Colorectal Cancer Highlights: ASCO 2021

DelveInsight’s consultants have put down their thoughts and viewpoints on some important abstracts in Colorectal Cancer from ASCO2021.

Abstract#3505: Promising results of HER2-targeting ADC—let’s hold out hope for 3L+ CRC patients

While the role of HER2 as a prognostic biomarker in colorectal cancer (CRCs) remains unknown, its pertinence as a therapeutic target has been lately studied. Recently, Daiichi Sankyo in collaboration with AstraZeneca has been working on this peculiar target in CRC. After achieving the victory in HER2-positive breast cancer and gastric or gastroesophageal junction adenocarcinoma (GC/GEJ), the duo decided to investigate their HER2-directed ADC (Trastuzumab deruxtecan; Enhertu) in various other cancers persuading them towards lung cancer, colorectal cancer and other selected solid tumors expressing HER2 biomarker. 

Recently, during the ASCO 2021 annual meeting, the company presented the final data from the phase II colorectal cancer trial (DESTINY-CRC01) evaluating Trastuzumab deruxtecan in patients with HER2-expressing advanced colorectal cancer. While, the treatment landscape for advanced CRC has been at most limited to chemotherapy combinations with anti-VEGF and anti-EGFR monoclonal antibodies in combination with chemotherapy for the third- or subsequent lines of the disease with limited clinical benefits, this was the first time an ADC is being evaluated for HER2-expressing CRC in this line of setting.

The trial enrolled a total of 86 patients with unresectable and metastatic disease with HER2 expression and RAS/BRAFV600E wild type (WT) and had previously received more than two prior lines of therapies allowing prior treatment with anti-HER2 targeted therapy. Majority of the patients had microsatellite stable CRC (MSS CRC) tumors’. The patients were categorized based on the HER2 expression of the tumor cells: Cohort A (HER2 IHC3+ or IHC2+/ISH+), Cohort B (IHC2+/ISH−) and Cohort C (IHC1+) with more than 75% IHC 3+ and 25% IHC 2+ in cohort A. 

The efficacy results from the study revealed that the confirmed objective response (ORR)—a primary endpoint of the study in cohort A was 45.3% with a disease control rate (DCR) of 83% and a median duration of response (mDOR) of 7.0 months. IHC 3+ was observed to be a good indicator of response in terms of tumor reduction in cohort A as compared to IHC 2+ population of the same cohort. The median progression free survival (mPFS) values also supported cohort A (6.9 months) over cohort B (2.1 months) and cohort C (1.4 months). Median overall survival values were highly impressive in heavily pretreated patients of cohort A (15.5 months) as compared to similar values in both the cohorts (cohort B: 7.3 months vs cohort C: 7.7 months).

The safety analysis from the study revealed that 65.1% of the overall patients experienced grade ≥3 adverse events (AEs) with nearly 50% experiencing drug-related treatment-emergent adverse events (TEAEs). The AEs of special interest involved interstitial lung disease (ILD) which showed that 8 patients (9.3%) suffered from any grade ILD during the study treatment, ILD remains a major adverse event in not just Enhertu but also in Daiichi’s TROP-2 targeting ADC, Datopotamab deruxtecan.

INSIGHTS: As there is a high unmet need in the third and subsequent-lines of therapy with limited clinical benefits, HER2-targeted ADC could be a possible treatment for this patient pool. Although, the early promising anti-tumour activity of trastuzumab deruxtecan in HER2-expressing CRC has been quite imposing, the continued follow-up of the study is still needed as the ADCs come up with a black box warning with dreadful safety results which might put patients’ life at risk. However, the company has not limited its research with the above mentioned ADC for this indication but has started exploring a new HER3-targeted ADC (Patritumab Deruxtecan) in HER3-expressing CRCs in the current pipeline. The evidence from DESTINY-CRC01 has also paved its way to DESTINY-CRC02 study evaluating trastuzumab deruxtecan in HER2-overexpressing locally advanced, unresectable or metastatic CRC. We can definitely expect ADCs to uplift the upcoming market with a more targeted approach and defying the law of one size fits all in oncology.

Abstract #3503: Amgen’s Panitumumab in combination with 5FU/LV could be the new treatment in maintenance line of RAS WT mCRC

The current standard of care in first-line maintenance therapy of RAS WT mCRC involves the use of 5FU/LV. However, Amgen is trying a combination therapy of 5FU/LV and panitumumab (Vectibix), an anti- EGFR, as a new approach for better maintenance of RAS WT mCRC patients in the first-line treatment setting. Amgen’s panitumumab, has been available in the first-line setting treatment of wild-type RAS mCRC since 2006, as monotherapy after treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy and also in combination with Folfox. The company has been conducting the phase II PANAMA trial in the maintenance therapy since 2014. Amgen had published data on the PANAMA trial in the past, which demonstrated that the combination is effective in this treatment setting. 

During the 4th day of ASCO 2021 virtual meeting, Amgen presented data from the phase II PANAMA trial in the oral abstract session. The primary endpoint of the trial was PFS while the secondary endpoints included OS, objective response to induction–and maintenance therapy along with quality of life. A total of 387 patients were included and the full analysis set consisted of 248 patients. The PFS had improved with panitumumab + 5FU/VL combination in maintenance setting (8.8 months versus 5.7 months). The OS was not yet mature but supported the use of this combination (28.7 months) as compared to 5FU/LV alone 25.7 months. The data also reported that in the arms 5FU/LV+ panitumumab versus 5FU/LV alone– the ORR was 40.8% and 26%, respectively, showing that the response of tumors during maintenance therapy was more frequently observed in the 5FU/LV+ panitumumab arm. Moreover, the maintenance therapy with 5FU/LV+ panitumumab was also well tolerated. The session was concluded by stating that 5FU/LV+ panitumumab should be considered as the favored choice for maintenance therapy following Folfox plus panitumumab in RAS WT mCRC patients.

Expert Opinion: “Panitumumab is active as maintenance therapy in combination with 5-FU/leucovorin. Therefore, the combination should be regarded as the preferred option of maintenance therapy following FOLFOX/panitumumab in patients with RAS wild-type metastatic CRC.”

RAS WT mCRC; RAS wild-type metastatic colorectal cancer; PFS- Progression free survival; OS- Overall survival; ORR - Objective response rate;

Have a look at some more abstracts presented in different cancers at ASCO 2021.