Breaking Treatment Barriers: Therapy for Advanced (Metastatic) EGFR-Mutated Non-Small Cell Lung Cancer After Targeted Therapy and Chemotherapy

Sponsored content by Daiichi Sankyo and AstraZeneca

Over 200,000 people are diagnosed annually with non-small cell lung cancer (NSCLC) in the United States accounting for approximately 77% of lung cancer cases.¹ Of patients with lung cancer , it is estimated that 10 to 15% have an EGFR mutation.² Despite advances in treatment, a critical need remains for subsequent treatment options that address the complexities of disease progression that many patients with EGFR-mutated NSCLC encounter.

For patients with NSCLC with tumors that have an EGFR mutation, the established first-line treatment in the advanced setting includes EGFR-directed therapy, either alone or in combination with platinum-based chemotherapy.² Although these regimens improve outcomes, most patients experience disease progression within two years.^3,4,5,6,7 Following progression, patients may receive a second EGFR-directed therapy with or without platinum-based chemotherapy or other systemic therapy; however, effective treatment options remain limited, highlighting the need for additional approaches.^3,4,8

“For patients living with advanced lung cancer who have undergone targeted treatments and chemotherapy, managing disease progression can be difficult, given the limitations we have seen in the development of later-line treatment options,” said Dr. Hatim Husain, Professor of Medical Oncology at UC San Diego Moores Cancer Center. “Fortunately, advancements in the field are unlocking additional pathways forward, offering the opportunity of more options for patients with NSCLC who have an EGFR mutation.”

Expanding Options with TROP-2-Directed Therapy 

In recent years, antibody–drug conjugates (ADCs) have emerged as an important therapeutic modality, demonstrating clinical benefit in a variety of tumor types, including NSCLC.By chemically linking monoclonal antibodies to cytotoxic agents, ADCs are designed to selectively deliver their payload to cancer cells, aiming to reduce systemic exposure.¹⁰ Although ADCs have established utility in multiple tumor types, their application in lung cancer is still being actively explored to meet the significant unmet needs of this patient population.

One promising treatment option is DATROWAY^® (datopotamab deruxtecan-dlnk), a TROP-2-directed ADC. TROP-2 is a transmembrane glycoprotein broadly expressed in NSCLC,^11,12 often associated with tumor proliferation and poor prognosis, supporting its investigation as a therapeutic target.

DATROWAY has been granted accelerated approval by the U.S. FDA for the treatment of adult patients with locally advanced or metastatic EGFR-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

The approval was based on results from a pooled subgroup analyses of the TROPION-Lung05 phase 2 and TROPION-Lung01 phase 3 trials.TROPION-Lung05 was a global, multicenter, single-arm, open-label trial in patients with previously treated, locally advanced or metastatic NSCLC with an actionable genomic alteration, and TROPION-Lung01 was a global, multicenter, randomized, active-controlled, open-label trial in patients with previously treated, locally advanced or metastatic NSCLC with or without an actionable genomic alteration. For both trials, eligible patients with EGFR-mutated NSCLC must have previously received an EGFR-directed therapy and platinum-based chemotherapy.

In TROPION-Lung05 and TROPION-Lung01, DATROWAY demonstrated a confirmed objective response rate of 45% (95% confidence interval [CI]: 35-54) in a pooled subgroup of patients (n=114) with previously treated locally advanced or metastatic EGFR-mutated NSCLC, as assessed by blinded independent central review (BICR) per RECIST v1.1. Complete responses were seen in 4.4% of patients and partial responses were seen in 40% of patients. The median duration of response was 6.5 months (95% CI: 4.2-8.4) by BICR.

