries of traditional cancer diagnostics. By developing an innovative Al tool that goes beyond human capabilities, the solution will be able to help determine which cancer patients are most likely to benefit from targeted therapies, potentially improving patient care."

Under this expanded collaboration, Roche Tissue Diagnostics and AstraZeneca will co-develop and commercialise a novel companion diagnostic in Roche’s navify Digital Pathology platform, based on the QCS computational pathology platform, to aid pathologists in interpreting an investigational VENTANA TROP2 assay.

As the leading provider of pathology lab solutions, Roche Tissue Diagnostics is delivering an end-to-end digital pathology workflow from tissue staining to producing high-quality digital images that can be reliably assessed using automated clinical image analysis algorithms.

Notes

Advanced non-small cell lung cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.6 NSCLC is the most common type of lung cancer, accounting for about 80% of cases.7 Approximately 75% and 25% of NSCLC tumours are of nonsquamous or squamous histology, respectively.8 While immunotherapy and targeted therapies have improved outcomes in the 1st-line metastatic setting, most patients eventually experience disease progression and receive chemotherapy.9-11 For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects.9-11

TROP2 is a protein broadly expressed in the majority of NSCLC tumours.1 There is currently no TROP2-directed ADC approved for the treatment of lung cancer.12,13

TROPION-Lung01
TROPION-Lung01 is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0mg/kg) versus docetaxel (75mg/m2) in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. Patients with actionable genomic alterations were previously treated with platinum-based chemotherapy and an approved targeted therapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The dual primary endpoints of TROPION-Lung01 are PFS as assessed by blinded independent central review (BICR) and OS. Key secondary endpoints include investigator-assessed PFS, objective response rate, duration of response, time to response, disease control rate as assessed by both BICR and investigator, and safety.

TROPION-Lung01 enrolled approximately 600 patients in Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov.

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 six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programmes in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanised anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive global clinical development programme is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple-negative breast cancer and HR-positive, HER2-negative breast cancer. The programme includes seven Phase III trials in lung cancer and five Phase III trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.

On September 8, 2024 Akeso (9926. HK) reported that its internally developed PD-1/VEGF bispecific antibody ivonescimab showed clinically significant results from a Phase II study, either as a monotherapy or in combination with chemotherapy, for the perioperative treatment of resectable non-small cell lung cancer (NSCLC) at the 25th World Conference on Lung Cancer (WCLC) (Press release, Akeso Biopharma, SEP 8, 2024, View Source [SID1234646408]). This marks ivonescimab’s third oral presentation at an international conference in 2024. Professor Zhao Xiaoliang from Tianjin Medical University Cancer Hospital delivered an oral presentation at WCLC, sharing China’s advancements in innovative cancer immunotherapies with global experts.

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As of February 2024, the AK112-205 study enrolled 60 patients, with 78.3% in stage III and 90% in N+ stage (Among N+ stage patients, 70% are in N2 stage). Of these, 49 underwent surgery (all R0 resections). The study results demonstrated that perioperative ivonescimab monotherapy or combined with chemotherapy for resectable NSCLC demonstrated high rates of pathological complete response (pCR) and major pathological response (MPR) in this phase II study.

Compared with ivonescimab monotherapy, rates of MPR and pCR in ivonescimab combined with chemotherapy were numerically higher, and across tumor stage and PD-L1 expression subgroups.

Ivonescimab + chemotherapy cohort: pCR rate was 43.6%, MPR rate was 71.8%. 69.2% of patients are with residual viable tumor (RVT) ＜ 5%.
As of Aug, 2024, 55 patients in this cohort completed surgery, pCR and MPR rates were improved to 52.7% and 72.7%, respectively. For squamous NSCLC, pCR and MPR rates were 63.6% and 84.1%, respectively.
Ivonescimab monotherapy cohort: pCR rate was 30.0%, MPR rate was 60.0%.
Event-Free Survival (EFS) is not mature yet. Related studies have point to a strong correlation between pCR and EFS.

The safety profile was manageable. There were no TRAEs that led to cancelled or delayed surgery or wound healing complications.

About Ivonescimab

Ivonescimab is a novel global first-in-class PD-1/VEGF bi-specific immunotherapy drug internally developed by Akeso. Ivonescimab has been approved in China for treating EGFR mutated locally advanced or metastatic non-squamous NSCLC patients who have progressed after EGFR TKI treatment. It is the world’s first approved bispecific antibody with a "cancer immunotherapy + anti-angiogenesis" synergistic mechanism.

Akeso out-licensed Summit Therapeutics exclusive rights to ivonescimab for the development and commercialization in certain territories including United States, Canada, Europe, Japan, Latin America, Africa and the Middle East. Ivonescimab is known as AK112 within Akeso and SMT112 in the territories licensed to Summit.

Currently, a Phase III study of ivonescimab monotherapy versus pembrolizumab monotherapy as first-line treatment for PD-L1+ NSCLC has met its primary endpoint of progression-free survival (PFS) in an interim analysis, achieving a decisive positive outcome. Based on this study, a supplemental New Drug Application (sNDA) for ivonescimab monotherapy as first-line treatment for PD-L1+ NSCLC has been submitted and granted priority review. Additionally, a Phase III clinical study of ivonescimab combined with chemotherapy versus tislelizumab combined with chemotherapy as first-line treatment for squamous NSCLC is ongoing. The HARMONi study, an international multicenter Phase III clinical study led by Akeso’s partner Summit, is investigating ivonescimab combined with chemotherapy for EGFR-mutated, locally advanced or metastatic nsq-NSCLC that has progressed after third-generation EGFR-TKI therapy. Another international multicenter Phase III study is comparing ivonescimab combined with chemotherapy to pembrolizumab combined with chemotherapy as first-line treatment for squamous NSCLC.

Furthermore, 3 new Phase III clinical studies are either initiated or about to start, including ivonescimab combined with AK117 (CD47) as first-line treatment for PD-L1 positive squamous cell carcinoma of the head and neck (vs. pembrolizumab), ivonescimab combined regimen as first-line treatment for cholangiocarcinoma (vs. durvalumab combined regimen), and ivonescimab combined regimen as first-line treatment for pancreatic cancer. Overall, ivonescimab is engaged in over 25 clinical trials across 17 indications, including lung cancer, pancreatic cancer, breast cancer, hepatocellular carcinoma, and colorectal cancer, through both monotherapy and combination therapy approaches.