VARIED RESULTS OBSERVED WITH ATEZOLIZUMAB COMBINATIONS IN TNBC
LBA15: Primary results from IMpassion131, a double-blind placebo-controlled randomised phase 3 trial of first-line paclitaxel (PAC) +/- atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC)
LBA16: IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer
Two studies investigating the combination of atezolizumab with chemotherapy for first-line treatment of TNBC were presented at ESMO 2020: IMpassion130, by Dr. Leisha Emens (University of Pittsburgh Medical Center) and IMpassion131, by Dr. David Miles (Mount Vernon Cancer Centre). While both studies investigated the addition of atezolizumab to chemotherapy, IMpassion130 utilized a nab-paclitaxel backbone, while IMpassion131 was based on paclitaxel. Both studies utilized progression-free survival in both the ITT and PD-L1-positive (>1% IC) as primary endpoints.
The final overall survival results of IMpassion130 were presented after a median follow up of at least 18 months in all patients, as OS in the ITT and PD-L1+ populations were also co-primary endpoints in this study. In the ITT population, a numerical increase in median OS was noted for patients receiving atezolizumab and nab-paclitaxel over placebo and nab-paclitaxel, at 21.0 vs 18.7 months (HR: 0.87, p=0.077). Since this difference was not statistically significant, formal testing of the PD-L1+ OS was not performed; however, a clinically meaningful increase was also seen for median OS in this population, at 25.4 vs 17.9 months (HR: 0.67). While a higher incidence of toxicities was noted in the atezolizumab arm, these patients also had longer durations of treatment exposure and the side effects remained manageable.
The IMpassion131 results are slightly less mature than those of IMpassion130, as the primary analysis was presented at ESMO. The primary endpoint of PFS in the PD-L1+ population was not met, with a median PFS of 6.0 months in the atezolizumab arm and 5.7 in the placebo group (HR: 0.82, p=0.20) and thus formal testing of PFS in the ITT group could therefore not be performed. The difference in treatment arms was even smaller in the ITT, with median PFS of 5.7 and 5.6 months for atezolizumab + paclitaxel and placebo + paclitaxel, respectively. The overall response rate was numerically higher in the atezolizumab arm, at 63.4% compared to 55.4%. Interim analysis of OS indicated no benefit for atezolizumab in both the ITT and PD-L1+ groups, with hazard ratios over 1 for each.
While the results of IMpassion131 are still immature, the apparent disconnect between the results of these two studies will certainly require future investigation.
ATEZOLIZUMAB + BEVACIZUMAB AND CHEMOTHERAPY FAILS TO BENEFIT PATIENTS WITH OVARIAN CANCER
LBA31: Primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo (pbo)-controlled randomised phase 3 trial of bevacizumab (bev)-containing therapy +/- atezolizumab (atezo) for newly diagnosed stage III/IV ovarian cancer (OC)
Dr. Kathleen Moore (University of Oklahoma Health Sciences Center) presented the phase 3 trial IMagyn050, which investigated the addition of atezolizumab to a standard bevacizumab-chemotherapy treatment for late-stage ovarian cancer, given the success of this approach in other cancers. Eligible patients either underwent primary cytoreductive surgery and had gross residual disease or had neoadjuvant chemotherapy and interval surgery. Patients were randomized to receive paclitaxel, carboplatin, and bevacizumab in combination with either atezolizumab or placebo, with the primary endpoint of PFS in both the PD-L1+ (IC > 1%) and ITT populations in parallel and OS in the same groups hierarchically.