The safety of DATROWAY (6 mg/kg) was evaluated in a pooled analysis of 125 patients with locally advanced or metastatic EGFR-mutated NSCLC who received DATROWAY in the TROPION-Lung05, TROPION-Lung01 and TROPION-PanTumor01 trials. The most common (≥20%) adverse reactions, including laboratory abnormalities, were stomatitis, nausea, alopecia, fatigue, decreased hemoglobin, decreased lymphocytes, constipation, increased calcium, increased aspartate aminotransferase, decreased white blood cell count, increased lactate dehydrogenase, musculoskeletal pain, decreased appetite, increased alanine aminotransferase and rash. Serious adverse reactions occurred in 26% of patients who received DATROWAY. Serious adverse reactions in more than 1% who received DATROWAY included COVID-19, stomatitis and pneumonia. More information for healthcare providers on DATROWAY and EGFR-mutated NSCLC is available at www.DATROWAYHCP.com/NSCLC.

Please see Important Safety Information and links to complete Prescribing Information below.

“As oncologists, we continue to explore new avenues to manage potential adverse effects on therapy. Many are versed in treating toxicities such as stomatitis and mucositis. Other concerns are frequently being supported through collaboration across disciplines, such as partnering with eye care professionals to manage ocular surface toxicity,” explains Dr. Husain. “As our experience with antibody drug conjugates like datopotamab deruxtecan-dlnk increase, strategies for the multidisciplinary management of toxicity will continue to evolve.”

Growing Development and Adoption of DATROWAY

DATROWAY’s approval in EGFR-mutated NSCLC offers a different treatment option for these patients.

“The introduction of antibody drug conjugates into the lung cancer treatment landscape reflects how our understanding of targeted therapy continues to evolve. This approach expands our ability to individualize and optimize treatment for patients in a setting where choices have historically been limited. I am eager to see how the biology of the disease may change through therapy. This progress defines a new chapter in how we manage the challenge of disease progression for this patient population,” says Dr. Husain.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease/Pneumonitis

DATROWAY can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis.

Locally Advanced or Metastatic NSCLC

In the pooled safety population of 484 patients with NSCLC from TROPION-Lung01, TROPION-Lung05, and TROPION-PanTumor01, ILD/pneumonitis occurred in 7% of patients treated with DATROWAY, including 0.6% of patients with Grade 3 and 0.4% with Grade 4. There were 8 (1.7%) fatal cases. The median time to first onset for ILD was 1.4 months (range: 0.2 months to 9 months). Eleven patients (2.3%) had DATROWAY withheld and 20 patients (4.1%) permanently discontinued DATROWAY due to ILD/pneumonitis. Systemic corticosteroids were required in 79% (26/33) of patients with ILD/pneumonitis. ILD/pneumonitis resolved in 45% of patients.

Patients were excluded from clinical studies for a history of ILD/pneumonitis requiring treatment with steroids or for ongoing ILD/pneumonitis.

Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever) during treatment with DATROWAY. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), promptly initiate systemic corticosteroid treatment (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Withhold DATROWAY in patients with suspected ILD/pneumonitis and permanently discontinue DATROWAY if >Grade 2 ILD/pneumonitis is confirmed.

Ocular Adverse Reactions

DATROWAY can cause ocular adverse reactions including dry eye, keratitis, blepharitis, meibomian gland dysfunction, increased lacrimation, conjunctivitis, and blurred vision.

In patients with locally advanced or metastatic NSCLC and other solid tumors, ocular adverse reactions occurred in 38% of patients treated with DATROWAY. Forty-two patients (3.1%) experienced Grade 3 ocular adverse reactions, which included keratitis and dry eye, and four patients (0.3%) experienced a Grade 4 ocular adverse reaction of keratitis, corneal epithelium defect, corneal lesion, and conjunctival hemorrhage. The most common (≥5%) ocular adverse reactions were dry eye (18%), keratitis (16%), increased lacrimation (6%), and conjunctivitis (5%). The median time to first onset for ocular adverse reactions was 2.3 months (range: 0.03 months to 30 months) and with a median duration of 2.3 months (range: 0.03 months to 19.5 months). Of the patients who experienced ocular adverse reactions, 39% had complete resolution, and 8% 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 dosage interruption in 4.3% of patients, dosage reductions in 2.8% of patients, and permanent discontinuation of DATROWAY in 0.9% of patients.

