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Clinical Pharmacology Modeling SimulationImmuno-Oncology Updates in the Virtual Era - ASCO 2020
This year’s ASCO Annual Scientific Meeting took place between May 29-31, with the Education Program planned for August 8-10. Unlike previous years, when researchers, clinicians, cancer nurses, industry partners and patient advocates from all over the world would gather in Chicago, this year’s meeting took place virtually to curb the impact of the coronavirus disease 2019 (COVID-19) pandemic. Despite challenges imposed by the new meeting format, ASCO created the perfect platform to provide the opportunity for exchanging information and expertise on the most recent (immuno-)oncology advances, of which a comprehensive summary is given below.
Emerging anti-cancer therapies
In addition to new developments regarding anti-programmed cell death protein 1 (PD-1) therapies, this year’s ASCO switched gears to emerging targeted and cellular therapies.
Pembrolizumab
Pembrolizumab is a humanized anti-PD-1 monoclonal antibody approved by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of several types of cancer, alone or in combination with other therapies. As a result of its promising efficacy and tolerable safety profile, pembrolizumab is currently being evaluated in new types of difficult-to-treat cancers. Pembrolizumab in combination with the oral multiple receptor tyrosine kinase inhibitor lenvatinib was evaluated in the KEYNOTE-524/Study 116 Phase 1b open-label trial in patients with unresectable hepatocellular carcinoma (HCC) who received no prior systemic therapy (Abstract 4519) and in the KEYNOTE-146/Study 111 Phase 1b/2 trial in patients with metastatic clear cell renal cell carcinoma (ccRCC) who progressed following immune checkpoint inhibitor therapy (Abstract 5008). Results discussed at ASCO reported that this treatment combination demonstrated an objective response rate (ORR) of 36% and a partial response (PR) rate of 35% in patients with HCC. In patients with ccRCC, the ORR and PR rates recorded were 55%, the stable disease rate was 36%, and median PFS was 11.3 months, outstanding results in a patient population with metastatic disease and no available treatment options. These results, together with those from the practice-changing KEYNOTE-177 trial (see section “Practice-changing trials” below), highlight the continued progress of pembrolizumab across multiple tumor types.
Targeted therapies
Several classes of emerging targeted therapies were discussed during this year’s ASCO, with a focus on next-generation tyrosine kinase inhibitors (TKIs) and other small molecules.
Tivozanib is an oral vascular endothelial growth factor (VEGF) receptor TKI for which a New Drug Application (NDA) was recently submitted to the FDA. Results from the final analysis of the Phase 3 TIVO-3 trial comparing tivozanib with sorafenib in third- and fourth-line renal cell carcinoma (RCC) (Abstract 5062) demonstrated PFS superiority (5.6 vs 3.9 months) and reported an ORR of 18% vs 8%. The most common adverse event (AE) in patients receiving tivozanib was hypertension (38% vs 25% for sorafenib), an AE known to reflect VEGF pathway inhibition. These results demonstrate the favorable risk/benefit of tivozanib in the growing population of patients with relapsed/refractory RCC.
Two other TKIs found in the spotlight of ASCO 2020 are tepotinib and tucatinib. Tepotinib is a c-Met TKI currently evaluated in the ongoing VISION Phase 2 open-label trial in patients with advanced non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations. Preliminary results (Abstract 9556) reported a 46.5% ORR and a median duration of response of 11.1 months. Noteworthy, ORR was consistent across treatment-naïve and previously treated patients. Results from this trial, published in the New England Journal of Medicine, led to tepotinib regulatory approval in March 2020 in Japan.
The second TKI gaining therapeutic momentum during this year’s ASCO is tucatinib (Abstract 1005), an investigational human epidermal growth factor receptor 2 (HER2) TKI evaluated in patients with HER2-positive metastatic breast cancer (MBC) with stable/active brain metastases in the HER2CLIMB pivotal Phase 2 trial. Primary results of the trial were published in the NEJM. The new exploratory data demonstrated that MBC patients with brain metastases who received tucatinib with trastuzumab-capecitabine vs trastuzumab-capecitabine alone had a 42% reduction in the risk of death, a 68% reduction in the risk of central nervous system disease progression, and >2-fold increase in the intracranial ORR (47% vs 20%). These excellent results give new hopes for treatment of patients with disease metastasized to the brain.
