On June 4, 2023 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported that Phase 1b clinical data of IBI110 (anti-LAG-3 monoclonal antibody) in the first-line treatment of gastric cancer and first-line treatment of hepatocellular carcinoma are presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ClinicalTrials.gov, NCT04085185) (Press release, Innovent Biologics, JUN 4, 2023, View Source [SID1234632432]).

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Efficacy and safety of IBI110 in combination with sintilimab in first-line advanced HER2-negative gastric cancer or gastroesophageal junction cancer: results from a Phase 1b study

Abstract #: 2576

In this Phase 1b study, the efficacy and safety of IBI110 in combination with sintilimab and chemotherapy as first-line therapy for advanced GC was evaluated.

17 untreated advanced GC patients received 200 mg IBI110 combined with sintilimab and chemotherapy (XELOX). As of the data cutoff date (Mar 22, 2023), median follow-up time was 15.8 (95% CI, 13.4 -16.6) months, 15 patients achieved PR, the ORR was 88.2%; the median DoR was 10.6 (95% CI, 2.5-14.4) months; the median PFS was 12.9 (95% CI, 3.8-15.8) months; the median OS was not mature yet.
As for safety, treatment related adverse events (TRAEs) ≥ grade 3 occurred in 11 patients, the most common TRAEs ≥ grade 3 were platelet count decreased (23.5%) and neutrophil count decreased (17.6%). 3 patients experienced irAE≥ grade 3. There were no treatment-related deaths.
Professor Nong Xu, The First Affiliated Hospital, School of Medicine, Zhejiang University, stated: "Gastric cancer is the second most common malignancy in China[1]. Most patients with GC are already locally advanced or metastatic when they were first diagnosed, and the 5-year survival rate is relatively low for those patients[2]. In recent years, immunotherapy has shown certain efficacy in advanced gastric cancer, but there is still room for improvement in clinical practice. In 2022, FDA and EMA approved the dual blocking therapy of PD-1 and LAG-3 for advanced melanoma, but no studies have reported clinical benefits of the combined therapy in patients with gastric cancer. In this study, based on the current standard treatment of sintilimab and chemotherapy, combination with IBI110 showed robust antitumor activity in untreated gastric cancer patients, and clinical benefits were observed both in tumor shrinkage and PFS, with manageable safety profile, which gave us more confidence to carry out follow-up studies."

Efficacy and safety of IBI110 (anti-LAG-3 mAb) in combination with sintilimab (anti-PD-1 mAb) in advanced hepatocellular carcinoma (HCC): results from a Phase 1b study

Abstract #: 2577

IBI110 is an IgG4κ recombinant human anti-LAG-3 monoclonal antibody developed by Innovent Biologics. The Phase 1b study aims to evaluate the efficacy and safety of IBI110 in combination with sintilimab and lenvatinib as first-line therapy for advanced HCC.

28 treatment-naïve advanced HCC patients received IBI110 (200 mg, Q3W) combined with sintilimab and lenvatinib and 27 of them received at least 1 post-baseline tumor assessment. As of the data cutoff date (Mar 22, 2023), median follow-up time was 12.2 (95% CI, 11.0 -12.6) months, the objective response rate (ORR) and disease control rate (DCR) was 29.6% and 85.2%, respectively; the median progression free survival (PFS) was 9.9 (95% CI, 5.7-NC) months; the PFS data was still immature and follow-up will be continued; the median overall survival (OS) was not reached.
In terms of safety, 16 patients experienced ≥ grade 3 TRAEs, the most common ≥ grade 3 TRAEs were hypertension (25%) and platelet count decreased (7.1%).
Professor Baocai Xing, Peking University Cancer Hospital & Institute, stated: "Immune-checkpoint inhibitors combined with anti-angiogenic agents has been approved as the first-line treatment for advanced HCC, but many patients develop disease progression within half a year of treatment, where exists an unmet clinical need[3]. In this study, IBI110 combined with sintilimab and lenvatinib showed robust antitumor activity in untreated advanced HCC patients, with a median PFS of 9.9 months, and no new safety signals were observed. This study is also the first clinical trial reporting preliminary efficacy and safety data of LAG-3 targeting therapy in first line treatment of patients with advanced HCC, suggesting the potential of further exploration in this indication."

