Despite the ongoing challenges of the COVID-19 pandemic, the practice-changing studies presented at the 2021 ASCO Annual Meeting clarified the continuing momentum in the oncology community to improve the lives of our patients.
Immunotherapy demonstrated efficacy in cancers where it had not been previously studied, and studies on promising agents for newer targets raised hope for patients whose tumors harbored heretofore undruggable targets. These advances should help improve the quality of life of patients with cancer and continue the progress made thus far in decreasing cancer-related mortality.
Two general areas of interest pervasive throughout the meeting included tailoring adjuvant therapy for early high-risk cancer and improving upon standard therapy for advanced and metastatic cancer, using both immunotherapeutic and targeted approaches.
GUEST EDITORS
Apar Kishor Ganti, MD, MS
Nicole Shonka, MD
Advances in Breast Cancer
Three pivotal trials focused on early breast cancer while another notable update focused on advanced disease. The OlympiA trial, presented during the Plenary Session, focused on maintenance therapy to reduce risk in patients with BRCA germline mutations, whereas ADAPT supported neoadjuvant dual HER2 therapy and EA1131 upheld the role of capecitabine for residual disease in triple-negative breast cancer. One year of adjuvant olaparib maintenance therapy in high-risk HER2-negative breast cancer with BRCA germline mutations improved disease-free survival from 77.1% to 85.9% with relatively good tolerance in the OlympiA placebo-controlled study, presented by Tutt et al.1 ADAPT, reported by Harbeck et al, addressed limiting paclitaxel in patients with HER2-positive breast cancer who achieved an early complete response from pertuzumab and trastuzumab.2 Those with high HER2 expression and nonbasal tumors were most likely to achieve a pathologic complete response without chemotherapy, with outcomes similar to those receiving triplet therapy.
In patients with triple-negative breast cancer who had residual disease after neoadjuvant chemotherapy, the noninferiority study EA1131, presented by Mayer et al, emphasized the role of capecitabine over cisplatin, the latter of which had evoked interest in preclinical studies supporting greater sensitivity to platinum agents in the basal subtype.3 The 3-year disease-free survival, which was lower than expected in both arms, was 42% in the more toxic platinum arm vs 49% in the capecitabine arm, and hazard ratios were more compelling in both basal and nonbasal subtypes.
Shifting to advanced breast cancer, Cristofanilli et al updated survival data at 73.3 months in the PALOMA-3 trial of palbociclib plus fulvestrant (vs placebo) for hormone receptor–positive, HER2-negative advanced breast cancer. They demonstrated a maintained overall survival benefit from dual therapy in those who had not received prior chemotherapy for advanced disease and those who were not refractory to prior endocrine therapy.4
New Options in Lung Cancer
In lung cancer, the results of the IMpower010 trial showed that adjuvant atezolizumab improved progression-free survival in patients with resected lung cancer, whose tumors expressed PD-L1, after completion of adjuvant chemotherapy.5
In the metastatic setting, cemiplimab-rwlc was previously shown to be better than chemotherapy in patients whose tumors had high PD-L1 expression (tumor proportion score ≥ 50%) in the EMPOWER-Lung 1 study.6 In a subset analysis of 68 patients from this trial, Özgüroglu et al demonstrated that this advantage persisted in patients who had treated stable brain metastases. Cemiplimab was shown to have intracranial activity, as in this cohort central nervous system (CNS) disease progression was seen in 5.9% of patients treated with cemiplimab compared to 11.8% of patients treated with chemotherapy.
KRAS has long been considered undruggable, but the results of the CodeBreaK 100 trial disproved that.7 This was a phase II study of 126 patients with advanced lung cancer and a KRAS G12C mutation who received sotorasib. In this cohort of patients, the vast majority of whom had received previous platinum-based therapy and immune checkpoint inhibitors, the response rate was an impressive 37.1%, whereas the median overall survival was 12.5 months.