Other novel targeted therapies gaining attention during ASCO 2020 were the anti-TIGIT immunotherapy tiragolumab (Abstract 9503) and the investigational first-in-class Kirsten rat sarcoma viral oncogene homolog (KRAS)G12C inhibitor sotorasib (Abstract 3511 and Abstract 4018). Results from the Phase 2 CITYSCAPE trial, the first randomized trial evaluating the efficacy and safety of tiragolumab plus atezolizumab as first-line treatment for patients with PD-L1-positive metastatic NSCLC vs atezolizumab alone, showed an improvement in the ORR (31.3% vs 16.2%) and a 43% reduction in the risk of disease worsening or death (median PFS: 5.4 vs 3.6 months). The combined treatment was well tolerated, with similar rates of ≥Grade 3 AEs as with atezolizumab alone (41.8% vs 44.1%). In view of these promising results, tiragolumab is currently being evaluated in patients with other solid tumors. The KRASG12C inhibitor sotorasib was evaluated in the CodeBreak Phase 1/2 trial in patients with KRAS pG12C mutant solid tumors, including colorectal carcinoma (CRC). Preliminary results from patients with CRC indicated an ORR of 7.1% and disease control rate of 76.2%. At the highest concentration (960 mg) of sotorasib, ORR and DCR were 12.0% and 80.0%. Three patients with PR had duration of response of 1.5, 4.2, and 4.3 months, respectively, and their responses were still ongoing at data cutoff.
Cellular therapies
Cellular therapies also seemed to be a hot topic during this year’s ASCO, with the progress of several types of chimeric antigen receptor (CAR) T-cell therapies being addressed.
The B-cell maturation antigen (BCMA)-directed CAR T-cell therapies idecabtagene vicleucel (Ide Cel) and JNJ-4528 were described to be effective in patients with relapsed/refractory multiple myeloma (Abstract 8503 - Ide Cel: ORR of 73% at all dose levels, with 33% CR rate; Abstract 8505 - JNJ-4528: ORR of 100%, with 97% of patients achieving a very good partial response and 3% PR rate). Similar results (Abstract 8002) were observed upon assessment of the anti-CD19 CAR T-cell therapy ALLO-501 in patients with non-Hodgkin lymphoma (ORR of 75% and CR rate of 44%). All three therapies had an acceptable safety profile, with cytopenias/neutropenias and cytokine release syndrome as some of the most frequently reported AEs, typical for this class of therapies.
Impact of COVID-19 on cancer
As expected, one of the main focuses of this year’s ASCO was the impact of COVID-19 on patients with cancer. The studies presented during the meeting covered new results from two cancer registries (CCC19 and TERAVOLT).
According to the first analysis of the ongoing COVID-19 and Cancer Consortium (CCC19) registry (Abstract LBA110), cancer patients with COVID-19 had a higher risk of dying when presenting with progressive disease. The multivariable logistic regression model employed for analysis of data from the 926 included patients revealed older age, male sex, former smoking, comorbidities, Eastern Cooperative Oncology Score (ECOG) performance status >2, and active cancer as factors associated with increased risk of death. A stable/responsive disease was associated with an approx. 2-fold increased risk (odds ratio [OR]=1.93, 95% confidence interval [CI] 1.06-3.5), whereas disease progression was associated with an approx. 4-fold increased risk (OR=3.79; 95% CI 178-8.08). Overall, 121/928 patients included in the analysis died at a median follow-up of 21 days.