Dr. Hui Zhou, Senior Vice President of Innovent, stated: "We are pleased to present our clinical development updates at the 2023 ASCO (Free ASCO Whitepaper) Meeting. IBI110 in combination with sintilimab demonstrated encouraging efficacy and safety data in the first-line treatment of GC and HCC. We will continue to provide updates on the clinical data for IBI110. As immunotherapy moves into the next era, we are actively advancing the development of next-generation immune checkpoint inhibitors, which we hope will benefit patients in need soon."

About IBI110

IBI110 is an IgG4κ recombinant human anti-LAG-3 monoclonal antibody independently developed by Innovent Biologics. Based on the mechanism of action and preclinical data of IBI110, it is assumed that IBI110 can inhibit the immune checkpoint signaling to achieve anti-tumor effect, which may further improve the efficacy of immunotherapy, overcome the primary drug resistance, and overcome the drug resistance after anti-PD-1 /PD-L1 monoclonal antibody treatment[4]. Based on the urgent clinical needs, Innovent has carried out clinical studies to explore the efficacy and safety of IBI110 in various advanced tumors.

On June 4, 2023 Harbour BioMed (HKEX: 02142) reported that the first patient has been dosed in its ongoing phase I trial of the first-in-class anti-B7H7 (HHLA2) antibody HBM1020 (NCT05824663/Study 1020.1) in the United States (Press release, Harbour BioMed, JUN 4, 2023, View Source [SID1234632431]). This study is evaluating the safety, tolerability, pharmacokinetics, and anti-tumor activity of HBM1020 in patients with advanced solid tumors.

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HBM1020, generated from Harbour Mice H2L2 transgenic mice platform, is the first therapeutic monoclonal antibody against B7H7/HHLA2 entering clinical development globally.

"We are delighted to announce the dosing of the first patient with our first-in-class B7H7/HHLA2 antibody HBM1020," said Dr. Jingsong Wang, Founder, Chairman and Chief Executive Officer of Harbour BioMed. "This milestone is a significant accomplishment for our team and represents a major step forward in our mission to transform patient care. We are excited about the potential of the B7H7/HHLA2 antibody to make a meaningful difference in the lives of patients suffering from advanced malignancies and we remain dedicated to advancing its clinical development globally."

About HBM1020
HBM1020 is a first-in-class fully human monoclonal antibody generated from Harbour Mice H2L2 transgenic mice platform, targeting B7H7/HHLA2.

B7H7, also known as HHLA2, is a novel immune modulatory molecule belonging to the B7 family. The B7 family is of central importance in regulating the T-cell response, making these pathways very attractive in cancer immunotherapy. Most of the validated targets in immune-oncology so far are related to B7 family, including PD-(L)1, and CTLA-4. The therapies against B7 family targets have already shifted the paradigm for cancer therapy with outstanding clinical benefits. As a newly discovered member of the B7 family, B7H7 expression is found non-overlapping with PD-L1 expression in multiple tumor types, which indicates an alternative immune evasion pathway besides PD-(L)1. In PD-L1 negative/ refractory patients, B7H7 potentially plays a critical role for tumor cells to escape immune surveillance. HBM1020 can enhance anti-tumor immunity by blocking the novel immune checkpoint target. Preclinical data demonstrated its immune activation and anti-tumor functional activities.

With its innovative biology mechanisms, HBM1020 presents a novel anti-tumor therapeutics complementary to PD-(L)1 therapeutics to patients, especially for PD-L1 negative/refractory patients.

On June 4, 2023 Astrazeneca reported that positive results from the ADAURA Phase III trial showed Tagrisso (osimertinib) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), compared to placebo in the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumour resection with curative intent (Press release, AstraZeneca, JUN 4, 2023, View Source [SID1234632430]).

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These results will be presented today in an oral presentation during the Plenary Session at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (abstract #LBA3) and have been simultaneously published in The New England Journal of Medicine.