After a median follow up of around 20 months, there were no significant differences in PFS in either the PD-L1+ or ITT populations; for the ITT, median PFS was 19.5 months with atezolizumab compared to 18.4 with placebo. Likewise, median PFS was only increased by 2.3 months in the PD-L1+ group (20.8 vs 18.5 months, HR: 0.8). In both populations, interim analysis of OS demonstrated hazard ratios near unity, pointing to no apparent benefit of atezolizumab. Exploratory subgroup analysis indicated benefit of atezolizumab for patients with PD-L1 IC > 5% or TC > 1% (PFS HR: 0.64 and 0.41, respectively). Adverse event profiles were as expected, with a higher incidence of serious adverse events in the atezolizumab arm (21% vs 35%). Overall, the study did not meet its endpoints, but some signals pointed to potential of the combination treatment in biomarker-selected populations, including high PD-L1-expressors.
NEOADJUVANT ATEZOLIZUMAB SHOWN TO BE SAFE FOR RESECTABLE NSCLC
1215O: Neoadjuvant atezolizumab (A) for resectable non-small cell lung cancer (NSCLC): results from the phase II PRINCEPS trial
Dr. Benjamin Besse (Gustave Roussy and Paris-Sud University) outlined the results of the phase 2 PRINCEPS trial, examining the impact of a single neoadjuvant dose of atezolizumab for resectable non-small cell lung cancer. Thirty patients received a dose of 1200 mg atezolizumab followed by surgery 21-28 days later, with the primary endpoint of safety – particularly, the two-month tolerance rate. This rate was defined as the absence of major toxicities or morbidities from the start of atezolizumab treatment through one month after surgery. Several imaging scans and pathological analyses were conducted, including 18F-FDG and CT scans prior to atezolizumab and surgery, and pathological analysis of archived tissue before atezolizumab treatment and fresh surgical specimens.
Surgery was completed a median of 24 days after atezolizumab treatment, with 29/30 patients undergoing R0 resection. No patients experienced a delay in surgery over 15 days, and there were no grade 4/5 complications. Within a month after surgery, 23% of patients experienced some form of complication. Responses were analyzed in a number of ways prior to surgery. By RECIST using CT scans, the response rate was 7%, which included two patients with partial responses. The remainder of patients had stable disease. Using pathological analysis of excised tumors, the MPR rate was 4/30, with another 41% of patients having a pathological response of greater than 50%. Finally, metabolic responses on FDG scans varied widely, with 25% of patients showing an increase in SUVmax of 20% or more, and another 11% having an SUVmax decrease of 20% or more. No correlations were seen between pathological response and either RECIST or metabolic responses; however, high PD-L1 expression in tumor samples at baseline did correlate with pathologic response. This study therefore demonstrated that neoadjuvant atezolizumab is safe, though response rates can still be improved.
A review from the Journal for ImmunoTherapy of Cancer (JITC) outlined current evidence for immunotherapies in NSCLC.
COMBINATION NIVOLUMAB AND CABOZANTINIB DEMONSTRATES BENEFIT FOR ADVANCED RCC
696O_PR: Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial
Given the efficacy that has been observed with nivolumab and cabozantinib monotherapies in advanced renal cell carcinoma, Dr. Toni Choueiri (Dana-Farber Cancer Institute) presented the CheckMate 9ER trial of nivolumab and cabozantinib combination therapy for aRCC with a clear cell component. The primary endpoint of the study was progression-free survival, and results were presented after a median follow up of 18.1 months.
At this first analysis, the study met all of its efficacy endpoints. The median PFS by BICR was doubled in patients receiving nivolumab + cabozantinib over sunitinib, at 16.6 vs 8.3 months (HR: 0.51, p < 0.0001). This trend was evident throughout the study, with a clear separation of the PFS curves from the start of the trial and continuing onward. While the median OS was not reached in either group, the combination treatment still showed a significant benefit, with a HR of 0.60 (p=0.001). Overall response rates and the duration of response also favored nivolumab + cabozantinib. Adverse events leading to discontinuation of at least one therapeutic component occurred in 15.3% of patients in the combination arm and 8.8% of those receiving sunitinib. Grade 3+ adverse events were similar in both arms at 75% and 71%. The benefits seen with the combination treatment also led to better HRQoL scores for these patients. Overall, this study demonstrates a strong immunotherapy combination option for patients with aRCC.