Patients with clinically significant corneal disease were excluded from clinical studies.

Advise patients to use preservative-free lubricant eye drops at least four times daily and as needed for prophylaxis. Advise patients to avoid use of contact lenses unless directed by an eye care professional.

Refer patients to an eye care professional for an ophthalmic exam including visual acuity testing, slit lamp examination (with fluorescein staining), intraocular pressure, and fundoscopy at treatment initiation, at end of treatment, and as clinically indicated. While on treatment, conduct visual acuity testing and slit lamp examination every 3 cycles.

Promptly refer patients to an eye care professional for any new or worsening ocular adverse reactions. Monitor patients for ocular adverse reactions during treatment with DATROWAY, and if diagnosis is confirmed, withhold, reduce the dose, or permanently discontinue DATROWAY based on severity.

Stomatitis

DATROWAY can cause stomatitis, including mouth ulcers and oral mucositis.

In patients with locally advanced or metastatic NSCLC and other solid tumors, stomatitis occurred in 63% of patients treated with DATROWAY, including 8% of patients with Grade 3 events and one patient with a Grade 4 reaction. The median time to first onset of stomatitis was 0.5 months (range: 0.03 months to 19.8 months) and with a median duration of 1.1 months (range: 0.03 months to 33.2 months). Stomatitis led to dosage interruption in 5% of patients, dosage reductions in 11% of patients, and permanent discontinuation of DATROWAY in 0.4% of patients.

Advise patients to use a steroid-containing mouthwash for prophylaxis and treatment of stomatitis. Instruct the patient to hold ice chips or ice water in the mouth throughout the infusion of DATROWAY.

Monitor patients for signs and symptoms of stomatitis. If stomatitis occurs, increase the frequency of mouthwash and administer other topical treatments as clinically indicated. Based on the severity of the adverse reaction, withhold, reduce the dose, or permanently discontinue DATROWAY.

Embryo-Fetal Toxicity

Based on its mechanism of action, DATROWAY can cause embryo-fetal harm when administered to a pregnant woman because the topoisomerase inhibitor component of DATROWAY, DXd, is genotoxic and affects actively dividing cells.

Advise patients of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with DATROWAY and for 4 months after the last dose.

Adverse Reactions

Locally Advanced or Metastatic NSCLC and Other Solid Tumors

The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to DATROWAY as a single agent at 6 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity in 1365 patients in TROPION-Lung05, TROPION-Lung01, TROPION-PanTumor01, TROPION-PanTumor02, and other clinical trials. Among the 1365 patients who received DATROWAY, 48% were exposed for greater than 6 months and 22% were exposed for greater than one year. In this pooled safety population, the most common (≥20%) adverse reactions were stomatitis (63%), nausea (51%), fatigue (42%), alopecia (38%), constipation (30%), vomiting (23%), decreased appetite (22%), and rash (20%). In this pooled safety population, the most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (8%), decreased hemoglobin (3.7%), decreased sodium (3.0%), and decreased blood potassium (2.3%).

Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer

TROPION-Lung05, TROPION-Lung01, TROPION-PanTumor01

The safety of DATROWAY was evaluated in 125 patients with EGFR-mutated NSCLC who received DATROWAY 6 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity in TROPION-Lung05 and TROPION-Lung01 as well as TROPION-PanTumor01. Among these patients, the median duration of treatment was 6.1 months (range 0.7 months to 41.7 months).

The median age was 63 years (range: 36 to 81), 56% of patients were <65 years, 62% of patients were female; 66% were Asian, 26% were White, 0.8% were Black, 6% were other races; and 2.4% were of Hispanic ethnicity.

Serious adverse reactions occurred in 26% of patients who received DATROWAY. Serious adverse reactions in >1% of patients who received DATROWAY were COVID-19 (4%), stomatitis (2.4%), and pneumonia (1.6%). Fatal adverse reactions occurred in 1.6% of patients who received DATROWAY, due to death not otherwise specified.