Tagrisso reduced the risk of death by 51% compared to placebo in both the primary analysis population (Stages II-IIIA) (21% data maturity, OS hazard ratio [HR] of 0.49; 95.03% confidence interval [CI] 0.33-0.73; p=0.0004), and in the overall trial population (Stages IB-IIIA) (18% data maturity, OS HR of 0.49; 95.03% CI 0.34-0.70; p<0.0001).

In the primary analysis population, an estimated 85% of patients treated with Tagrisso were alive at five years compared to 73% on placebo. In the overall trial population, an estimated 88% of patients treated with Tagrisso were alive at five years compared to 78% on placebo. Median OS was not yet reached in either population or treatment group. Patients on placebo that recurred with metastatic disease had the opportunity to receive Tagrisso as a subsequent treatment.

Roy S. Herbst, MD, PhD, Deputy Director and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, New Haven, Connecticut, US, and principal investigator in the trial, said: "These highly anticipated overall survival results, with 88 per cent of patients alive at five years, are a momentous achievement in the treatment of early-stage EGFR-mutated lung cancer. These data underscore that adjuvant treatment with osimertinib provides patients with the best chance of long-term survival."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Tagrisso cut the risk of death by more than half in the adjuvant setting, further establishing this transformative medicine as the backbone treatment for EGFR-mutated lung cancer. These results emphasise the importance of diagnosing patients with lung cancer early, testing for EGFR mutations and treating all those with an EGFR mutation with Tagrisso."

Summary of OS results: ADAURAi

Tagrisso

Placebo

Stages II-IIIA (primary population)

(n=233)

(n=237)

Median OS (in months)

Not reached

Not reached

Hazard ratio (95.03% CI)

0.49 (0.33-0.73)

p-value

0.0004

OS rate (%) (five years) (95% CI)

85 (79-89)

73 (66-78)

Stage IB-IIIA (overall population)

(n=339)

(n=343)

Median OS (in months)

Not reached

Not reached

Hazard ratio (95.03% CI)

0.49 (0.34-0.70)

p-value

<0.0001

OS rate (%) (five years) (95% CI)

88 (83-91)

78 (73-82)

i The data cut-off date was 27 January, 2023.

At the previously reported disease-free survival analysis, all patients had completed or discontinued treatment. The safety and tolerability of Tagrisso with extended follow-up were consistent with its established profile and previous analyses with no new safety concerns reported. Adverse events at Grade 3 or higher from all causes occurred in 23% of patients in the Tagrisso arm versus 14% in the placebo arm.

Notes

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer.2 Each year there are an estimated 2.2 million people diagnosed with lung cancer globally with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.1-3 The majority of all NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.4-5 Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.6-7

For patients with resectable tumours, the majority eventually develop recurrence despite complete tumour resection and adjuvant chemotherapy.8 Further, 73% of patients with Stage IB and 56-65% of patients with Stage II disease will survive for five years.9 This decreases to 41% for patients with Stage IIIA, reflecting a high unmet medical need.9 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.10-12 These patients are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which block the cell-signalling pathways that drive the growth of tumour cells.13

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

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

Though the primary data readout was originally anticipated in 2022, data from the trial were reported early following a recommendation from an Independent Data Monitoring Committee based on its determination of overwhelming efficacy.

In May 2020, AstraZeneca announced Tagrisso demonstrated a statistically significant and clinically meaningful improvement in DFS in this setting. In September 2022, updated results demonstrated a median DFS of nearly five and a half years.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat nearly 700,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

Tagrisso is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. These include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage (IB, II and IIIA) EGFRm NSCLC.

In May, Tagrisso demonstrated clinical benefit in combination with chemotherapy in the FLAURA2 Phase III trial in advanced EGFRm NSCLC.

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

On June 4, 2023 ImmunoGen Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported detailed results from the Phase 3 confirmatory MIRASOL trial (GOG 3045/ENGOT OV-55) evaluating the safety and efficacy of ELAHERE (mirvetuximab soravtansine-gynx) compared to chemotherapy in patients with folate receptor alpha (FRα)-positive platinum-resistant ovarian cancer (PROC) (Press release, ImmunoGen, JUN 4, 2023, View Source [SID1234632421]). The results are being presented by Dr. Kathleen Moore in a late-breaking oral abstract session today at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois. These data have also been selected for the 2023 Best of ASCO (Free ASCO Whitepaper) program, which will be held this summer following the ASCO (Free ASCO Whitepaper) Annual Meeting.