BIOMARKER ANALYSIS HELPS SELECT PROPER THERAPIES FOR ADVANCED KIDNEY CANCER
LBA25: Results from the phase 2 BIOmarker driven trial with Nivolumab (N) and Ipilimumab or VEGFR tyrosine Kinase inhibitor (TKI) in naïve metastatic Kidney cancer (m-ccRCC) patients (pts): the BIONIKK trial
The BIONIKK trial, investigating biomarker-driven treatment selections for metastatic clear cell renal cell carcinoma, was presented by Dr. Yann-Alexandre Vano (Hôpital Européen Georges-Pompidou). The study was founded on four previously identified gene signature classes: class 1 was “immune-low”, class 2 was “angiogenesis-high”, class 3 was “normal-like” and class 4 was “immune-high”. Patients in classes 1 and 4 received either nivolumab monotherapy or nivolumab and ipilimumab, while those in classes 2 and 3 received nivolumab/ipilimumab or a tyrosine kinase inhibitor. The primary endpoint was overall response rate.
The cohorts were not evenly divided, with 64, 59, 7 and 33 patients in classes 1, 2, 3 and 4 respectively. Within the immune-low class 1, a higher response rate and prolonged PFS were seen with nivolumab/ipilimumab over nivolumab monotherapy: ORRs were 39.4% and 20.7%, while median PFS was 8.0 vs 4.6 months. The immune-high patients in class 4 had similar benefit from both therapies, with ORRs of 53% and 50% for combination and monotherapy, and median PFS of 12.2 and 7.8 months. The angiogenesis-high cohort benefitted from TKI treatment, increasing the ORR from 48.3% with nivo/ipi to 53.8% with TKI. Given the small size of cohort 3, analysis is immature; however, the only responses were seen after treatment with nivolumab/ipilimumab. Overall survival data is immature across the study. The highest rate of grade 3+ adverse events occurred with TKI treatment at 55%, followed by 44% with nivolumab/ipilimumab and 18% with nivolumab monotherapy. Additional biomarker analysis is ongoing and may be able to further guide rational selection of therapies for patients based on their unique tumor characteristics.
A recent article from JITC investigated biomarkers of response for immunotherapy and targeted therapy for advanced renal cell carcinoma.
COMBINATION IMMUNOTHERAPY MAY BENEFIT PD-L1+ ADVANCED UROTHELIAL CARCINOMA
697O: A phase 3, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE)
Dr. Thomas Powles (Barts Cancer Center) presented the DANUBE trial, a phase 3 study to investigate three therapeutic regimens for first-line management of locally advanced or metastatic urothelial cancer: durvalumab, durvalumab + tremelimumab, or chemotherapy. The primary endpoint was OS, with slightly different criteria across arms: for durvalumab compared to chemotherapy, the primary endpoint was OS in the PD-L1+ population (>25% CPS), while for durvalumab + tremelimumab the endpoint was OS in the ITT population. Median follow up was 41 months.
The median overall survival in patients with PD-L1-positive disease receiving durvalumab was 14.4 months, compared to 12.1 months in PD-L1-positive patients receiving chemotherapy. This difference was not statistically significant, with a hazard ratio of 0.89 and a characteristic “crossing of the curves” was evident – that is, chemotherapy outperformed durvalumab for the first 9-12 months, with durvalumab then having more benefit after that point. In the ITT population, the median OS for durvalumab + tremelimumab was 15.1 months and 12.1 months for chemotherapy (HR: 0.85), with a crossing of the curves again present. Interestingly, over 50% of patients receiving durvalumab had progressive disease as their best response, compared to <20% with chemotherapy. Higher response rates were noted for the two immunotherapy regimens for patients with PD-L1-positive disease, leading to a clinically meaningful benefit for PD-L1+ patients treated with durvalumab + tremelimumab (HR: 0.74), though this could not be formally statistically tested. The incidence of adverse events was also lower in the immunotherapy arms than the chemotherapy arm. This study therefore points to a potential application of combination PD-1 and CTLA-4 inhibition in PD-L1+ advanced urothelial cancer, though further investigation is warranted.
