Jordan Hill, PharmD BCOP
Ambulatory Oncology Pharmacy Specialist, Solid Tumors
West Virginia University Medicine
Morgantown, WV

The 2019 American Society of Clinical Oncology–Society for Immunotherapy of Cancer (ASCO-SITC) Clinical Immuno-Oncology Symposium was held February 28–March 2, 2019, in San Francisco, CA. The following is a summary of the highlights.

Lung Cancer

Nivolumab Dosing in Advanced Non-Small-Cell Lung Cancer
Two different dosing schedules of nivolumab were investigated for the treatment of advanced non-small-cell lung cancer (NSCLC) in the Checkmate 384 trial. Patients were randomized to receive nivolumab 240 mg every 2 weeks (n = 163) or 480 mg every 4 weeks (n = 166). The median progression-free survival (PFS) was similar, at 12.1 months and 12.2 months, respectively. Toxicities were also similar, with 61% of patients experiencing a treatment-related adverse event (AE) in the every-2-week group and 48% in the every-4-week group, showing that a more convenient dosing schedule is both safe and effective for treating NSCLC.¹

Neoadjuvant Atezolizumab in Resectable NSCLC
Immunophenotyping data of two cycles of neoadjuvant atezolizumab (day 1 and 22) prior to resection for NSCLC were presented. Of the 54 patients who had follow-up through surgery, 15 patients had a grade 3-4 AE, 3 of which were treatment-related. The primary objective was major pathological response, defined as ≤10% viable tumor. Ten of the 45 patients evaluated achieved this response. The authors also noted that almost all patients had some degree of pathologic regression. There were 3 patients with partial response (PR), and 49 had stable disease (SD); the study plans to accrue a total of 180 patients.²

Plasma ctDNA Predict Response to Nivolumab
Targeted gene sequencing of plasma circulating tumor DNA was analyzed in 98 patients receiving nivolumab in the second-line setting for advanced NSCLC. Samples were collected before treatment and 1 month into treatment. In patients with a PTEN or STK11 mutation, the median PFS was 2 months, compared to 8 months in patients without these mutations.  In patients with KRAS or TP53 mutations, the median PFS was 11 months, compared to 2 months for those without these mutations. The authors concluded that using plasma gene sequencing covering a limited number of relevant mutations could predict responders to immunotherapy versus those who should be treated with chemotherapy.³

Combination Immunotherapy

Anti-TIM-3 Antibody Alone or in Combination with an Anti-PD-L1 Antibody for Relapsed or Refractory Solid Tumors
In an ongoing phase 1 trial, patients with relapsed or refractory advanced solid tumors were randomized to receive either anti-TIM-3 antibody LY3321367 alone (n = 23) or in combination with anti-programmed death-ligand 1 (PD-L1) antibody LY3300054 (n = 18). No dose-limiting toxicities occurred in either arm. One patient experienced a grade-3 toxicity (anemia). Efficacy data was available for the monotherapy cohort: 1 patient with a PR and 10 patients with SD, for a disease control rate (DCR) of 48%. Expansion cohorts with both monotherapy and combination therapy are ongoing in various malignancies such as lung, gastric, head and neck, and bladder cancers.⁴

Ipilimumab, Nivolumab, and Trabectedin for Soft-Tissue Sarcoma
The SAINT phase 1/2 trial investigated ipilimumab 1 mg/kg, nivolumab 3 mg/kg, and escalating doses of trabectedin in the first-line treatment of advanced soft-tissue sarcoma. In phase 2 (n = 16), 3 patients had a PR, and 11 patients had SD, yielding a DCR of 87.5%, with the most common AE being elevations in liver function tests. The authors concluded that this regimen is safe and may control tumor growth in patients with advanced soft-tissue sarcoma. This trial is ongoing.⁵

NKTR-262 with NKTR-214 in Patients with Advanced or Metastatic Solid Tumors
The currently enrolling REVEAL study is a phase 1b/2 trial investigating NKTR-262 (a Toll-like receptor 7/8 agonist) with NKTR-214 (a CD122 agonist) in advanced or metastatic solid tumors. Of the 7 efficacy-evaluable patients (4 with melanoma, 2 with sarcoma, and 1 with colorectal cancer), 6 had a PR or SD. Two of the 4 melanoma patients had a PR, while both sarcoma patients had SD. These agents are now being studied in combination with nivolumab in a phase 2 study.⁶

Ovarian Cancer

IL-12 Plasmid Given Intraperitoneally with Neoadjuvant Chemotherapy in Advanced Ovarian Cancer
In a dose-escalation phase 1 trial, weekly intraperitoneal GEN-1 was given in combination with weekly paclitaxel and every-3-week carboplatin to 18 advanced epithelial ovarian cancer patients. The most common treatment-related toxicities were nausea, abdominal pain, and fatigue, and 12 patients received all eight scheduled doses with no dose-limiting toxicities. Two patients had a complete response (CR), 10 had a PR, and 2 had SD at the time of interval debulking surgery. GEN-1 is currently being investigated in an ongoing phase 1/2 study.⁷

