The year 2019 has offered up many advances in immunotherapy. These advances shed light on such important aspects as biomarkers, better targeted therapies, chemotherapy outcomes, and resistance. Summarized herein are several high-profile conference presentations that highlight key advances in the field.

The year has not quite come to an end yet, but as predicted by many experts in the field, 2019 has offered up many advances in immunotherapy. These advances shed light on such important aspects as biomarkers, better targeted therapies, chemotherapy outcomes, and resistance. Summarized herein are several high-profile conference presentations that highlight key advances in the field.

From the Mystic trial

Researchers explored the relationship between STK11, KEAP1, and ARID1A mutations and chemotherapy outcomes/prognostic factors in a follow-up to the phase III MYSTIC trial. Results were presented at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer (WCLC).[1]

In phase III MYSTIC trial patients with metastatic non-small-cell lung cancer (NSCLC) without epidermal growth-factor receptor and anaplastic lymphoma kinase mutations, investigators compared durvalumab monotherapy and durvalumab–tremelimumab with chemotherapy versus standard-of-care platinum-based chemotherapy as first line treatment.[2,3] A subset of patients with high tumor mutational burden (TMB) was examined in the current follow-up.High tumor mutational burden was defined as more than 20 mutations/megabase.[1] Of note, although the MYSTIC trial did not reach its primary endpoint in terms of overall survival (OS), the hazard ratio of combination therapy was 0.85 (98.77% CI, 0.611–1.173; P = .202), which suggested that further exploration of patient subsets was warranted.[2,3]

In the 943 patients from the study population that could be evaluated, the frequency of STK11, KEAP1, and ARIDIA mutations was 16%, 18%, and 12%, respectively. In the general population, after p53 and KRAS mutations, STK11 and KEAP1 are the most common lung cancer mutations.[1]

In his presentation, primary author Naiyer A. Rizvi, MD, director of thoracic oncology for the division of hematology/oncology at Columbia University Medical Center in New York, stated: “ARID1A patients are about 10% of the population and seem to do particularly well with durvalumab–tremelimumab. The key finding is the response rate of patients with ARID1A mutations in the durvalumab–tremelimumab arm being pretty impressive as well as overall survival in this patient population. The STK11-KEAP1 mutations also influence outcomes and need to be factored into our analysis of TMB and other outcomes of lung cancer.”[1]

New hope for advanced urothelial cancer

For patients with urothelial cancer who progress after receiving platinum/checkpoint inhibitors, few treatment options exist. Enfortumab vedotin (EV) could be effective in these patients, according to preliminary results from the EV-201 trial presented at ASCO 2019.[4]

The phase II results closely replicate the results from phase I according to primary author Daniel P. Petrylak, MD, professor of medicine and urology at Yale Cancer Center in New Haven, Connecticut. This therapy may be instrumental for patients who don’t benefit from checkpoint inhibitors.[5]

In this open-label, single-arm, phase II study, patients were given 1.25 mg/kg EV on days 1, 8, and 15 of each 28-day cycle, with the primary outcome being objective response rate (ORR). Secondary outcomes were progression-free survival (PFS), overall survival (OS), duration of response, and safety/tolerability. Patients with locally advanced or metastatic urothelial cancer (squamous differentiation or mixed cell types allowed) were split into two cohorts. Cohort 1 included participants with prior checkpoint inhibitor treatment and platinum-containing chemotherapy, and cohort 2 included patients who only received checkpoint inhibitor therapy.[4]

At the conference, results from cohort 1 (N = 128; 70% men; median age, 69 years; median of 2 prior systemic therapies) were presented. Petrylak et al found that about 44% of patients experienced tumor shrinkage or no tumor growth, thus responding to treatment. An additional 12% of patients were free of detectable disease.[4,5]

With respect to previous treatments, 41% of patients who did not respond to checkpoint inhibitors did respond to EV, with 38% of those with liver metastases specifically responding. The median OS in patients from cohort 1 was 11.7 months. Overall, tolerability and safety of the drug were good.[5]

Utility of TMB

Tumor mutational burden is a measurement of mutations carried by tumor cells and is a predictive biomarker being studied to evaluate its association with response to immunotherapy. TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker across some cancer types.For some time, researchers have wondered about the value of tumor mutational burden (TMB) as a predictive marker fro response to immunotherapy. In disappointing news, TMB has been found to not be related to the efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy in patients with metastatic nonsquamous NSCLC.

