ASCO 2020: AstraZeneca and Daiichi Sankyo’s Enhertu Impresses with Benefits in Lung, Stomach and Colorectal Cancer Trials

By Ruchi Jhonsa, Ph.D.

Following the success in the breast cancer market, Daiichi Sankyo and AstraZeneca evaluated their potential blockbuster, Enhertu on 3 different cancer indications. The data presented at ASCO demonstrated the HER2 directed, antibody drug conjugate’s benefit in heavily pretreated patients who have no other treatment options.

Among several top studies presented at the ASCO virtual meeting, the mid-stage findings from DESTINY-Lung01, DESTINY-Gastric01, and DESTINY-CRC01 trials that evaluated the inhibitory effect of Enhertu on lung, stomach, and colorectal cancers respectively drew special attention. Data supports that the drug’s overall response in three indications is quite remarkable. However, patient deaths due to treatment-associated lung toxicity is a serious concern that needs to be addressed.

Enhertu (Trastuzumab-deruxtecan-T-Dxd) is a membrane-permeable antibody-drug conjugate made by joining an anti-HER2 monoclonal antibody and topoisomerase I inhibitor with a cleavable tetrapeptide-based linker. HER2 is a tyrosine kinase, which belongs to the epidermal growth factor receptor family. Amplification or overexpression of this gene has been shown to play an important role in the development and Progression of certain aggressive types of cancer. Last year, T-Dxd got the FDA’s accelerated approval for treating patients with unresectable or metastatic HER2 positive breast cancer.

DESTINY-Lung01

Non Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer that can progress due to many causative mutations, including HER2. Around 2-4% of patients with NSCLC have a HER2 mutation, which drives the spread of cancer and is associated with poor prognosis. In Phase 1 DESTINY-Lung01 trial, 8 of 11 T-Dxd treated patients harboring HER2- mutated NSCLC showed confirmed objective response rate (ORR). An ORR of 73% is so far the highest achieved for any NSCLC therapy. These exciting results paved the path for the evaluation of the drug in the Phase 2 trial.

The Phase 2 trial evaluated the efficacy of the drug in patients with non-squamous NSCLC overexpressing HER2 or containing HER2-activating mutation. Patients were treated with 6.4mg/Kg of the drug every three weeks through an IV infusion. The 42 patients enrolled in the study had previously received either platinum-based chemotherapy or anti-PD-1 or –PD-L1 treatment. The trial determined whether the drug could shrink the tumors (ORR) and prevent further growth or Progression of the disease (PFS).

Overall Response Rate (61.9%)Disease control rateMedian treatment duration Overall survival14.0 monthsComplete remissionPartial responseStable disease90.5%7.75 monthsNot reached 2.4%59.5%28.6%

All patients experienced adverse events. The majority of them experienced grade 3 events, including decreased neutrophil count and anemia. Five patients experienced drug-related interstitial lung disease. The adverse events caused dose interruption in 25 patients, dose reduction in 16 patients, and treatment discontinuation in 10 patients.

Take home message

Although the drug showed a high response rate in patients with NSCLC, it also led to severe adverse events, including lung toxicity, which needs attention. Dr. Egbert Smit, the professor of pulmonary medicine at the Netherlands Cancer Institute and the presenter of the data, said, “T-Dxd demonstrated clinical activity in this interim analysis with high ORR and durable responses in patients with HER2-mutated NSCLC. These data demonstrate the potential of T-Dxd as a new treatment option for patients with HER2 mutated NSCLC. Enrollment in this HER2-mutated cohort was expanded with an additional 50 patients to better characterize the risk-benefit ratio of T-Dxd in patients with HER2-mutated NSCLC”.

DESTINY-Gastric01

Gastric cancer usually begins in the cells lining the stomach. For several decades, a reduction in the rate of cancer affecting the stomach body is seen, but there has been a simultaneous increase in the cancers affecting the top part of the stomach, also known as gastroesophageal junction. Daiichi and AstraZeneca aimed to explore whether their conjugate drug T-Dxd can be used for treating gastric cancers, as 10% to 15% of patients with this indication are HER2 positive. In Phase, I, Destiny-Gastric01 trial, T-Dxd demonstrated an ORR of 43.2% and median PFS of 5.6 months in 44 patients with HER2-positive gastric cancer.

