The wealth of new data available for the treatment of patients with non–small cell lung cancer has led to numerous effective immunotherapy combinations in similar patient subsets, explained Karen L. Reckamp, MD, MS. Clinical trials going forward seem to primarily focus on the combination of immunotherapeutic and targeted agents, which may result in even more options for this tumor type.
Karen L. Reckamp, MD, MS
The wealth of new data available for the treatment of patients with nonsmall cell lung cancer (NSCLC) has led to numerous effective immunotherapy combinations in similar patient subsets, explained Karen L. Reckamp, MD, MS. Clinical trials going forward seem to primarily focus on the combination of immunotherapeutic and targeted agents, which may result in even more options for this tumor type.
“Part of the issue that we see is that this area is getting more and more data. And as we get more and more data, even with the experts, there is less consistency in how you can treat a patient,” Reckamp, medical director of clinical research operations at City of Hope Comprehensive Cancer Center in Duarte, California, said to an audience at the20th AnnualInternational Lung Cancer Congress, hosted by Physicians’ Education Resource®, LLC.1“It’s not so crystal clear today.”
Reckamp focused her presentation on the advances announced exclusively in 2019, with a look to ongoing trials. One prevalent theme across studies in 2019 is a lack of clarity on the role of tumor mutational burden (TMB), she said. Moreover, as more trials continue, the synergies between anti-angiogenesis inhibitors and immune checkpoint inhibition will usher in several more combinations in the near future.
Although a negative trial overall, the MYSTIC study provided some evidence of the role of TMB in NSCLC, Reckamp noted. In this phase III trial, patients with stage IV NSCLC were randomized to receive the PD-L1 inhibitor durvalumab (Imfinzi) alone (n = 374) or in combination with the CTLA-4 inhibitor tremelimumab (n = 372) compared with a control arm of platinum-based chemotherapy (n = 372).2
In a blood-based TMB analysis presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, patients with TMB ≥8 mutations per megabase experienced a significant improvement in overall survival (OS) with the durvalumab/tremelimumab combination compared with chemotherapy (HR, 0.79; 95% CI, 0.63-0.98). This benefit became more pronounced as that number increased, with the most impressive findings seen at ≥20 mutations per megabase (HR, 0.49; 95% CI, 0.32-0.74).
Additionally, those with a blood-based TMB of ≥12 mutations per megabase saw an improvement in OS with single-agent durvalumab versus chemotherapy (HR, 0.72; 0.56-0.93). Correlations of TMB and PD-L1 found that responses did occur in those with a high TMB regardless of PD-L1 status, although the numbers for this analysis were small. Strong responses were seen for those with low PD-L1 expression and high TMB.
“This has garnered a lot of excitement,” said Reckamp. “But there is a caution that we need to heed, and that is, be careful of subset analyses. So, here we are with blood TMB in a subset analysis, but it is a subset analysis of a negative study.”
Despite initial enthusiasm for TMB, the biomarker landscape seems to be shifting back toward PD-L1, which is not an ideal biomarker, Reckamp noted. This was evidenced by the CheckMate 227 trial, she said. Initial findings from the phase III trial heralded the role of TMB, showing an improvement in progression-free survival (PFS) with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) compared with chemotherapy in patients with high TMB (7.2 vs 5.5 months; HR, 0.58; 97.5% CI, 0.41-0.81;P<.001).3
In subsequent updates, however, the focus shifted toward PD-L1 status, she noted. On July 24, 2019, Bristol-Myers Squibb, the developer of both drugs, announced that nivolumab and ipilimumab improved OS compared with chemotherapy for patients with NSCLC and PD-L1 expression ≥1%. There was no update for the TMB arm. Full data will be presented during the 2019 ESMO 2019 Congress.4
“There are lots of caveats and lots of subtleties, but it is funny how in the past year and a half we have moved back to PD-L1,” said Reckamp. “I don’t think the blood TMB story ends here. I think for patients with low PD-L1, this is a group of patients where blood TMB could be helpful. I will say, though, that this press release dampened my enthusiasm.”