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"I am thrilled to share these impressive results from the confirmatory MIRASOL trial at ASCO (Free ASCO Whitepaper), which further demonstrate the potential of ELAHERE to become the new standard of care for patients with FRα-positive PROC," said Kathleen Moore, Associate Director of Clinical Research and Director of the Oklahoma TSET/Sarah Cannon Phase I Program, Professor of the Section of Gynecologic Oncology at The University of Oklahoma and MIRASOL Principal Investigator. "As we saw in the top-line data announced last month, ELAHERE demonstrated an improvement versus chemotherapy across all efficacy endpoints and, importantly, is the first treatment to show an overall survival benefit in this patient population. The 33% reduction in the risk of death, along with the differentiated and well-characterized safety profile seen in MIRASOL, reinforce the potential of ELAHERE to serve as a transformative option for ovarian cancer patients and change how this disease is treated."

MIRASOL is a randomized Phase 3 trial of ELAHERE versus investigator’s choice (IC) of single-agent chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan). Eligibility criteria include patients with PROC whose tumors express high levels of FRα, using the Ventana FOLR1 Assay, and who have been treated with up to three prior regimens. The primary endpoint of this trial is progression-free survival (PFS) by investigator assessment. Key secondary endpoints include objective response rate (ORR) and overall survival (OS).

MIRASOL enrolled 453 patients. Patients were stratified by number of prior lines of therapy (14% had one prior line of therapy, 40% had two prior lines of therapy, and 46% had three prior lines of therapy) and by IC chemotherapy, with paclitaxel as the most commonly chosen (41%), followed by PLD (36%) and topotecan (23%). 62% of patients received prior bevacizumab; 55% received a prior PARP inhibitor. As of the data cutoff on March 6, 2023, the median follow-up time for OS was 13.1 months; 14% of patients on the ELAHERE arm remained on study drug compared to 3% on the IC chemotherapy arm.

ELAHERE demonstrated a statistically significant and clinically meaningful improvement in PFS by investigator assessment compared to IC chemotherapy, with a hazard ratio (HR) of 0.65 (95% confidence interval [CI]: 0.52, 0.81; p<0.0001), which represents a 35% reduction in the risk of tumor progression or death in the ELAHERE arm compared to the IC chemotherapy arm. The median PFS in the ELAHERE arm was 5.62 months (95% CI: 4.34, 5.95) compared to 3.98 months (95% CI: 2.86, 4.47) in the IC chemotherapy arm.
ELAHERE demonstrated a statistically significant and clinically meaningful improvement in OS compared to IC chemotherapy. With 204 OS events reported as of March 6, 2023, the median OS was 16.46 months (95% CI: 14.46, 24.57) in the ELAHERE arm, compared to 12.75 months (95% CI: 10.91, 14.36) in the IC chemotherapy arm, with a HR of 0.67 (95% CI: 0.50, 0.89; p=0.0046). This represents a 33% reduction in the risk of death in the ELAHERE arm in comparison to the IC chemotherapy arm.
ORR by investigator assessment in the ELAHERE arm was 42.3% (95% CI: 35.8%, 49.0%), including 12 complete responses (CRs), compared to 15.9% (95% CI: 11.4%, 21.4%), with no CRs, in the IC chemotherapy arm.
In addition to data on the primary and key secondary endpoints, further safety and efficacy analyses from MIRASOL will be presented:

In the bevacizumab-naïve subset (n=172), the PFS HR was 0.66, (95% CI: 0.46, 0.94; p=0.0210); in the bevacizumab-pretreated subset (n=281), the PFS HR was 0.64 (95% CI: 0.49, 0.84; p=0.0011).
In the bevacizumab-naïve subset, the OS HR was 0.51 (95% CI: 0.31, 0.86; p=0.0099); in the bevacizumab-pretreated subset, the OS HR was 0.74 (95% CI: 0.54, 1.04; p=0.0789).
PFS and ORR results by blinded independent central review (BICR) were concordant with investigator assessment.
The HR for PFS by BICR was 0.72 (95% CI: 0.56, 0.92; p=0.0082).
ORR by BICR in the ELAHERE arm was 36.1% (95% CI: 29.9, 42.7), including 16 complete responses (CRs), compared to 14.6% (95% CI: 10.3, 19.9), with 4 CRs, in the IC chemotherapy arm.
ELAHERE was well-tolerated, consistent with the known safety profile seen in the broader development program. No new safety signals were identified in MIRASOL.
Compared with IC chemotherapy, ELAHERE was associated with lower rates of grade 3 or greater treatment-emergent adverse events (TEAEs) (42% vs 54%) and serious adverse events (24% vs 33%).
Dose delays due to TEAEs occurred in 54% of patients on both arms; dose reductions due to TEAEs occurred in 34% of ELAHERE treated patients vs 24% of IC chemotherapy patients; discontinuations due to TEAEs occurred in 9% of ELAHERE treated patients vs 16% of IC chemotherapy patients.
The safety profile of ELAHERE consists of predominantly low-grade ocular and gastrointestinal TEAEs.
Detailed safety data will be presented, including rates of all grade and grade 3+ ocular, gastrointestinal, neuropathy, and hematologic TEAEs for ELAHERE vs IC chemotherapy (paclitaxel, PLD, topotecan).
"We are incredibly pleased the MIRASOL results were selected as a late-breaking presentation at ASCO (Free ASCO Whitepaper)," said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen. "As the first novel therapy to extend overall survival in platinum-resistant disease, and with consistent efficacy regardless of prior bevacizumab use, ELAHERE is a much-needed advance in the ovarian cancer treatment paradigm. We look forward to submitting the MAA and sBLA for ELAHERE in the EU and US, respectively, during the second half of the year, and to progressing the broader ELAHERE development program as we work to deliver this biomarker-directed ADC to eligible patients."

In November 2022, the US Food and Drug Administration (FDA) granted accelerated approval for ELAHERE for the treatment of adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic treatment regimens based on ORR and duration of response data from the pivotal SORAYA trial.

LATE-BREAKING ORAL PRESENTATION
Title: Phase III MIRASOL (GOG 3045/ENGOT-ov55) Study: Initial Report of Mirvetuximab Soravtansine vs. Investigator’s Choice of Chemotherapy in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers with High Folate Receptor-Alpha Expression
Presenter: Dr. Kathleen Moore, Associate Director of Clinical Research and Director of the Oklahoma TSET/Sarah Cannon Phase I Program, Professor of the Section of Gynecologic Oncology at The University of Oklahoma and MIRASOL Principal Investigator
Session: Late-Breaking Abstract Session: Presentation and Discussion of LBA5507
Date: Sunday, June 4, 2023
Time: 7:30 am to 8:05 am CT / 8:30 am to 9:05 am ET

POSTER PRESENTATIONS
ImmunoGen is also presenting two trial-in-progress posters at ASCO (Free ASCO Whitepaper).

Title: GLORIOSA: A Randomized, Open-Label, Phase 3 Study of Mirvetuximab Soravtansine with Bevacizumab vs. Bevacizumab as Maintenance in Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Presenter: Dr. David O’Malley, Professor, Director of Gynecologic Oncology at the Ohio State University and the James Cancer Center
Abstract: TPS5622
Poster Board: 312a

Title: A Phase 1b/2 Study of Pivekimab Sunirine in Combination with Venetoclax/Azacitidine or Magrolimab for Patients with CD123-Positive Acute Myeloid Leukemia
Presenter: Dr. Naval Daver, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center
Abstract: TPS7073
Poster Board: 203a

Additional information can be found at www.asco.org.

ABOUT OVARIAN CANCER
Ovarian cancer is the leading cause of death from gynecological cancers in the US. Each year, roughly 20,000 patients are diagnosed, and 13,000 patients will die. Most patients present with late-stage disease and will typically undergo surgery followed by platinum-based chemotherapy. Unfortunately, the majority of patients eventually develop platinum-resistant disease, which is difficult to treat. In this setting, standard of care single-agent chemotherapies are associated with low response rates, short durations of response, and significant toxicities.