The analysis of the ongoing Thoracic cancERs international coVid 19 cOLlaboraTion (TERAVOLT) registry (Abstract LBA111) revealed that prior chemotherapy but not immunotherapy or tyrosine kinase inhibitor (TKI) treatment was associated with increased risk of death for patients with thoracic malignancies and COVID-19. Additional associated factors identified during the multivariate analysis were older age, ECOG performance status, and use of steroids >10 mg/day. Overall, 141/400 (35%) patients included in the analysis died at a median follow-up of 33 days, with 10.6% attributable to cancer and 79.4% to COVID-19 alone.
Use of algorithms for targeted treatments
Identification of molecular therapeutic targets using novel approaches has the potential to advance the use of precision medicines, such as targeted therapies, for enhancing treatment of difficult recurrent/relapsed pediatric cancers.
Part of this international registry, 526 children with relapsed cancers were evaluated using a 7-step treatment algorithm (Abstract LBA10503). Overall, 149 children were matched to targeted drugs, of whom 20 had a very-high priority molecular target (e.g. ALK, BRAF, or NRAS mutations, or MET and NTRK fusions). This subset had a significantly longer PFS vs the rest of the children: 204.5 vs 111 days, p=0.0093). Additionally, 40 children with potential cancer predisposition syndrome were identified, 17 of whom were unaware of their syndrome. This algorithm successfully identified in children with relapsed cancers molecular targets and matching targeted therapies, thus paving the way for several biomarker-driven pediatric Phase 1/2 trials.
Practice-changing trials
During the live broadcast of the ASCO plenary sessions, a series of trials with the potential to change clinical oncology practice in the United States and the European Union were discussed in detail. The top three considered by ASCO attendees and the reviewing committee to be the most relevant and impactful are:
In the Phase 3 JAVELIN Bladder 100 trial (Abstract LBA1), avelumab addition to best supportive care (BSC) in maintenance treatment of patients with unresectable advanced urothelial carcinoma led to significantly longer overall survival (OS; hazard ratio [HR]=0.56; 95% CI 0.40-0.79; p=0.0003) and progression-free survival (PFS; HR=0.62; 95% CI 0.52-0.75; p<0.001). According to Dr. Thomas Powles, from Queen Mary University of London, the safety profile of avelumab was similar to other immune checkpoint inhibitors (ICIs), thus highlighting its therapeutic potential as a new first-line standard of care (SOC) for advanced urothelial cancer.
The Phase 3 KEYNOTE-177 trial (Abstract LBA4) assessed efficacy and safety of pembrolizumab vs chemotherapy in patients with microsatellite instability-high (MSI-H)/mismatched repair deficient (dMMR) metastatic colorectal cancer. At one year, the PFS, overall survival (OS), and complete response (CR) rates were higher in the pembrolizumab vs the chemotherapy arms (55.3% vs 48.3%, 43.6% vs 33.1%, and 11.1% vs 3.9%). Noteworthy, at a median follow-up of approx. 28 months, median PS was >8 months longer for pembrolizumab, with a 40% reduction in the risk of disease progression or death. Pembrolizumab also displayed a better safety profile, leading to a lower frequency of ≥Grade 3 adverse events (AEs) than chemotherapy (22% vs 66%) and no treatment-related deaths. These clinically meaningful changes put pembrolizumab forward as a potential new SOC for this hard-to-treat patient population.
In the Phase 3 ADAURA trial (Abstract LBA5), adjuvant treatment with the endothelial growth factor receptor (EGFR) inhibitor osimertinib significantly improved disease-free survival (DFS) vs placebo in a large patient population (N=682) with non-small cell lung cancer (NSCLC). In patients with stage II-IIIA NSCLC, an 83% reduction in the risk of disease was recorded following osimertinib vs placebo (DFS HR=0.17; 95% CI 0.12-0.23; p<0.0001), with 2-year DFS rates of 90% vs 44%. Similar results were obtained after inclusion of patients with stage IIIB disease in the analysis, thus making osimertinib the first targeted agent in a global randomized trial to show clinically meaningful DFS improvements in patients with EGFR-mutation-positive NSCLC.