Melanoma

Checkpoint Inhibitor–Experienced Patients in the COSMUS-1 Trial
Patterns of use and safety of talimogene laherparepvec (T-VEC) in the real-world setting were presented in the COSMUS-1 trial. Here, patients who had previously received checkpoint inhibitor therapy were analyzed. Of the 33 patients who had received a checkpoint inhibitor, 21 received T-VEC alone, and 12 received T-VEC while continuing their checkpoint inhibitor. In the monotherapy group, 3 patients had a pathologic CR or no remaining injectable lesions, and in the combination therapy group, 2 patients continue on therapy. AEs occurred in 33% of the monotherapy group and in 50% of the combination group, and all were consistent with the known safety profile of the agents. Given this subset analysis, the authors concluded that further studies are warranted to understand the use of T-VEC following therapy with checkpoint inhibitors.⁸

Certain Cytokine Elevations and Prediction of Immune-Related Adverse Events with Checkpoint Inhibitors
Forty-five patients’ blood samples were collected at the University of Colorado Comprehensive Cancer Center prior to the patients’ starting treatment with a checkpoint inhibitor for melanoma. Tumor necrosis factor (TNF) alpha was elevated in 60% of the patient samples, and interferon (IFN) alpha 2 was elevated in 44%. Grade-3 toxicities occurred in 79% of patients with baseline elevations of TNF alpha and in 68% with baseline elevations of IFN alpha 2, compared to less than 30% incidence in all other biomarkers tested, suggesting that baseline elevations of either are associated with higher grades of immune-related AEs; however, no associations between the number or type of AEs patients experienced in relation to elevations were seen.⁹

Hematologic Disease

NK Cells Administered After Haploidentical Transplantation
A phase 1 dose-escalation trial at MD Anderson Cancer Center investigated the antitumor and antiviral effect of infusions of mb-IL21 ex vivo expanded NK cells administered peri-transplant (day -2 and days +7 and +28) to 25 patients with myeloid malignancies (18 with acute myeloid leukemia or myelodysplastic syndrome and 7 with chronic myelogenous leukemia). The cumulative incidence of grade-2 acute graft versus host disease was 38% at day 100, and 2-year treatment-related mortality was 21%. The 1-year relapse rate was 8%, and 10 patients had reactivated CMV. Lower relapse rates and viral reactivation post-transplant suggest that NK cells exert antitumor and antiviral effects.¹⁰

The 2020 ASCO-SITC Clinical Immuno-Oncology Symposium will be held February 6–8 in Orlando, FL.

References

1. Garon, EB, Reinmuth N, Falchero L, et al. CheckMate 384: phase IIIb/IV trial of nivolumab (nivo) 480 mg Q4W versus 240 mg Q2W after ≤ 12 months of nivo in previously treated advanced NSCLC. Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28–March 2, 2019; San Francisco, CA. Abstract 100.
2. Oezkan F, He K, Owen DH, et al. Neoadjuvant atezolizumab in resectable NSCLC patients: updated clinical and immunophenotyping results from a multicenter trial. Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28-March 2, 2019; San Francisco, CA. Abstract 99.
3. Guibert, N, Jones G, Beeler, JF, et al. Targeted sequencing of plasma cell-free DNA to predict response to PD1 inhibitors in advanced non-small cell lung cancer. Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28–March 2, 2019; San Francisco, CA. Abstract 103.
4. Harding JJ, Patnaik A, Moreno V, et al. A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): interim safety, efficacy, and pharmacokinetic findings in advanced cancers. Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28–March 2, 2019; San Francisco, CA. Abstract 12.
5. Chawla SP, Chua-Alcala VS, Kim, K. The SAINT: initial results of a phase I/II study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma. Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28–March 2, 2019; San Francisco, CA. Abstract 22.
6. Diab A, Marcondes M, Kotzin B, et al. Phase Ib: preliminary clinical activity and immune activation for NKTR-262 [TLR 7/8 agonist] plus NKTR-214 [CD122-biased agonist] in patients (pts) with locally advanced or metastatic solid tumors (REVEAL phase Ib/II trial). Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28–March 2, 2019; San Francisco, CA. Abstract 26.
7. Thaker PH, Bradley WH, Leath CA, et al. Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced-stage ovarian cancer. Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28–March 2, 2019; San Francisco, CA. Abstract 2
8. Perez M, Amatruda T, Conry RM, et al. Checkpoint inhibitor (CPI) experienced patients (pts) from COSMUS-1: a clinical observational study of talimogene laherparepvec (T-VEC) in United States practice. Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28–March 2, 2019; San Francisco, CA. Abstract 142.
9. Head L, Gorden N, Van Gulick R, et al. Biomarkers to predict immune-related adverse events with checkpoint inhibitors. Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28–March 2, 2019; San Francisco, CA. Abstract 131.
10. Ciurea SO, Saliba R, Soebbing D, et al. Enhanced antitumor effect and lower viral reactivation with high doses of ex vivo expanded NK cells administered after haploidentical transplantation. Presented at 2019 ASCO-SITC Clinical Immuno-Oncology Symposium; February 28–March 2, 2019; San Francisco, CA. Abstract 74.