The current data presented at the meeting highlighted key findings from the DESTINY-Gastric Phase 2 trial that evaluated T-Dxd versus the physician’s choice of treatment. According to the presenter, Kohei Shitara, MD, Chief of Experimental Therapeutics and Gastrointestinal Oncology at the National Cancer Center Hospital East, Tokyo “Antitumor activity was noted in patients who had disease progression while they had been receiving regimens including trastuzumab.”

The trial included patients with HER2- expressing locally advanced or metastatic gastric or gastroesophageal junction cancer that had progressed after the patient had received at least two previous treatments with fluoropyrimidine and trastuzumab. A total of 187 patients were enrolled in the trial, of which 125 received T-Dxd, and 62 received chemotherapy of physician’s choice.

Results show an overall improvement in ORR, median PFS, median OS, and DCR for the T-Dxd in comparison to control. The occurrence of an adverse event with T-Dxd treatment was approximately half of that of chemotherapy, as determined by the hazard ratio (0.59). The most common side effects observed were neutropenia, anemia, leukopenia. Common across the lung cancer trial and the gastric trial was the occurrence of interstitial lung disease adverse events. In total, 101 patients died during the trial. While 50% died in the T-Dxd treatment arm, 63% died in the chemotherapy control arm.

Take home message

Dr. Shitara concluded the meeting on a high note. He said, “Patients receiving T-Dxd had a significantly higher ORR than those receiving standard treatment including 11 CRs in the T-Dxd arm as well as longer OS. Additionally, PFS and the median duration of confirmed responses were longer with T-Dxd treatment. The safety profile was consistent with previous studies. Based on these findings, T-Dxd can be an effective treatment option with advanced, HER2 positive gastric or GEJ adenocarcinoma who have progressed after trastuzumab-containing treatment. Recently, the FDA granted the drug breakthrough therapy designation based on these results.

DESTINY-CRC01

HER2 amplification occurs in approximately 5% to 6% of patients with colorectal cancer (CRC) and in about 15% to 20% of patients who have wild-type RAS and BRAF. This led to the evaluation of Enhertu on HER2-positive colorectal cancer patients. Data from the Phase 1 DESTINY-CRC01 trial showed promising activity of T-Dxd in advanced HER2-expressing tumors.

Phase 2 of the study evaluated the efficacy and safety of the drug in patients with centrally confirmed HER2-expressing, RAS-wildtype metastatic CRC that progressed after two or more chemotherapy regimens. The patients were divided into three cohorts based on the expression of HER2 and received 6.4mg/Kg of the drug every three weeks.

ORR (45.3%)Disease control rateMedian treatment duration

Median Overall survival

6.9 monthsComplete remissionPartial responseStable disease83.0%3.5 monthsNot reached 1 patient CR23 patients PR28.6%

Grade 3 adverse events occurred in 61.5% of patients receiving treatment. Among those, the most common were neutropenia and anemia. Five patients had treatment-related interstitial lung diseases.

Take home message

Dr. Siena, Professor of Medical Oncology, Italy, concluded the talk by highlighting interesting findings from the trial. T-Dxd demonstrated remarkable activity in patients with HER2-expressing colon cancer, which does not respond to standard therapies. The safety profile of the drug was consistent with the one seen in DESTINY-Gastric01 and DESTINY-Lung01 studies. However, Interstitial lung disease consistently appeared as an adverse event in all the trials, which requires careful recognition and intervention.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: ASCO 2020: Keytruda Shines as New Quality of Care in Treating metastatic Colorectal Cancer

References

1. https://meetinglibrary.asco.org/record/184803/abstract
2. https://meetinglibrary.asco.org/record/185492/abstract
3. https://meetinglibrary.asco.org/record/185482/abstract

Author

Ruchi Jhonsa