ABOUT ELAHERE
ELAHERE (mirvetuximab soravtansine-gynx) is a first-in-class ADC comprising a folate receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, a potent tubulin inhibitor designed to kill the targeted cancer cells.

Indication and Usage
ELAHERE is indicated for the treatment of adult patients with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Select patients for therapy based on an FDA-approved test.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Important Safety Information
BOXED WARNING: OCULAR TOXICITY

ELAHERE can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis.
Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first 8 cycles, and as clinically indicated.
Administer prophylactic artificial tears and ophthalmic topical steroids.
Withhold ELAHERE for ocular toxicities until improvement and resume at the same or reduced dose.
Discontinue ELAHERE for Grade 4 ocular toxicities.
WARNINGS and PRECAUTIONS
Ocular Disorders
ELAHERE can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis.

Ocular adverse reactions occurred in 61% of patients with ovarian cancer treated with ELAHERE. Nine percent (9%) of patients experienced Grade 3 ocular adverse reactions, including visual impairment, keratopathy/keratitis (corneal disorders), dry eye, photophobia, and eye pain; and one patient (0.2%) experienced Grade 4 keratopathy. The most common (≥5%) ocular adverse reactions were visual impairment (49%), keratopathy (36%), dry eye (26%), cataract (15%), photophobia (13%), and eye pain (12%).

The median time to onset for first ocular adverse reaction was 1.2 months (range: 0.03 to 12.9). Of the patients who experienced ocular events, 49% had complete resolution and 39% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Ocular adverse reactions led to permanent discontinuation of ELAHERE in 0.6% of patients.

Premedication and use of lubricating and ophthalmic topical steroids eye drops during treatment with ELAHERE are recommended. Advise patients to avoid use of contact lenses during treatment with ELAHERE unless directed by a healthcare provider.

Refer patients to an eye care professional for an ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation, every other cycle for the first 8 cycles, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms.

Monitor for ocular toxicity and withhold, reduce, or permanently discontinue ELAHERE based on severity and persistence of ocular adverse reactions.

Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease, including pneumonitis, can occur in patients treated with ELAHERE. Pneumonitis occurred in 10% of patients treated with ELAHERE, including 0.8% with Grade 3 events, and 1 patient (0.2%) with a Grade 4 event. One patient (0.2%) died due to respiratory failure in the setting of pneumonitis and lung metastases.

Monitor patients for pulmonary signs and symptoms of pneumonitis. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.

Withhold ELAHERE for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤ Grade 1 and consider dose reduction. Permanently discontinue ELAHERE in all patients with Grade 3 or 4 pneumonitis. Patients who are asymptomatic may continue dosing of ELAHERE with close monitoring.

Peripheral Neuropathy (PN)
PN occurred in 36% of patients with ovarian cancer treated with ELAHERE across clinical trials; 2% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (19%), peripheral sensory neuropathy (9%), paraesthesia (6%), neurotoxicity (3%), hypoaesthesia (2%), peripheral motor neuropathy (1%), neuralgia (0.4%), polyneuropathy (0.2%) and oral hypoesthesia (0.2%).

Monitor patients for signs and symptoms of neuropathy. For patients experiencing new or worsening PN, withhold dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of PN.

Embryo-Fetal Toxicity
Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for 7 months after the last dose.

ADVERSE REACTIONS
Serious adverse reactions occurred in 31% of patients. The most common (≥2%) serious adverse reactions were intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Fatal adverse reactions occurred in 2% of patients, including small intestinal obstruction (1%) and pneumonitis (1%).

Permanent discontinuation of ELAHERE due to adverse reactions occurred in 11% of patients. The most common (≥2%) adverse reactions leading to permanent discontinuation were intestinal obstruction (2%) and thrombocytopenia (2%). One patient (0.9%) permanently discontinued ELAHERE due to visual impairment (unilateral decrease to BCVA < 20/200 that resolved to baseline after discontinuation).

Dosage delays of ELAHERE due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage delays in ≥3% of patients included visual impairment (15%), keratopathy (11%), neutropenia (6%), dry eye (5%), cataracts (3%) and increased gamma-glutamyltransferase (3%).