Osimertinib is the mainstay of the management of patients with advanced lung adenocarcinoma whose tumors harbor an activating EGFR mutation. However, resistance invariably develops, and these patients do not typically have any targeted options. Bauml et al presented updated results of a study using the combination of amivantamab (a fully human bispecific antibody targeting EGFR and MET) and lazertinib (a third-generation EGFR tyrosine kinase inhibitor) in patients who relapsed on osimertinib.8 Of the 45 patients, 36% had a confirmed response, and the median progression-free survival was 4.9 months.
Novel Immunotherapies in Melanoma
Especially notable advances in melanoma were for advanced and metastatic disease, wherein current immunotherapy was improved with the addition of novel treatments harnessing the immune system. Although tremendous strides have been made with immune checkpoint inhibitors, most patients will experience disease progression on these agents and have limited treatment options. Lipson et al presented the global RELATIVITY-047 study targeting lymphocyte-activation gene 3 (LAG-3) using relatlimab with nivolumab to improve progression-free survival in newly diagnosed unresectable or metastatic melanoma stratified for BRAF status and PD-L1 and LAG-3 expression.9 Unsurprisingly, there were more toxicities with combination therapy; however, toxicity was still less than typically seen with combinations targeting the PD-1 and CTLA-4 pathways.
Larkin et al reported on another global study, the phase II open label C-144-01 trial.10 One infusion of lifileucel, an adoptive T-cell therapy using tumor-infiltrating lymphocytes, given after disease progression on anti–PD-1 therapy, led to significant responses, most notably in those with shorter duration of PD-1 therapy and more rapidly progressing disease.
Genitourinary Cancer Plenary Sessions
Of interest for genitourinary cancers were the VISION trial and KEYNOTE-564, which were both featured in the Plenary Session at the Annual Meeting. VISION, presented by Morris et al, randomly assigned patients with taxane-refractory metastatic castrate-resistant prostate cancer to standard of care with or without lutetium-177, a prostate-specific membrane antigen.11 Progression-free survival and overall survival were both improved, the latter by 4 months.
The placebo-controlled KEYNOTE-564 randomly assigned postnephrectomy patients with high-risk clear cell renal cell carcinoma to pembrolizumab vs placebo for up to 1 year.12 As discussed by Choueiri et al, at 24 months, disease-free survival was not reached in either group, but the risk of disease recurrence or death was reduced in the treatment arm by 32%.
Checkpoint Inhibitors Effective in Head and Neck Cancer
Immune checkpoint inhibitors demonstrated efficacy in two additional malignancies, esophageal squamous cell carcinoma and nasopharyngeal carcinoma. In the CheckMate 648 study, nivolumab plus chemotherapy and nivolumab plus ipilimumab were shown to decrease the risk of mortality in patients with advanced squamous cell carcinoma of the esophagus, as compared to chemotherapy.13 In the intent-to-treat population, the risk of death was decreased by 26% in the nivolumab plus chemotherapy arm and by 22% in the nivolumab plus ipilimumab arm. The corresponding numbers in the PD-L1–expressing patients were an impressive 46% and 36%, respectively.
In patients with recurrent or metastatic nasopharyngeal carcinoma, the novel PD-1 inhibitor toripalimab showed improved progression-free survival, overall response rate, and duration of response when combined with cisplatin plus gemcitabine compared to chemotherapy alone in the JUPITER-02 trial, which was presented by Xu et al during the Plenary Session.14 While overall survival data are not yet mature, these data represent evidence that immunotherapy is active in this malignancy as well.
Standard of Care Upheld in Advanced Cervical Cancer
Pelvic chemoradiation with weekly cisplatin remains the standard of care in patients with locally advanced cervical cancer. In the OUTBACK study, presented during the Plenary Session by Mileshkin et al, the addition of adjuvant chemotherapy with four cycles of carboplatin and paclitaxel did not improve outcomes but resulted in increased adverse events in women with FIGO 2008 stages IB1 and positive lymph nodes, IB2, II, IIIB, or IVA cervical cancer.15
BTK Inhibitors in CLL
Bruton’s tyrosine kinase (BTK) inhibitors are commonly used in chronic lymphocytic leukemia (CLL), but they need to be continued to disease progression. The results of the CAPTIVATE study demonstrated that a fixed dose of a combination of ibrutinib and venetoclax (3 cycles of ibrutinib followed by 12 cycles of ibrutinib and venetoclax) can produce high progression-free survival rates at 2 years (96%).16 This strategy can enable a treatment-free interval for patients and potentially help prevent development of intolerance or resistance.