Permanent discontinuation of DATROWAY due to an adverse reaction occurred in 8% of patients. Adverse reactions which resulted in permanent discontinuation of DATROWAY in >1% of patients included ILD/pneumonitis (2.4%) and abnormal hepatic function (1.6%).

Dosage interruptions of DATROWAY due to an adverse reaction occurred in 43% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 (13%), stomatitis (7%), fatigue (6%), pneumonia (4%), anemia (2.4%), amylase increased (2.4%), keratitis (2.4%), ILD/pneumonitis (1.6%), decreased appetite (1.6%), dyspnea (1.6%), rash (1.6%), and infusion-related reaction (1.6%).

Dose reductions of DATROWAY due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dose reduction in >1% of patients included stomatitis (14%), keratitis (1.6%), fatigue (1.6%), decreased weight (1.6%) and COVID-19 (1.6%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, were stomatitis (71%), nausea (50%), alopecia (49%), fatigue (42%), decreased hemoglobin (34%), decreased lymphocytes (32%), constipation (31%),increased calcium (31%), increased AST (28%), decreased white blood cell count (27%), increased lactate dehydrogenase (23%), musculoskeletal pain (22%), decreased appetite (20%), increased ALT (20%), and rash (20%).

Clinically relevant adverse reactions occurring in <10% of patients who received DATROWAY included dry skin, blurred vision, abdominal pain, conjunctivitis, dry mouth, ILD/pneumonitis, skin hyperpigmentation, increased lacrimation, and visual impairment.

Use in Specific Populations

• Pregnancy: Based on its mechanism of action, DATROWAY can cause embryo-fetal harm when administered to a pregnant woman because the topoisomerase inhibitor component of DATROWAY, DXd, is genotoxic and affects actively dividing cells. There are no available data on the use of DATROWAY in pregnant women to inform a drug-associated risk. Advise patients of the potential risks to a fetus.
• Lactation: There are no data regarding the presence of datopotamab deruxtecan-dlnk or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with DATROWAY and for 1 month after the last dose.
• Females and Males of Reproductive Potential: Pregnancy Testing: Verify pregnancy status of females of reproductive potential prior to initiation of DATROWAY. Contraception: Females: Advise females of reproductive potential to use effective contraception during treatment with DATROWAY and for 7 months after the last dose. Males: Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with DATROWAY and for 4 months after the last dose. Infertility: Based on findings in animal toxicity studies, DATROWAY may impair male and female reproductive function and fertility. The effects on reproductive organs in animals were irreversible.
• Pediatric Use: Safety and effectiveness of DATROWAY have not been established in pediatric patients.
• Geriatric Use: Of the 125 patients with EGFR-mutated NSCLC in TROPION-Lung05, TROPION-Lung01, TROPION-PanTumor01 treated with DATROWAY 6 mg/kg, 44% were ≥65 years of age and 10% were ≥75 years of age. No clinically meaningful differences in efficacy and safety were observed between patients ≥65 years of age versus younger patients.
• Renal Impairment: Monitor patients with renal impairment for increased adverse reactions, including respiratory reactions. A higher incidence of ILD/pneumonitis has been observed in patients with creatinine clearance (CLcr) 30 to <90 mL/min (estimated by Cockcroft Gault). No dosage adjustment is recommended in patients with CLcr 30 to <90 mL/min. The pharmacokinetics of datopotamab deruxtecan-dlnk or DXd in patients with CLcr <30 mL/min is unknown.
• Hepatic Impairment: Monitor patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN and any AST) for increased adverse reactions. Limited data are available in patients with moderate hepatic impairment.No dosage adjustment is recommended in patients with mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST). The recommended dosage of DATROWAY has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

INDICATION

DATROWAY^® (datopotamab deruxtecan-dlnk) is a Trop-2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who have received prior EGFR-directed therapy and platinum-based chemotherapy.

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

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see Prescribing Information and Medication Guide for additional Important Safety Information.

References

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