Countless clinical trials are currently examining large quantities of immunotherapy combinations, making it nearly impossible to present all of the ongoing trials, Reckamp noted. However, she highlighted several regimens that are high on her watch list, given their potential and recent updates at the 2019 ASCO Annual Meeting. The first combination partner Reckamp spotlighted was second mitochondria-derived activator of caspase, or SMAC, mimetic, which has shown synergy with PD-1 inhibitors in preclinical trials. The specific combination she highlighted was birinapant and pembrolizumab (Keytruda), which is being explored in the phase I/II BPT-201 trial (NCT02587962). The response rate was 5.3% across 19 evaluable patients; the 1 patient with a response to therapy had microsatellite-stable colorectal carcinoma.5
Next she mentioned inhibitors of the stimulator of interferon genes pathway, which activate interferon gene complexes, resulting in potentially better immunotherapy responses. The specific agents she drew attention to for this combination were MIW815 (ADU-S100) plus the monoclonal antibody spartalizumab. Partial responses were observed with the combination for patients with triple-negative breast cancer and those with PD-1 inhibitor relapsed/–refractory melanoma. Although patient numbers were small, the response rate tended to be around 20% to 25%.6
Additionally, dual checkpoint inhibition continues to be studied, not just with CTLA-4 but also with the checkpoint receptor LAG-3. Data were recently presented for the LAG-3 inhibitor REGN3767 with the PD-1 inhibitor cemiplimab (Libtayo). The response rate was 4.8% with the combination and 16.7% for those who received the LAG-3 inhibitor alone followed by the combination.7
“There are many more combinations that I can present today, but they all have limited data,” Reckamp noted.
A number of VEGF/VEGFR inhibitors are being examined with immunotherapies. In December 2018, the FDA approved atezolizumab (Tecentriq) in combination with bevacizumab (Avastin), carboplatin, and paclitaxel for the first-line treatment of patients with metastatic nonsquamous NSCLC.8 In renal cell carcinoma, VEGF inhibition with the tyrosine kinase inhibitor axitinib (Inlyta) is approved in combination with either pembrolizumab or avelumab (Bavencio).
The next combination on the horizon is the VEGFR2 inhibitor ramucirumab (Cyramza) plus pembrolizumab, which has been explored across several tumor types, Reckamp said. Findings for patients with lung cancer from a phase Ia/b trial were presented at the 2018 ASCO Annual Meeting, and based on the promise seen in early studies, this combination was added to the Lung-MAP trial (NCT03971474).
In 27 patients in the second to fourth-line settings with NSCLC, efficacy was analyzed by PD-L1 status, with median PFS of 9.7 and 6.9 months in patients with PD-L1 negative and –positive disease, respectively. The OS was not reached in the positive group and was 17.0 months in the PD-L1–negative arm.9
Various approaches have been examined prior to surgery, in an attempt to improve major pathologic responses (MPRs). Across studies, the highest level of MPR in neoadjuvant trials has been experienced by patients receiving immunotherapy in combination with chemotherapy, Reckamp said. Building upon this, several phase III studies are currently enrolling to further examine these combinations.
The CheckMate 816 trial is examining platinum doublet chemotherapy with or without nivolumab alone or in combination with ipilimumab for patients with stage IB to IIIA disease (NCT02998528). KEYNOTE-167 is exploring platinum doublet chemotherapy with or without pembrolizumab for patients with stage II, IIIA, and IIIB disease (NCT03425643). IMpower030 is exploring platinum doublet chemotherapy with or without atezolizumab for stage II to IIIB disease (NCT03456063). AEGEAN is exploring platinum-doublet chemotherapy with or without durvalumab for stage IIA to IIIB disease (NCT03800134).
“I think that the move forward is more focused on combinations of immunotherapy with chemotherapy,” Reckamp said. “These trials are moving forward and will hopefully be in our clinics very soon.”