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Practice-Changing Trials From ASCO 2022 Plenary Session

The 2022 ASCO Annual Meeting was held during 3 – 7 June and offered the best of both worlds: a return to an in-person annual meeting for the first time since 2019, along with a fully virtual attendance option. More than 42,000 participants from around the world gathered in Chicago or online to hear the latest research data on multidisciplinary cancer treatment, new technologies, and promising drugs in the pipeline. The theme of this year’s meeting, ‘Advancing Equitable Cancer Care Through Innovation’ was reflected in the multiple educational and scientific sessions, during which around 2900 abstracts were presented. As always, the Plenary Session was the meeting’s highlight and included results from four practice-changing trials, summarized below.  

First-line panitumumab plus mFOLFOX for RAS wild-type and left-sided mCRC

A survival benefit when adding an upfront anti-EGFR antibody to chemotherapy was suggested in a retrospective pooled analysis of six randomized trials of patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) with a left-sided primary tumor location. PARADIGM is the first prospective trial to test the superiority of panitumumab vs. bevacizumab in combination with standard first-line doublet chemotherapy (FOLFOX) in patients with RASWT and left-sided mCRC. In this open-label, multicenter, phase III trial conducted in Japan, 823 patients were randomized to receive either panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. At a median follow-up of 61 months, patients with left-sided mCRC who received the panitumumab regimen achieved a statistically significant improvement in median OS (37.9 vs. 34.3 months; hazard ratio [HR], 0.82; P = 0.031). In the overall population of both left- and right-sided tumors, the HR was 0.84 (P = 0.030), which was also statistically significant. Progression-free survival (PFS) was comparable in both treatment groups. However, the response rate was higher with panitumumab (80.2% vs. 68.6%), as was the R0 resection rate (18.3% vs. 11.6%). No new safety signals were observed. Dr Takayuki Yoshino (National Cancer Center Hospital East, Chiba, Japan), who presented the trial, concluded that the results support panitumumab plus mFOLFOX6 as a first-line therapy for patients with RAS WT and left sided mCRC. The discussant, Dr Chiara Cremolini (University of Pisa, Pisa, Italy) agreed that the data support the regimen for patients who have microsatellite stable (MSS) RAS WT and BRAF WT left-sided mCRC. However, for patients who are microsatellite-high (MSI-H), she advocated upfront immunotherapy, and for BRAF-mutant patients, upfront chemotherapy plus bevacizumab followed by encorafenib plus cetuximab at progression.

High-dose ifosfamide improves survival in recurrent/refractory Ewing sarcoma

Recurrent/refractory (RR) Ewing sarcoma patients have a dismal prognosis, with a 5-year survival rate of less than 15%. These patients are treated with chemotherapy, although the regimens in use are not supported by randomized data. The rEECur trial was a multi-arm, multi-stage, phase II/III “drop a loser” randomized trial of the four most used chemotherapy regimens in patients with RR Ewing sarcoma. In total, 439 patients were randomized to either topotecan plus cyclophosphamide (TC; n=162), irinotecan plus temozolomide (IT; n=127), gemcitabine plus docetaxel (GD; n=72), or high-dose ifosfamide (IFOS; n=78). However, the GD and IT arms were halted following the results of two interim analyses showing a worse objective response and event-free survival (EFS) than with TC and IFOS, which were subsequently evaluated in the phase III study. At median follow up of 40 months, patients receiving IFOS experienced a longer median EFS compared with TC (5.7 vs. 3.5 months) and longer median OS (16.8 vs. 10.4 months). A greater survival difference was observed for patients aged <14 years than those aged ≥14 years (for both EFS and OS). Although grade 3/4 toxicity, including infections, nausea, encephalopathy, and renal toxicity were higher with IFOS, quality-of-life scores appeared to favor the IFOS over TC in children but not in adults. Dr Martin MacCabe (University of Manchester, Manchester, UK) concluded that the results are applicable to standard care, but there remain unanswered questions related to the two arms that were dropped. Discussant, Dr Katherine Janeway (Dana-Farber Cancer Institute, Boston, US) congratulated the investigators for the high-quality efficacy and safety data, and highlighted that based on the rEECur results, “We will need to consider ifosfamide as a potential chemotherapy backbone in combination with targeted agents.”