SEQUENCING OF TARGETED THERAPY AND IMMUNOTHERAPY INVESTIGATED FOR MELANOMA
LBA45: First report of efficacy and safety from the phase II study SECOMBIT (SEquential COMBo Immuno and Targeted therapy study)
Dr. Paolo Ascierto (National Tumour Institute Fondazione “G. Pascale”) discussed an investigation of the optimal sequencing of targeted therapy and immunotherapy for patients with BRAF V600-mutated melanoma. The targeted therapies (TT) in the trial were encorafenib and binimetinib, while the immunotherapies (IO) were ipilimumab 3 mg/kg and nivolumab 1 mg/kg. Three regimens were investigated: TT followed by IO at progression (arm A), IO followed by TT at progression (arm B), and a “sandwich” approach in arm C, with 8 weeks of TT followed by IO until progression and then TT again. The primary endpoint of the trial was OS, for which data were not yet mature.
A few characteristics were slightly imbalanced across groups, with more patients with LDH > 1xULN and >3 lesion sites in arm B, with other characteristics largely matched including LDH >2xULN and M1c disease. After a median follow up of 17.5 months, over 30 patients were still on treatment on each arm. The median PFS on the first treatment for patients in arms A, B and C were 15.8, 7.2 and 11.4 months, respectively; this difference between arms was lost at two years, with rates of PFS across all arms between 35 and 39%. The total PFS rate at two years (which included both treatments in sequence) was 48%, 58% and 62%, respectively, for arms A, B and C. Grade 3-4 treatment-related adverse events were most common in arm B at 54%, compared to 28% in A and 32% in C. Continued follow up of this study is ongoing, with overall survival and biomarker data expected in the coming year.
NOVEL MYELOID-SPECIFIC ANTIBODY EXPLORED IN SOLID TUMORS
524O: Initial Results of a Phase 1 Study of MK-4830, a First-in-Class Anti–immunoglobulin-like Transcript 4 (ILT4) Myeloid-Specific Antibody in Patients (pts) With Advanced Solid Tumors
A phase 1 trial of an ILT4-specific antibody was presented by Dr. Lillian Siu (Princess Margaret Cancer Center). The trial enrolled patients with advanced solid tumors to receive escalating doses of MK-4830 as monotherapy or in combination with pembrolizumab. Doses of MK-4830, which is an IgG4 monoclonal antibody targeting myeloid-specific ILT4, ranged from 3 to 1600 mg, with the primary goal of evaluating safety and tolerability.
Fifty patients were treated in the dose escalation monotherapy cohort, 18 of which then crossed over to combination treatment at progression. Thirty-four patients were treated with the combination up front. Grade 3-4 treatment-related adverse events occurred in 6% of monotherapy patients and 8% in the combination group, with no maximum tolerated dose defined. Target saturation was observed at monotherapy doses of 300 mg or greater, and the 800 mg dose level was chosen for future investigation. Overall response rate was modest with monotherapy, with one patient achieving a partial response; however, in the combination group, the ORR was 24%, which included five patients with prior progression on PD-1/PD-L1 therapy. Of patients that crossed over from monotherapy to the combination, 6% demonstrated an objective response. Expansion cohorts in a variety of cancers are being planned for future investigation.
Continue reading about the importance of myeloid cells in immune responses to cancer in this JITC article.
TUMORS WITH PATHOGENIC POLE MUTATIONS MAY BENEFIT FROM NIVOLUMAB TREATMENT
526O: High activity of Nivolumab in patients with pathogenic exonucleasic domain POLE (edPOLE) mutated Mismatch Repair proficient (MMRp) advanced tumors
Dr. Benoit Rousseau (Memorial Sloan Kettering Cancer Center) discussed an investigation of nivolumab in advanced tumors with missense exonucleasic domain POLE mutations and mismatch repair proficiency. The primary endpoint of the trial was the overall response rate at 84 days for the 16 enrolled patients, with a median follow up of 7 months for this report.