During a presentation at IASLC 2019 WCLC, first author Marina C. Garassino, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, stated the following: “Our data suggest that tissue TMB may not help select patients who would have better outcomes with the combination of pembrolizumab plus pemetrexed and a platinum given as first-line therapy for metastatic nonsquamous NSCLC. Pembrolizumab plus chemotherapy had a similar overall survival benefit in the TMB-high and TMB-low subgroups.”[6]

In the trial, 616 patients were randomized 2:1 to receive either pembrolizumab and chemotherapy or placebo with chemotherapy. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. The clinical utility of TMB on outcomes was assessed using prespecified TMB cut points of 175 and 150 Mut/.To measure the clinical importance of TMB, prespecified TMB thresholds were established.

For either chemotherapy alternative, TMB was not associated with OS, ORR, or PFS in patients who could be evaluated. Notably, baseline characteristics in the study population were similar to the general population.[6]

At the conference, Corey J. Langer, MD, director of thoracic oncology at the University of Pennsylvania Abramson Cancer Center, presented another similar study examining the relationship between TMB and pembrolizumab.[7]

“I think it’s still an investigational marker,” he said. “From my own perspective as a clinical researcher, the approach to TMB can be divided into two groups: the TMB cultists and the TMB skeptics. I would group myself in the latter. Although I still think it has a potential role, we haven’t figured it out. It would not be used, at least not yet, in therapeutic decision making.”[7]

Dr. Langer also opened the door to further considerations regarding TMB. For instance, he wondered whether patients with high TMB and programmed death ligand-1 expression would perform well with different combinations of immunotherapy and chemotherapy agents. He also wondered whether blood samples would more accurately mirror TMB levels as compared with single tissue samples, which were used in the study.

Surmounting anti-PD1 resistance

In patients who had progressed with melanoma after previous anti-programmed death 1 (PD-1) treatment, the experimental histone deacetylase (HDAC) inhibitor entinostat plus anti-PD-1 therapeutic pembrolizumab showed early efficacy per results of an open-label, single-arm, phase Ib/2 trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2019.[8]

“A number of studies, including this trial, are endeavoring to identify key immunotherapy combinations to overcome resistance to checkpoint blockade immunotherapy,” stated Ryan Sullivan, MD, an assistant professor of hematology and oncology at Massachusetts General Hospital Cancer Center in Boston.

Patients received 5 mg orally of entinostat weekly plus 200 mg intravenously of pembrolizumab every 3 weeks in this single-arm trial, with the primary outcome being ORR. The median duration of prior anti-PD-1 treatment was 4.9 months. Partial response was evidenced in 9 of 53 patients, with one patient experiencing complete response. The ORR in the study was 19%.[8]

“Our results suggest that this combination may be an active regimen for patients who never responded to or progressed during treatment with PD-1 inhibitors,” said Dr. Sullivan. “A key next step will be to identify a biomarker to better determine which patients will respond to this treatment.”[8]

Financial Disclosure: The author and reviewer have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Rizvi N, Cho BC, Reinmuth N, et al. Mutations associated with sensitivity or resistance to immunotherapy in MNSCLC: analysis from the Mystic trial. Presented at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer; September 8, 2019; Barcelona, Spain. Abstract OA04.07.

2. ClinicalTrials.gov. Phase III open label first line therapy study of MEDI 4736 (durvalumab) with or without tremelimumab versus SOC in non small-cell lung cancer (NSCLC) (MYSTIC). NCT02453282.

3. AstraZeneca provides update on the Phase III MYSTIC trial of Imfinzi and tremelimumab in stage IV non-small cell lung cancer. [Press release] November 16, 2018.

4. Petrylak DP, Balar AV, O’Donnell PH, et al. EV-201: results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol. 2019;37(suppl):abstr LBA4505.

5. ASCO Post. 2019 ASCO: Enfortumab vedotin shows activity in previously treated, locally advanced or metastatic urothelial cancer. Updated August 5, 2019. Available at: https://www.ascopost.com/News/60108. Accessed September 30, 2019.

6. Garassino M, Rodriguez-Abreu D, Gadgeel S, et al. Evaluation of TMB in keynote-189: pembrolizumab plus chemotherapy vs placebo plus chemotherapy for nonsquamous NSCLC. Presented at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer; September 8, 2019; Barcelona, Spain. Abstract OA04.06.

7. Langer C, Gadgeel S, Borghaei H, et al. TMB and outcomes for carboplatin and pemetrexed with or without pembrolizumab for nonsquamous NSCLC. Presented at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer; September 8, 2019; Barcelona, Spain. Abstract OA04.05 Keynote-021.

8. Sullivan RJ, Moschos SJ, Johnson ML et al. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy. Presented at the American Association for Cancer Research (AACR) Annual Meeting; April 1, 2019; Atlanta, GA. Abstract CT072.