In the ELEVATE-RR trial of patients with previously treated CLL and del(17p) or del(11q), the second- generation BTK inhibitor acalabrutinib was shown to be equally effective as the first-generation inhibitor, ibrutinib.17 However, acalabrutinib was associated with a decreased incidence of cardiac toxicity (24% vs 30%). Atrial fibrillation and hypertension were less common in patients treated with acalabrutinib.
The 2021 ASCO Annual Meeting revealed continuing efforts not only to improve survival across many cancers, but also to differentiate treatments for specific cancer subtypes in terms of risk. As therapies advance and survival improves, the oncology community will endeavor to individualize treatment to abrogate long-term toxicities in survivorship.
DISCLOSURE: Dr. Ganti has served in a consulting or advisory role for AstraZeneca, BeiGene, Blueprint Medicines, Cardinal Health, Flagship Biosciences, G1 Therapeutics, Genentech/Roche, Jazz Pharmaceuticals, and Mirati Therapeutics; has received research funding from Takeda; and has received institutional research funding from Apexigen, Merck, Nektar, Novartis, and TopAlliance BioSciences Inc. Dr. Shonka has reported no conflicts of interest.
REFERENCES
1. Tutt A, Garber JE, Kaufman B, et al: 2021 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2021.
2. Harbeck N, Gluz O, Christgen M, et al: 2021 ASCO Annual Meeting. Abstract 503. Presented June 6, 2021.
3. Mayer IA, Zhao F, Arteaga CL, et al: 2021 ASCO Annual Meeting. Abstract 605. Presented June 6, 2021.
4. Cristofanilli M, Rugo HS, Im S-A, et al: 2021 ASCO Annual Meeting. Abstract 1000. Presented June 5, 2021.
5. Wakelee H, Altorki N, Zhou C, et al: 2021 ASCO Annual Meeting. Abstract 8500. Presented June 6, 2021.
6. Özgüroglu M, Sezer A, Kilickap S, et al: 2021 ASCO Annual Meeting. Abstract 9085. Presented June 4, 2021.
7. Skoulidis F, Li BT, Govindan R, et al: 2021 ASCO Annual Meeting. Abstract 9003. Presented June 4, 2021.
8. Bauml J, Cho BC, Park K, et al: 2021 ASCO Annual Meeting. Abstract 9006. Presented June 4, 2021.
9. Lipson EJ, Tawbi HAH, Schadendorf K, et al: 2021 ASCO Annual Meeting. Abstract 9503. Presented June 6, 2021.
10. Larkin J, Sarnaik A, Chesney JA, et al: 2021 ASCO Annual Meeting. Abstract 9505. Presented June 4, 2021.
11. Morris MJ, De Bono JS, Chi KN, et al: 2021 ASCO Annual Meeting. Abstract LBA4. Presented June 6, 2021.
12. Choueiri TK, Tomczak P, Park SH, et al: 2021 ASCO Annual Meeting. Abstract LBA5. Presented June 6, 2021.
13. Chau I, Doki Y, Ajani JA, et al: 2021 ASCO Annual Meeting. Abstract 4001. Presented June 5, 2021.
14. Xu RH, Mai HQ, Chen QY, et al: 2021 ASCO Annual Meeting. Abstract LBA2. Presented June 6, 2021.
15. Mileshkin L, Moore KN, Barnes EH, et al: 2021 ASCO Annual Meeting. Abstract LBA3. Presented June 8, 2021.
16. Ghia P, Allan JN, Siddiqi T, et al: 2021 ASCO Annual Meeting. Abstract 7501. Presented June 6, 2021.
17. Byrd JC, Hillmen P, Ghia P, et al: 2021 ASCO Annual Meeting. Abstract 7500. Presented June 5, 2021.