Trastuzumab deruxtecan, a new standard of care for HER2-low metastatic breast cancer

Around half of patients with metastatic breast cancer (mBC) express low levels of HER2 (IHC1+ or IHC2+/ISH). Patients with HER2-low mBC are treated similarly to patients with HER-negative disease, but treatment efficacy in later lines is limited. The antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), which is approved for HER2-positive mBC, has also shown promising efficacy in a phase I study for HER2-low heavily pretreated patients. The DESTINY-Breast04 was a global, open-label, randomized, phase III trial comparing the efficacy and safety of T-DXd vs. physician’s choice of single-agent chemotherapy, in HER2-low mBC patients treated with 1 – 2 prior lines of chemotherapy. Patients with HER2-low tumors and endocrine refractory disease were also included. Among 557 patients, 88.7% had hormone receptor-positive (HR) disease and 11.3% had HR-negative mBC. At a median follow-up of 18.4 months, patients with HR-positive, HER2-low disease had a median PFS of 10.1 months with T-DXd vs. 5.4 months with chemotherapy (HR, 0.51; P < 0.001), and OS was 23.9 vs. 17.5 months, respectively (HR, 0.64; P = 0.003). Similarly, in the ‘all patient’ population, T-DXd improved PFS (9.9 vs. 5.1 months; HR, 0.50; P < 0.001) and OS (23.4 vs. 16.8 months; HR, 0.64; P = 0.001). Exploratory analyses in patients with HR-negative disease showed a median PFS of 8.5 vs. 2.9 months (HR, 0.46) and a median OS of 18.2 vs. 8.3 months (HR, 0.48). The overall response rate was also about three-fold higher with T-DXd. The safety profile was consistent with previously reported data. Interstitial lung disease (ILD) or pneumonitis, an adverse event of special interest for T-DXd, was observed in 12% of patients who received T-DXd. Although most patients experienced low-/moderate-grade ILD, three patients died (0.8%). Dr Shanu Modi (Memorial Sloan Kettering Cancer Center, New York, US) who presented these unprecedented results from DESTINY-Breast04, concluded that, “These results establish HER2-low mBC as a targetable population of breast cancer with T-DXd as a new standard of care in this setting.” Discussant, Dr Patricia LoRusso (Yale University, New Haven, US) enthusiastically agreed that the results are practice-changing and emphasized a need for more sensitive tools to better define the most appropriate patient population. Results from the study were simultaneously published in the New England Journal of Medicine.

PFS benefit of autologous stem cell transplant in newly diagnosed multiple myeloma

The optimal use of induction therapy, autologous stem cell transplantation (ASCT) and maintenance in transplant-eligible patients with newly diagnosed multiple myeloma (MM) continues to evolve. The effect of adding ASCT to triplet induction therapy (lenalidomide, bortezomib, and dexamethasone [RVd]) and lenalidomide maintenance until disease progression, is unknown. This was explored in the large, randomized, phase III DETERMINATION trial, which included 722 patients with newly diagnosed MM. Patients were randomized to receive RVd plus ASCT or RVd alone followed by lenalidomide maintenance in both groups. At a median follow-up of 76 months, patients with ASCT experienced longer median PFS than those who did not receive ASCT (67.5 vs 46.2 months; HR, 1.53, P < 0.0001). Despite a 21-month PFS improvement, 5-year OS was similar between both arms (80.7 vs. 79.2%; HR, 1.10; P = 0.99). Overall response rate and rates of complete response and very good partial response were similar among the groups, while rates of MRD-negative responses at the start of lenalidomide maintenance were higher in RVd plus ASCT (54.4% vs. 39.8%). However, RVd plus ASCT was associated with significantly higher rates of toxicity, transient clinically meaningful decrease of quality of life, and a higher rate of secondary acute myeloid leukemia and myelodysplastic syndrome. Dr Paul Richardson (Dana-Farber Cancer Institute, Boston, US), who presented the data, highlighted that the results of the study confirm that ASCT remains the standard of care in transplant-eligible MM, but its use can be “personalized”. Discussant Dr Joseph Mikhael (Translational Genomics Research Institute, Phoenix, US), commented that, “Historically we’ve thought of ASCT as a frontline approach. This study adds further evidence that in the timing of transplant, like any other intervention, there isn’t a perfect sequence, and it doesn’t necessarily have to be used frontline,” Results of the DETERMINATION study were simultaneously published in the New England Journal of Medicine.