Across all patients, the overall response rate was 38%, with the most responses seen in patients with colorectal and endometrial cancers. This led to a median PFS of 5.3 months. The pathogenicity of the POLE mutations in the enrolled patients was evaluated, and 8 were found to be pathogenic; 5 were non-pathogenic; and 3 were of unknown pathogenicity. Responses were found to vary by the pathogenicity of mutations, with ORRs of 50%, 0%, and 66% for patients with pathogenic, non-pathogenic, and unknown mutations, respectively. The PFS benefit was also restricted to those with pathogenic or unknown mutations. Given these results, future investigation in this study is restricted to patients with pathogenic POLE mutations.
Learn more about POLE mutations and immune responses in a recent article from JITC.
SEVERAL STUDIES INVESTIGATE POTENTIAL OF NIVOLUMAB FOR GASTROINTESTINAL CANCERS
LBA6: Nivolumab (NIVO) Plus Chemotherapy (Chemo) Versus Chemo as First-Line (1L) Treatment for Advanced Gastric Cancer/Gastroesophageal Junction Cancer (GC/GEJC)/Esophageal Adenocarcinoma (EAC): First Results of the CheckMate 649 Study
LBA7: Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study
LBA9: Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer (EC/GEJC) Following Neoadjuvant Chemoradiation Therapy (CRT): First Results of the CheckMate 577 Study
Several studies presented during a Presidential Session at ESMO 2020 discussed the potential of immunotherapy for gastric, gastroesophageal junction, and esophageal cancers. These included the Checkmate 649 study, presented by Dr. Markus Moehler (Johannes-Gutenberg University Clinic), ATTRACTION-4, discussed by Dr. Narikazu Boku (National Cancer Center Hospital, Tokyo), and CheckMate 577, presented by Dr. Ronan Kelly (Charles A. Sammons Cancer Center at Baylor University Medical Center). CheckMate 649 and ATTRACTION-4 involved first-line treatment options, while CheckMate 577 investigated adjuvant nivolumab.
The results presented from CheckMate 649 compared nivolumab and chemotherapy combination treatment to chemotherapy alone in a cohort of over 1500 previously untreated patients. The primary endpoints of the trial were OS and PFS, tested first in PD-L1 CPS > 5 and then in other groups. Overall survival was significantly extended in the PD-L1-high population with the combination treatment compared to chemotherapy alone, at 14.4 compared to 11.1 months (HR: 0.71, p < 0.0001). The trend for longer OS with nivolumab/chemotherapy carried across the PD-L1 > 1 and ITT populations as well. Similarly, the median PFS was extended with the combination treatment, with hazard ratios across all investigated groups below 0.77. The safety profile was as expected in both groups, with no new signals.
The ATTRACTION-4 trial also tested nivolumab and chemotherapy or chemotherapy for frontline management of G/GEJ cancers, only in patients from Japan, Korea, or Taiwan. This trial did not report outcomes by PD-L1 status for the primary endpoints of OS and PFS. At interim analysis, median PFS significantly favored the nivolumab arm, at 10.45 months compared to 8.34 months (HR: 0.68, p = 0.0007). However, the final OS results were not significant, as median OS was 17.45 months with nivolumab and 17.15 months with placebo (HR: 0.90, p = 0.257). Higher overall response rates were noted with the nivolumab combination, as well as longer duration of response. Safety profiles were in line with expectations. It may be likely that subsequent treatments for patients on the placebo arm impacted the OS results, leading to a significant PFS benefit without an OS improvement.