Dose reductions of ELAHERE due to an adverse reaction occurred in 20% of patients. Adverse reactions which required dose reductions in ≥3% of patients included visual impairment (9%) and keratopathy (7%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, were vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin.

DRUG INTERACTIONS
Strong CYP3A4 Inhibitors
DM4 is a CYP3A4 substrate. Concomitant use of ELAHERE with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure, which may increase the risk of ELAHERE adverse reactions. Closely monitor patients for adverse reactions with ELAHERE when used concomitantly with strong CYP3A4 inhibitors.

USE IN SPECIAL POPULATIONS
Lactation
Advise women not to breastfeed during treatment with ELAHERE and for at least 1 month after the last dose.

Pediatric Use
Safety and effectiveness of ELAHERE have not been established in pediatric patients.

Hepatic Impairment
Avoid use of ELAHERE in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN).

Please see full Prescribing Information, including Boxed Warning for ELAHERE.

On June 4, 2023 G1 Therapeutics, Inc. (Nasdaq: GTHX), a commercial-stage oncology company, reported results from 24 patients enrolled in its Phase 2, single arm mechanism of action study of trilaciclib administered as a single agent to patients with early-stage triple-negative breast cancer (TNBC) prior to receiving trilaciclib and neoadjuvant therapy (Press release, G1 Therapeutics, JUN 4, 2023, View Source [SID1234632419]). These results highlight the potential for trilaciclib to enhance long term immune surveillance by increasing T cell function and generation of certain memory T cells and demonstrate gene expression profiles that may be associated with improved clinical outcome. These data support earlier findings from this Phase 2 trial demonstrating an increase in the ratio of CD8+ T cells to regulatory T cells (Tregs); a high ratio of CD8+ T cell to Tregs is predictive of overall survival (OS) and is associated with pathologic complete response (pCR). As expected, high rates of pCR were observed in patients with PD-L1(+) tumors and in patients with inflamed tumor immune microenvironments.

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Data generated across multiple preclinical and clinical studies to date show that trilaciclib has the greatest effect on longer term endpoints including OS rather than earlier efficacy measures such as objective response rate (ORR), pCR, and progression free survival (PFS), consistent with other immunotherapies like checkpoint inhibitors. These results suggest that this is likely due to trilaciclib’s immune-mediated mechanism of action that protects the immune system from damage caused by cytotoxic therapy and enhances long-term immune surveillance by increasing the generation of certain memory T cells. This dual benefit may provide important longer-term benefits for patients by improving their ability to generate robust immune responses, particularly when treated with future subsequent therapies.

"Trilaciclib is a highly active molecule that enhances T cell activation, favorably alters the tumor microenvironment, and improves long term immune surveillance; these new immune analyses help identify potential correlates of treatment response and extend our understanding of the mechanism," said Raj Malik, M.D., Chief Medical Officer at G1 Therapeutics. "Trilaciclib drives increases in certain memory T cells which are important for longer term outcomes like overall survival, consistent with our understanding of the mechanism of action of trilaciclib."

These results are being presented today at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The poster, titled, "Neoadjuvant Single-Dose Trilaciclib Prior To Combination Chemotherapy in Patients with Early Triple-Negative Breast Cancer: Safety, Efficacy, And Immune Correlate Data from a Phase 2 Study," can be found here.

Patient Demographics

As of the data cut date of April 3, 2023, all patients (N = 24) had received a median (range) of 16 (3–16) cycles of treatment; 21 (87.5%) patients received pembrolizumab, and 21 (87.5%) patients received carboplatin, per investigator discretion. All patients completed the study; five underwent definitive surgery prior to completing planned study treatment. At diagnosis, 79% of patients had stage II tumors and 88% had ductal carcinoma; 38% of patients had PD-L1+ tumors, consistent with early TNBC.

Tumor immune microenvironment status was determined at baseline. All participants with immune-desert tumor microenvironments at baseline had PD-L1(-) tumors; an additional nine participants with immune-excluded tumor microenvironments had PD-L1(-) tumors. All participants with immune-inflamed tumor microenvironments at baseline had PD-L1(+) tumors; an additional five participants with immune-excluded tumor microenvironments had PD-L1(+) tumors. Data published by G1 and others show that trilaciclib can promote trafficking of immune cells out of the stroma and into the tumor microenvironment via chemokine release, thus leading to an inflamed tumor immune microenvironment status.

