Wealth of Immunotherapy Combinations Places Emphasis on Biomarkers for NSCLC

The magnitude of data becoming available on immunotherapy combinations for patients with non–small cell lung cancer has made treatment selection complicated.

Karen L. Reckamp, MD

The magnitude of data becoming available on immunotherapy combinations for patients with non—small cell lung cancer (NSCLC) has made treatment selection complicated, with few agreeing on one specific option given the wealth of effective regimens, explained Karen L. Reckamp, MD, MS, during a presentation at the 2019 International Lung Cancer Congress.

"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," said Reckamp, medical director, Clinical Research Operations, City of Hope Comprehensive Cancer Center. "It's not so crystal clear today."

Reckamp focused her presentation to the advances announced exclusively in 2019, with a look to ongoing trials in progress. One prevalent theme across studies in 2019 was a lack of clarity on the role of tumor mutation 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.

TMB for NSCLC in 2019

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).

In a blood-based TMB analysis presented at the 2019 ASCO Annual Meeting,1 patients with TMB ≥8 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 the number of mutations per megabase increased, with the most impressive findings seen at ≥20 (HR, 0.49; 95% CI, 0.32-0.74).

Additionally, those with a blood-based TMB of ≥12 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 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 CheckMate-227 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 status (7.2 vs 5.5 months; HR, 0.58; 97.5% CI, 0.41-0.81).2

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% of cells; however, there was not an update of the TMB arm provided. Full data are scheduled to be presented at an upcoming medical meeting.

"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."

Novel Combinations on Horizon

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 a number of regimens that were high on her watch list, given their potential and recent data updates at the 2019 ASCO Annual Meeting.

The first combination partner Reckamp spotlighted were SMAC mimetics, which have shown synergy with PD-1 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 5.6% across 18 evaluable patients. This was exclusively seen in a patients with microsatellite stable colorectal carcinoma.3

Next, she mentioned STING inhibitors, which activate interferon gene complexes resulting in potentially better immunotherapy responses. The specific agents she drew attention to for this combination were MIW815 plus spartalizumab. Partial responses were observed with the combination for patients with triple-negative breast cancer and those with PD-1 relapsed/refractory melanoma. Although patient numbers were small, the response rate tended to be around 20% to 25%.4

Additionally, dual checkpoint inhibition continues to be studied, not just with CTLA-4 but also with the checkpoint LAG-3. Data were 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.5

"There are many more combinations than I can’t present today, but they all have limited data," Reckamp noted.

Immunotherapy Plus Anti-Angiogenesis

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. Additionally, in renal cell carcinoma, the VEGF TKI axitinib (Inlyta) is approved in combination with either pembrolizumab or avelumab.

The next combination on the horizon is the VEGFR2 inhibitor ramucirumab plus pembrolizumab, which has been explored across several tumor types, Reckamp suggested. 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.

In 27 patients in the second- to fourth-line setting with NSCLC efficacy was analyzed by PD-L1 status, with median PFS of 9.7 months and 6.9 months in PD-L1—negative and –positive patients, respectively. The OS was not reached in the positive group and was 17.0 months in the PD-L1–negative arm.6

Immunotherapy in the Neoadjuvant Setting

Various approaches have been examined prior to surgery, in an attempt to improve major pathologic responses (MPR). Across studies, the highest level of MPR in neoadjuvant trials has been experienced by patients receiving immunotherapy in combination with chemotherapy, Reckamp noted. Building upon this, a number of phase III studies are currently enrolling to further examine these combinations.

The CheckMate-816 trial is examining platinum doublet chemotherapy with or without nivolumab for patients with stage IB-IIIA disease (NCT02998528). KEYNOTE 617 is exploring platinum doublet chemotherapy with or without pembrolizumab for patients with stage IIB-IIIA disease (NCT03425643). IMpower030 is exploring platinum doublet chemotherapy with or without atezolizumab for stage II to IIIB disease (NCT03456063). AEGEAN is exploring platinum-doubled 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."


  1. Rizvi NA, Cho BC, Reinmuth N, et al. Blood tumor mutational burden (bTMB) and tumor PD-L1 as predictive biomarkers of survival in MYSTIC: First-line durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in metastatic (m) NSCLC. J Clin Oncol. 2019; 37 (suppl; abstr 9016).
  2. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093-2104.
  3. Schilder RJ, Albertella M, Strauss JF, et al. Determination of the recommended phase II dose of birinapant in combination with pembrolizumab: Results from the dose-escalation phase of BPT-201. J Clin Oncol. 2019;37 (suppl; abstr 2506).
  4. Meric-Bernstam F, Sandhu SK, Hamid O, et al. Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas. J Clin Oncol. 2019;37 (suppl; abstr 2507).
  5. Papadopoulos KP, Lakhani NJ, Johnson ML, et al. First-in-human study of REGN3767 (R3767), a human LAG-3 monoclonal antibody (mAb), ± cemiplimab in patients (pts) with advanced malignancies. J Clin Oncol. 2019;37 (suppl; abstr 2508).
  6. Herbst RS, Chau I, Petrylak DP, et al. Activity of ramucirumab (R) with pembrolizumab (P) by PD-L1 expression in advanced solid tumors: Phase 1a/b study in later lines of therapy. J Clin Oncol. 2018;36 (suppl; abstr 3059).

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