Adjuvant immunotherapy was tested in CheckMate 577, wherein patients were treated with neoadjuvant chemoradiotherapy followed by R0 resection and then randomized to nivolumab or placebo for one year with the primary endpoint of disease-free survival. This interim report, after a median follow up of 24.4 months, demonstrated a significant improvement in DFS in patients receiving nivolumab, at 22.4 months compared to 11.0 months (HR: 0.69, p = 0.0003). Importantly, the safety profile for nivolumab treatment was acceptable with a low incidence of serious adverse events. Health status reports by patients also demonstrated similar outcomes with either nivolumab or placebo. Taken together, the results of this study point to a safe, effective adjuvant option for patients with esophageal or gastroesophageal junction cancers.
PEMBROLIZUMAB + RT MAY BE SAFER, BUT NO MORE EFFECTIVE THAN CETUXIMAB + RT FOR LA-HNSCC
LBA38: Pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): Results of the GORTEC 2015-01 “PembroRad” randomized trial
Dr. Yungan Tao (Gustave Roussy) presented the findings of the phase 2 PembroRad trial, in which patients with stage III-IVa-b head and neck cancer and unfit for cisplatin were treated with standard once-daily IMRT to 70 Gy concomitant with either cetuximab or pembrolizumab at standard dosing. The primary endpoint of the study was the 15-month loco-regional control rate, and the results were presented after a median follow-up of 25.6 months.
Efficacy results were very similar between the two arms for all primary and secondary endpoints. Statistical significance was not achieved for the primary endpoint of 15-month loco-regional control, with a rate of 60% in the pembrolizumab arm and 59% in the cetuximab arm, with an OR of 1.05. The landmark PFS and OS rates were also not significantly different with the two treatments: the 2-year PFS rate was 42% for pembrolizumab and 40% for cetuximab (HR: 0.83), while the 2-year OS rates were 62% and 55%, respectively (HR: 0.83). The safety profiles did differ across arms, with a higher incidence of grade 3+ acute events in the cetuximab arm than in the pembrolizumab arm (92% vs. 74%, respectively; p=0.006). The incidence of radiotherapy-related adverse events was higher in the cetuximab arm, mainly accounting for the difference between the two therapies. Hypothesized reasons for the lack of benefit with pembrolizumab in this study include insufficient doses of pembrolizumab, potential adverse impact of elective total neck irradiation, and a lack of biomarker-based patient selection.
A study of biomarkers in head and neck cancer was recently published in JITC.
NO BENEFIT FOR AVELUMAB ADDITION TO CRT FOR LOCALLY ADVANCED HEAD AND NECK CANCER
910O: Primary results of the phase 3 JAVELIN Head & Neck 100 trial: avelumab plus chemoradiotherapy (CRT) followed by avelumab maintenance vs CRT in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN)
The results of the JAVELIN Head & Neck 100 trial were discussed by Dr. Ezra Cohen (University of California – San Diego), which explored the potential of avelumab in addition to standard-of-care chemoradiation therapy (CRT) in patients with locally advanced squamous cell head and neck cancer. While many studies have investigated immunotherapy for recurrent/metastatic head and neck cancer, their application to locally advanced disease has been less explored. This trial randomized patients to either avelumab + CRT followed by avelumab maintenance, or placebo + CRT and placebo maintenance for up to one year. The primary endpoint was investigator-assessed PFS.
As an interim analysis crossed the futility boundary, the study was unblinded. The treatment exposure was similar in the two arms, with a median duration of treatment of 9.8 months for the avelumab arm and 12.4 months for placebo. At the time of analysis, over 80% of patients had entered the maintenance phase in both arms. While the median PFS was not reached for either arm of the study, the hazard ratio for PFS was 1.21, in favor of the placebo arm. While not statistically significant, subgroup analysis did indicate a potential benefit for avelumab treatment in patients with high expression of PD-L1 at baseline. Overall survival results also favored the placebo arm, with a hazard ratio of 1.31. Overall response rates were similar, at 74 and 75%, while a slightly higher rate of grade 3+ adverse events was noted in the avelumab arm (88% vs 82%). Overall, while the results of this study were negative, the investigators are exploring the potential impact of this trial for future study designs.