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When deciding optimal treatment strategies for patients with metastatic colorectal cancer (mCRC), the significance of the primary tumor location as a predictive and prognostic factor has recently become evident. Malignancies originating from specific regions within the colon exhibit distinct characteristics, and numerous findings have demonstrated genetic and immunological differences between the right- and left-sided colorectum in mCRC.1, 2
Retrospective data pooled from 6 randomized clinical trials (CRYSTAL [NCT00154102], FIRE-3 [NCT00433927], CALGB 80405 [NCT00265850], PRIME [NCT00364013], PEAK [NCT00819780] and 20050181 [NCT00339183]) have indicated patients with primary left-sided RAS wild-type mCRC show superior benefit with anti-EGFR therapy compared to anti-VEGF therapy in combination with chemotherapy.3 The open-label, multicenter Phase III PARADIGM (NCT02394795) trial is the first prospective study to explore treatment for patients with primary left-sided RAS wild-type mCRC, investigating the EGFR-targeted monoclonal antibody, panitumumab, versus the VEGFR-targeted monoclonal antibody, bevacizumab, with mFOLFOX6.4
A total of 823 patients were randomized to receive either panitumumab (n=400) or bevacizumab (n=402) plus mFOLFOX6 in the full-analysis set (FAS). 312 and 292 patients in each arm had left-sided primary tumors, respectively.
The primary endpoint was overall survival (OS), hierarchically tested in patients with left-sided tumors, followed by those in the FAS population. Key secondary endpoints included progression-free survival (PFS), response rate (RR), and curative resection (R0) rate.
After 448 OS events in left-sided patients with a median follow-up of 61 months, OS was analyzed. Patients receiving panitumumab demonstrated a significantly improved OS compared to bevacizumab in both populations. The median OS in the left-sided population receiving panitumumab plus mFOLFOX6 was 37.9 months compared with 34.3 months in the bevacizumab and mFOLFOX6 arm (HR, 0.82; 95.798% CI, 0.68-0.99, p = 0.031, which crossed the boundary of significance [0.042]) and in the FAS population, OS was 36.2 months versus 31.3 months for panitumumab versus bevacizumab, respectively (HR, 0.84; 95% CI, 0.72-0.98; p = 0.030, with < 0.05 as the boundary). OS difference for right-sided mCRC was not statistically different.
PFS was similar between the treatment arms in left-sided mCRC, however RR and R0 resection were significantly higher for patients receiving panitumumab versus bevacizumab. No new safety signals were observed.
The results of the PARADIGM trial demonstrates that panitumumab leads to significantly increased OS in combination with chemotherapy, when compared to bevacizumab in patients with left-sided RAS wild-type mCRC, indicating a new standard first-line treatment regimen for this patient population.
HER2-low breast cancer is define as breast cancer with a immunohistochemistry score (IHC) of 1+ or 2+, comprising approximately 50% of patients with primary breast cancer. Previously, HER2-targeted therapies have been ineffective at treating HER2-low breast cancer and, as such, these patients have historically been labelled as HER2-negative.5 For the first time, DESTINY-Breast04 (NCT03734029), a randomized Phase III clinical trial exploring HER2-targeted therapy for HER2-low breast cancer, demonstrated statistically significant and clinically meaningful benefits for patients with HER2-low metastatic breast cancer (mBC) with the antibody-drug conjugate (ADC), trastuzumab deruxtecan (T-DXd). Patients enrolled had previously been treated with 1-2 lines of chemotherapy in the metastatic setting. 6
The multicenter, open-label, Phase III trial randomized 557 patients 2:1 with centrally confirmed HER2-low mBC to receive either T-DXd (n= 373) or chemotherapy of physician’s choice (n=184; TPC [capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel]), the results of which were presented at the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting. The primary endpoint was progression-free survival (PFS) in patients with hormone-receptor positive (HR+) mBC. Key secondary endpoints included PFS in patients with HER2-low mBC in the full analysis set (FAS) and overall-survival (OS) in patients with HR+ disease and in FAS. Additional endpoints were duration of response (DoR), objective response rate (ORR) and safety.