Baseline Correlates of Clinical Outcome: Pathologic Complete Response (pCR)

Tumor infiltrating lymphocytes (TIL) infiltration is associated with better outcomes with trilaciclib. In this mechanism of action trial, the pCR rate is higher (77.8%) in patients with PD-L1(+) tumors relative to that of the overall enrolled patient population. The pCR rate in the overall enrolled population (41.7%) is comparable to that of standard neoadjuvant therapy in this population of patients. As anticipated, the pCR rate was higher in patients with an immune-inflamed tumor microenvironment (75.0%) than those with immune-excluded (35.7%) or immune desert (33.3%) tumor microenvironments.

The tumor status of four enrolled patients converted from PD-L1(-) at baseline to PD-L1(+) after trilaciclib monotherapy (day 7); 50% of these patients achieved pCR during the study.

Immunomodulatory Effects of Trilaciclib

Trilaciclib was shown to enhance the number and function of CD8+ T cells in the tumor microenvironment. Seven days after monotherapy with trilaciclib, the number of CD8+ T cells and GZMB+ cells, which is a surrogate marker for T cell function, were enhanced with statistical significance in patients achieving a pCR. There was also an increase in stromal TILs within the tumor microenvironment after a single dose of trilaciclib.

RNA-sequence analysis revealed 59 genes that were differentially expressed seven days after single-dose trilaciclib in patients who achieved pCR, compared to those who did not. Furthermore, assessment of signaling pathways associated with pCR revealed significant enrichment in pathways associated with immune modulation including T cell receptor signaling and cytokine-cytokine receptor interaction that were not observed at baseline. Key genes associated with memory T cells – SELL (CD62L), IL-7R, and TCF7 – increased from baseline to Day 7, and a subset analysis based on pCR status revealed significant increases in these genes when individually assessed and as a gene signature among patients who achieved pCR.

These results help confirm the role of trilaciclib in increasing the pool of functional memory T cells that could contribute to long-term immune surveillance and efficacy, as measured by longer term endpoints like OS.

Safety Results (n=24)

Trilaciclib continues to show a strong tolerability profile. Trilaciclib in combination with anthracycline (doxorubicin)/ cyclophosphamide/paclitaxel (AC/T) ± pembrolizumab ± carboplatin in the neoadjuvant setting for early-stage TNBC has a similar safety and tolerability profile as standard neoadjuvant regimens. The most common treatment-related adverse events (TRAEs; any grade) related to any study drug were fatigue, nausea, alopecia, and neutropenia/neutrophil count decreased. There were no adverse events leading to discontinuation of trilaciclib.

Trilaciclib Phase 2 Mechanism of Action Trial Design

Tumor tissue was obtained at baseline prior to study drug administration. Patients then received a single dose of monotherapy (240 mg/m2) trilaciclib, followed by a tumor biopsy approximately one week later to assess the ability of a single dose of trilaciclib monotherapy to favorably alter the tumor microenvironment. Paired tumor biopsies were available for 22 patients. Patients then entered the treatment phase in which trilaciclib is administered on day 1 of each cycle of anthracycline/cyclophosphamide for four cycles followed by trilaciclib administered on day 1 of each weekly cycle of taxane chemotherapy for 12 cycles. Pembrolizumab and/or carboplatin was added at the discretion of the investigator. Three to five weeks after the treatment phase, patients had definitive surgery and a final tumor tissue sample was collected if the patient has residual disease. pCR was assessed at definitive surgery by a local pathologist, per the current American Joint Committee on Cancer staging system .

The primary objective was to evaluate the immune-based mechanism of action of a single dose of trilaciclib as measured by the change in the ratio of CD8+ T cells to Tregs in the tumor microenvironment. Secondary endpoints include assessment of pCR rate at the time of definitive surgery, and safety of the combination of trilaciclib with neoadjuvant regimen. Exploratory endpoints include assessment of the immune response, and identification of molecular and cellular biomarkers in tumor or blood samples that may be associated with clinical response/resistance, pharmacodynamic activity, and/or the mechanism of action of trilaciclib.