In the Journals

Targeted therapy shows promise for HER2-mutant NSCLC, other solid tumors

Bob Li, MD
Bob Li

The novel HER2-targeted antibody-drug conjugate fam-trastuzumab deruxtecan-nxki appeared active in a cohort of patients with various heavily pretreated HER2-expressing or HER2-mutant solid tumors, according to results of a dose-expansion study published in Cancer Discovery.

The agent demonstrated particularly promising antitumor activity among patients with HER2-mutant non-small cell lung cancer.

Researchers identified interstitial lung disease as an important — and potentially serious — adverse event that requires careful monitoring and prompt intervention, but the efficacy results support continued development of trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo) for this population, they wrote.

“We are very excited by the results of this preliminary study,” researcher Bob Li, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, said in a press release. “[This agent] shows early promise for transforming the standard of care for patients with HER2-overexpressing or HER2-mutated cancers, and we look forward to continuing this important research in future clinical trials.”

The HER2 gene can promote cancer progression when it is mutated or expressed at high levels. Researchers have observed high HER2 expression levels in many malignancies, including breast, gastric, colorectal and lung cancers.

The FDA has approved multiple HER2-targeted therapies for breast cancer and one for treatment of gastric cancer. However, no HER2-targeted therapies are approved for patients with other HER2-mutated or -overexpressing cancers.

“Conventional therapies for these other HER2-overexpressing cancers tend to have limited efficacy and considerable side effects, [so] additional treatment options are urgently needed for these patients,” Li said.

Trastuzumab deruxtecan is a novel antibody-drug conjugate with three components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab (Herceptin, Genentech); a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.

In December, the FDA granted accelerated approval to the agent for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who received at least two prior anti-HER2-based regimens in the metastatic setting.

Li and colleagues evaluated the safety and efficacy of trastuzumab deruxtecan for 60 patients who had HER2-overexpressing nonbreast or nongastric cancers and/or HER2-mutated solid tumors of any type.

The cohort included 20 patients with colorectal cancer and 18 with NSCLC. The remaining 22 patients had other malignancies; these included eight patients with salivary gland tumors; two each with esophageal cancer, endometrial cancer, biliary tract cancer or Paget’s disease; and one each with pancreatic cancer, uterine cervix carcinoma, extraskeletal myxoid chondrosarcoma or small intestine adenocarcinoma. Researchers also enrolled two patients with HER2-mutated breast cancer.

Patients received trastuzumab deruxtecan dosed at 6.4 mg/kg every 3 weeks. Treatment continued until withdrawal of patient consent, progressive disease, death or loss to follow-up.

Researchers allowed dose interruptions of up to 4 weeks.

Efficacy endpoints included objective response rate, duration of response, time to response, disease control rate, percent change in target lesion, duration of stable disease, PFS and OS.

Median follow-up for the entire cohort was 7.8 months (range, 0.1-28.6).

Seventeen patients (28.3%) achieved objective response per independent central review. Investigators reported median PFS of 7.2 months and median OS of 23.4 months.

The agent exhibited the most activity in the subgroup of patients with NSCLC. In this group, 10 of the 18 patients (55.6%) achieved partial response, including eight (72.7%) who had HER2-mutant NSCLC.

Investigators reported one partial response (5%) in the subgroup with colorectal cancer, and six responses (27.3%) — one complete and five partial — in the subgroup of patients with other cancers.

More than half (62.7%) of patients experienced grade 3 or higher treatment-emergent adverse events, and 30.5% experienced serious treatment-emergent adverse events.

The most common adverse events included anemia; decreased counts of neutrophils, white blood cells and platelets; decreased appetite; increased aspartate aminotransferase levels; febrile neutropenia; and decreased blood levels of sodium.

Five patients experienced drug-related interstitial lung disease.

Five patients experienced grade 5 adverse events, two of which appeared related to treatment. One involved drug-related interstitial lung disease. The other patient — who had a history of hepatic dysfunction and metastases at baseline — experienced events of abnormal hepatic function, disseminated intravascular coagulation and febrile neutropenia.

Forty-nine patients discontinued treatment due to disease progression, adverse events, death, patient withdrawal or other reasons.

“The safety profile of [trastuzumab deruxtecan] is consistent with the previously reported breast and gastric cancer cohorts,” Li said. “Interstitial lung disease is an important identified adverse event that may be serious — even fatal — and thus requires monitoring and prompt intervention. Further research is required to minimize and manage this risk.” – by Mark Leiser

Disclosures: Daiichi Sankyo funded this study. Li reports advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana Therapeutics, Roche/Genentech and Thermo Fisher Scientific, as well as research grants to his institution from Amgen, AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, Eli Lilly, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, MORE Health and Roche/Genentech. He also is an inventor on two pending institutional patents at Memorial Sloan Kettering Cancer Center. Please see the study for all other authors’ relevant financial disclosures.

