Catch up on highlights from the 2022 ASCO Congress

Day Three Highlights: Exciting results from the DESTINY, PARADIGM and rEECur trials

By Dawn O’Shea

One of the most hotly anticipated events of Day 3 of ASCO 2022 was the presentation of results from the DESTINY-Breast04 trial, the first prospective phase 3 trial of the HER2 antibody-drug conjugate (ADC) trastuzumab (T-DXd) in patients with HER2-low (IHC score 1+ or 2+ and negative ISH test) unresectable or metastatic breast cancer.

A new category of HER2 expression in breast cancer

The results from DESTINY-Breast04⁶ are thought to be pivotal in treating HER2-low breast cancer. The results demonstrated efficacy in a difficult-to-treat patient population and delineated a new category of HER2 expression in breast cancer.

The results, presented by Dr Shanu Modi from Memorial Sloan Kettering Cancer Center, New York, show that patients treated with T-DXd achieved a mean progression-free survival (mPFS) of 9.9 months compared to 5.1 months with standard care⁶. 

In HR-positive patients, T-DXd was associated with mPFS of 10.1 months versus 5.4 months with standard chemotherapy. In HR-negative patients, mPFS was 8.5 versus 2.9 months. Overall survival (OS) was 23.9 versus 17.5 months in HR-positive patients and 18.2 vs 8.3 months in HR-negative patients⁶. 

The results show a potential to significantly improve survival for more than half of patients who would traditionally have been categorised as having HER2-negative breast cancer.

However, it must be noted that 12.1% of patients treated with T-DXd developed interstitial lung disease or pneumonitis⁶, which would need to be monitored, with early intervention if necessary.

Dr Jane Meisel, a medical oncologist at Emory University in Atlanta, said the findings “fundamentally change the way we think about HER2 status and how we classify this in our metastatic patients”

“This study extends the benefits of the agent to a whole new group of patients that traditionally has been quite difficult to treat, our endocrine-refractory, HR-positive, [or] triple-negative patients who have progressed on one or two lines of treatment and are HER2-low. As we have seen, T-DXd improved PFS and OS in clinically and statistically meaningful ways,” she said.

The trial achieved the most extended survival ever for RAS wild type CRC

Dr Takayuki Yoshino from the National Cancer Center Hospital East, Japan, presented more positive data, this time from the world’s first prospective trial of panitumumab for RAS wild-type (wt) metastatic colorectal cancer (mCRC).

The PARADIGM trial⁷ reported the most extended survival ever to be reported in a phase 3 trial of first-line treatment of this patient group.

PARADIGM randomised patients with treatment with panitumumab plus mFOLFOX or bevacizumab plus mFOLFOX. In the overall cohort, OS was 36.2 months with panitumumab versus 31.3 months with bevacizumab. In patients with a left-sided primary tumour, mean survival was 37.9 versus 34.3 months⁷.

“These results establish a new standard first-line combination regimen for patients with RAS wild type left-sided metastatic colorectal cancer,” Dr Yoshino said.

He added that a large-scale biomarker analysis is currently underway using plasma and tumour tissue samples collected pre- and post-treatment.

Commenting on the research, Dr Cathy Eng from the MD Anderson Cancer Center in Houston said: “It is essential to remember that the expected five-year survival is still only 15% for our patients with the surgically unresectable disease. It has only changed about 6% over the past 20 years.”

First randomised controlled trial of chemotherapy for Ewing sarcoma

Dr Martin McCabe, senior lecturer in paediatric and adolescent oncology at the University of Manchester, presented the findings of the international rEECur trial⁸, the first randomised controlled trial of chemotherapy in children and young people with recurrent and primary refractory Ewing sarcoma.

The trial of 451 patients with this rare cancer concluded that ifosfamide delivered higher survival benefits than topotecan plus cyclophosphamide. The median overall survival was 5.7 months with ifosfamide compared to 3.5 months with topotecan plus cyclophosphamide. Six-month survival was 47% versus 37%, respectively⁸. 

In the phase 3 comparison, ifosfamide appeared to be more effective at prolonging event-free and overall survival. Dr McCabe reported that this benefit was more significant in children than adolescents or adults⁸. 

Both regimens caused similar rates of neutropenic infection, but ifosfamide was associated with more severe kidney and CNS toxicity.

Dr McCabe commented on the findings: “Although we have shown that ifosfamide is better than topotecan and cyclophosphamide, which is better than irinotecan plus temozolomide, the differences were quite subtle and what we need is better drugs to cure more patients.”

He went on to add, “Before this study, there was a lack of high-quality evidence on which to base clinical decisions about treatment. These findings will provide valuable guidance on the optimal treatment of these patients.”

“The rEECur study has, for the first time, accrued randomised data for four widely used chemotherapy regimens and is now accruing data for a fifth regimen. Before the rEECur study, the basis for choosing drugs for patients with relapsed or refractory Ewing sarcoma was weak and lacked randomised trials to inform clinicians or patients about which treatments were most effective or toxic” Dr McCabe said.

References

1. Spira AI, Riely GJ, Gadgeel SM, Heist RS, Ou S-HI, Pacheco JM, et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non–small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at the ASCO Annual Meeting 2022, 3 June. Chicago, IL, USA. 9002. Available at: https://meetings.asco.org/abstracts-presentations/208088. Accessed 7 June 2022.
2. Akinboro O. Outcomes of anti–PD-(L)1 therapy with or without chemotherapy (chemo) for first-line (1L) treatment of advanced non–small cell lung cancer (NSCLC) with PD-L1 score ≥ 50%: FDA pooled analysis. Presented at the ASCO Annual Meeting 2022, 3 June. Chicago, IL, USA. 9000. Available at: https://meetings.asco.org/abstracts-presentations/208075. Accessed 7 June 2022.
3. Lin NU. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at the ASCO Annual Meeting 2022, 4 June 2022. Chicago, IL, USA. 1005. Available at: https://meetings.asco.org/abstracts-presentations/185141. Accessed 7 June 2022.
4. Rugo HS, Bardia A, Marmé F, Cortes J, Schmid P, Loirat D, et al. Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer. Presented at the ASCO Annual Meeting 2022, 4 June. Chicago, IL USA. LBA1001. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA1001. Accessed 10 June 2022.
5. Tie J, Cohen J, Lahouel K, Lo SN, Wang Y, Wong R, et al. Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: The randomized DYNAMIC trial. Presented at the ASCO Annual Meeting 2022, 4 June. LBA100. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA100. Accessed 10 June 2022.
6. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Results of DESTINY-Breast04, a randomized, phase 3 study. Presented at the ASCO Annual Meeting 2022, 5 June. LBA3. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA3. Accessed 10 June 2022.
7. Yoshino T, Watanabe J, Shitara K, Yasui H, Ohori H, Shiozawa M, et al. Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC): Results from the phase 3 PARADIGM trial. Presented at the Journal of Clinical Oncology 2022, 5 June. LBA1. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA1. Accessed 10 June 2022.
8. McCabe M, Kirton L, Khan M, Fenwick N, Strauss SJ, Valverde C, et al. Phase III assessment of topotecan and cyclophosphamide and high-dose ifosfamide in rEECur: An international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES). Presented at the ASCO Annual Meeting 2022, 5 June. LBA2. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA2. Accessed 10 June 2022.