After a median follow-up of 18.4 months, an approximate 50% reduction in the risk of disease progression or death was demonstrated with T-DXd versus TPC (median PFS: 9.9 vs 5.1 months; HR 0.50, 95% CI [0.40, 0.63]; P < .0001), as well as in the HR+ (median PFS: 10.1 vs. 5.4 months, HR = 0.51, P < .0001; overall: 23.9 vs. 17.5 months, HR = 0.64, P = .0028) and HR- subgroups (median PFS: 6.6 vs. 2.9 months, HR = 0.45, P = 0.0135; overall: 16.6 vs. 10.3 months, HR = 0.63, P = 0.1732).
Additionally, a 36% reduction in the risk of death (median OS: 23.4 vs 16.8 months; HR 0.64, 95% CI [0.49, 0.84]; P = .0010) was observed in the FAS population. ORR for T-DXd was 53% and 50% for HR+ and HR- subgroups, respectively, versus 16% and 17% with TPC, respectively. 5, 6
52.6% of patients receiving T-DXd compared to 67.4% if patients receiving TPC experienced grade 3 or higher treatment-related adverse events. 45 patients receiving T-DXd had independently adjudicated drug-related interstitial lung disease [ILD]/pneumonitis, compared to 1 patient receiving TPC, resulting in the deaths of 3 individuals on T-DXd, highlighting the importance of closely monitoring this potential risk for patients undergoing T-DXd treatment.
DESTINY-Breast04 is the first randomized clinical trial to show significant survival benefits to targeting HER2 in patients with HER2-low mBC. Conclusively, T-DXd demonstrated a marked increase in PFS and OS compared to standard treatment, establishing a new standard of care for HER2-low mBC.
EGFR tyrosine kinase inhibitors (TKIs) have proven beneficial for survival outcome in patients with EGFR-mutated non-small cell lung cancer (NSCLC). However, disease progression due to acquired resistance mutations is inevitable. Amivantamab is an EGFR-MET bispecific antibody that binds to the extracellular domain of each receptor, allowing it to overcome resistance at the TKI binding site. Additionally, amivantamab initiates EGFR and MET internalization and degradation and directs immune cell activity resulting in antibody-dependent cellular cytotoxicity. Lazertinib is a brain-penetrant, 3rd-generation EGFR TKI with efficacy against EGFR activating and T790M mutations. The combination of amivantamab with lazeritinib may generate potent activity against resistance EGFR mutations in NSCLC by generating synergy via simultaneous targeting of the EGFR extracellular domain with amivantamab and the kinase domain with lazertinib. 7
The Phase 1/1b CHRYSALIS-2 (NCT04077463) trial was designed to evaluate whether the combination of amivantamab with lazertinib could provide antitumor activity via targeting EGFR-mutated NSCLC in patients following failure with the EGFR-TKI, osimertinib, and platinum-based chemotherapy.
Cohort A evaluated amivantamab with lazertinib in patients with EGFR exon 19 deletion who had progressed on first- or second-line osimertinib followed by platinum-based chemotherapy as the last line of treatment (target population, n=106). The combination was additionally assessed in a more heavily-pretreated population (n=56) who had progressed following osimertinib and platinum-based chemotherapy with or without additional therapies, regardless of the number or sequence of these therapies. Investigator- and blinded independent central review-assessed response was reported on. 8
50 patients in the target population were evaluable, demonstrating an overall-response rate (ORR) by blinded independent central review of 36% (95% CI, 23–51), with 1 complete response (CR) and 17 partial responses (PRs), and a clinical benefit rate (CBR) of 58% (95% CI, 43–72). Based on blinded independent central review, median duration of response (mDOR) was not reached. After a median follow-up of 8.3 months, 7 responders (39%) achieved a DOR of 6 or more months by blinded independent central review. Investigator-assessed response was consistent with blinded independent central review. 56 patients in the heavily pretreated population were evaluable, and, following a median follow-up of 8.7 months, achieved an ORR by INV of 29% (95% CI, 17–42), with 1 CR and 15 PRs. CBR was 55% (95% CI, 42–69) and mDOR was 8.6 mo (95% CI, 4.2–NR). Results via blinded independent central review are forthcoming. Most common treatment-related adverse events of grade 3 or more were infusion-related reactions (7%), acneiform dermatitis (5%), and hypoalbuminemia (4%). Discontinuation due to treatment-related adverse events occurred in 12% and 7% of either or both amivantamab and lazertinib, respectively.
In conclusion, the results indicate encouraging antitumor activity plus a manageable safety profile with the combination of amivantamab and lazertinib in unselected patients who had previously acquired resistance to the standard of care osimertinib with platinum-based chemotherapy.
Written by Ellie Jackson
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