Bob Li, MD
Bob Li

The novel HER2-targeted antibody-drug conjugate fam-trastuzumab deruxtecan-nxki appeared active in a cohort of patients with various heavily pretreated HER2-expressing or HER2-mutant solid tumors, according to results of a dose-expansion study published in Cancer Discovery.

The agent demonstrated particularly promising antitumor activity among patients with HER2-mutant non-small cell lung cancer.

Researchers identified interstitial lung disease as an important — and potentially serious — adverse event that requires careful monitoring and prompt intervention, but the efficacy results support continued development of trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo) for this population, they wrote.

“We are very excited by the results of this preliminary study,” researcher Bob Li, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, said in a press release. “[This agent] shows early promise for transforming the standard of care for patients with HER2-overexpressing or HER2-mutated cancers, and we look forward to continuing this important research in future clinical trials.”

The HER2 gene can promote cancer progression when it is mutated or expressed at high levels. Researchers have observed high HER2 expression levels in many malignancies, including breast, gastric, colorectal and lung cancers.

The FDA has approved multiple HER2-targeted therapies for breast cancer and one for treatment of gastric cancer. However, no HER2-targeted therapies are approved for patients with other HER2-mutated or -overexpressing cancers.

“Conventional therapies for these other HER2-overexpressing cancers tend to have limited efficacy and considerable side effects, [so] additional treatment options are urgently needed for these patients,” Li said.

Trastuzumab deruxtecan is a novel antibody-drug conjugate with three components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab (Herceptin, Genentech); a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.

In December, the FDA granted accelerated approval to the agent for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who received at least two prior anti-HER2-based regimens in the metastatic setting.

Li and colleagues evaluated the safety and efficacy of trastuzumab deruxtecan for 60 patients who had HER2-overexpressing nonbreast or nongastric cancers and/or HER2-mutated solid tumors of any type.

The cohort included 20 patients with colorectal cancer and 18 with NSCLC. The remaining 22 patients had other malignancies; these included eight patients with salivary gland tumors; two each with esophageal cancer, endometrial cancer, biliary tract cancer or Paget’s disease; and one each with pancreatic cancer, uterine cervix carcinoma, extraskeletal myxoid chondrosarcoma or small intestine adenocarcinoma. Researchers also enrolled two patients with HER2-mutated breast cancer.

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Patients received trastuzumab deruxtecan dosed at 6.4 mg/kg every 3 weeks. Treatment continued until withdrawal of patient consent, progressive disease, death or loss to follow-up.

Researchers allowed dose interruptions of up to 4 weeks.

Efficacy endpoints included objective response rate, duration of response, time to response, disease control rate, percent change in target lesion, duration of stable disease, PFS and OS.

Median follow-up for the entire cohort was 7.8 months (range, 0.1-28.6).

Seventeen patients (28.3%) achieved objective response per independent central review. Investigators reported median PFS of 7.2 months and median OS of 23.4 months.

The agent exhibited the most activity in the subgroup of patients with NSCLC. In this group, 10 of the 18 patients (55.6%) achieved partial response, including eight (72.7%) who had HER2-mutant NSCLC.

Investigators reported one partial response (5%) in the subgroup with colorectal cancer, and six responses (27.3%) — one complete and five partial — in the subgroup of patients with other cancers.

More than half (62.7%) of patients experienced grade 3 or higher treatment-emergent adverse events, and 30.5% experienced serious treatment-emergent adverse events.

The most common adverse events included anemia; decreased counts of neutrophils, white blood cells and platelets; decreased appetite; increased aspartate aminotransferase levels; febrile neutropenia; and decreased blood levels of sodium.

Five patients experienced drug-related interstitial lung disease.

Five patients experienced grade 5 adverse events, two of which appeared related to treatment. One involved drug-related interstitial lung disease. The other patient — who had a history of hepatic dysfunction and metastases at baseline — experienced events of abnormal hepatic function, disseminated intravascular coagulation and febrile neutropenia.

Forty-nine patients discontinued treatment due to disease progression, adverse events, death, patient withdrawal or other reasons.

“The safety profile of [trastuzumab deruxtecan] is consistent with the previously reported breast and gastric cancer cohorts,” Li said. “Interstitial lung disease is an important identified adverse event that may be serious — even fatal — and thus requires monitoring and prompt intervention. Further research is required to minimize and manage this risk.” – by Mark Leiser

Disclosures: Daiichi Sankyo funded this study. Li reports advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana Therapeutics, Roche/Genentech and Thermo Fisher Scientific, as well as research grants to his institution from Amgen, AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, Eli Lilly, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, MORE Health and Roche/Genentech. He also is an inventor on two pending institutional patents at Memorial Sloan Kettering Cancer Center. Please see the study for all other authors’ relevant financial disclosures.