Immune Checkpoint Combination Strategies Evolving in NSCLC


A number of clinical trials are now assessing PD-1 and PD-L1 inhibitors in combination with chemotherapy, targeted therapies, and radiation therapy in an attempt to further improve outcomes for patients with non–small cell lung cancer.

Karen Kelly, MD

Following the demonstration of success as single-agents, a number of clinical trials are now assessing PD-1 and PD-L1 inhibitors in combination with chemotherapy, targeted therapies, and radiation therapy in an attempt to further improve outcomes for patients with non—small cell lung cancer (NSCLC), according to presentations at the 2015 International Lung Cancer Congress.

At this time, investigations into combinations of checkpoint inhibitors with targeted therapies or radiation are largely in their nascence, with an extensive demonstration of efficacy still pending. However, early findings for chemotherapy with PD-1/PD-L1 inhibitors have shown promising signs of clinical efficacy and tolerability, resulting in the initiation of several phase III investigations.

PD-1/PD-L1 With Chemotherapy

"Ideally, we want these agents to cause immunogenic cell death," Karen Kelly, MD, associate director for clinical research at the UC Davis Comprehensive Cancer Center, said at the meeting. "This is defined as a form of regulated cell death that is capable of activating an adaptive immune response, and importantly inducing immunologic memory. It relies on the release of endogenous danger signals from dying cells. Several chemotherapeutics can elicit this type of cell death."In the phase I CheckMate-012 study, nivolumab with platinum-based doublet chemotherapy demonstrated signs of efficacy as a frontline treatment for patients with NSCLC.1 This study explored a number of chemotherapy doublets, including gemcitabine and cisplatin (gem/cis), pemetrexed and cisplatin (pem/cis), and paclitaxel and carboplatin (pac/carbo).

In patients treated with the 10-mg/kg dose of nivolumab, the objective response rate (ORR) was 33% with gem/cis (n = 12) and 47% each with pem/cis (n = 15) and pac/carbo (n = 15). For nivolumab at 5 mg/kg in combination with pac/carbo (n = 14), the ORR was 43%.

The 18-month overall survival (OS) rates were 33%, 60%, and 40% in the 10-mg/kg arm for gem/cis, pem/cis, and pac/carbo, respectively. The median OS was 51, 83, and 65 weeks, for gem/cis, pem/cis, and pac/carbo, respectively. In the pac/carbo plus nivolumab at 5-mg/kg arm, the OS rate was 86%. The median OS was not yet reached in this arm.

"My impression of this data is really that if there's a signal here, it's a very faint signal, at least for nivolumab in this combination," Kelly said.

In addition to data for nivolumab, findings presented at the 2015 ASCO Annual Meeting showed a reasonable safety profile and antitumor activity with the frontline combination of pembrolizumab and platinum-based doublet chemotherapy.2

In this study, patients received pembrolizumab for up to 2 years at 10 mg/kg or 2 mg/kg in combination with 4 cycles of pac/carbo or pemetrexed plus carboplatin (pem/carbo). The ORR in those who received pac/carbo was 28%, across both doses of pembrolizumab. At the 2 mg/kg (n = 13) and 10 mg/kg (n = 12) doses, the ORR was 38% and 17%, respectively.

In the pem/carbo arm, the ORR across both doses was 58%. The best response was seen with the 10-mg/kg dose of pembrolizumab (n = 12), with an ORR of 75% and a disease control rate (DCR) of 100%. In the 2-mg/kg arm (n = 12), the ORR was 42% and the DCR was 100%.

"With paclitaxel and carboplatin it really was not impressive. However, when we look at the pem/carboplatin, the response rate was a little more impressive," Kelly said. "There could perhaps be a hint of activity here with pem/carboplatin in this early phase I trial in a highly selected group of patients."

Pembrolizumab combination strategies continue to be explored in the phase II KEYNOTE-021. This study will combine pembrolizumab at various doses with chemotherapy doublets. Additionally, the study will assess the PD-1 inhibitor along with bevacizumab, gefitinib, erlotinib, and ipilimumab for applicable patients (NCT02039674).

In addition to PD-1 inhibitors, the PD-L1 agent atezolizumab has shown promising efficacy in a phase Ib study for patients with chemotherapy-naive advanced NSCLC.3 Across all arms the ORR was 67% with the combination of atezolizumab and chemotherapy. The ORR was 60% with pac/carbo (n = 8), 75% with pem/carbo (n = 14), and 62% with nab-paclitaxel plus carboplatin (n = 15). In the nab-paclitaxel arm, 2 patients experienced a complete response.

"I get more optimistic when I see data like this, but I do want to remind everyone that these are going to be highly selected patients and the numbers are small," Kelly said.

Based on these early data, six phase III studies have been launched to explore atezolizumab in the first- and second-line setting for patients with NSCLC across histologies. In the non-squamous population, these studies include the IMpower 150 (NCT02366143), 130 (NCT02367781), and 110 (NCT02409342). For those with squamous histology, atezolizumab is being explored in the IMpower 131 (NCT02367794) and 111 (NCT02409355) trials. The IMpower 010 (NCT02486718) study is accepting patients with both histologies.

Early Data Characterize Potential EGFR/ALK TKI Combinations

"We're trying to understand the other mechanisms of cell death and how they are associated with the immune system, and how we can make these agents into an immunogenic cell death process," Kelly said. "I think this is a very interesting area of research."Preclinical work has hinted at the potential for the combination of TKIs and immune checkpoint inhibitors. To explore this further, a study presented at the 2015 ASCO Annual Meeting looked at PD-L1 and CD8 immunohistochemistry expression on biopsy samples from patients with EGFR or ALK-positive advanced NSCLC.4

In EGFR-mutant samples, PD-L1 was co-expressed in 15% of patients prior to treatment and in 25% after treatment with a TKI (P = .181). However, this pre- and post-treatment trend was reversed in ALK-positive samples. Prior to treatment, PD-L1 positivity was seen in 52% of patients versus 21% after therapy (P = .089).

Pre-treatment PD-L1 positivity and CD8+ TILs were seen in 5% of EGFR-mutant tumors and in 17% of ALK-positive tumors. Prior to treatment, this was 13% and 0%, for EGFR and ALK, respectively.

In the clinical setting, a 21-patient phase I study showed promising efficacy for the combination of erlotinib and nivolumab in EGFR-mutant NSCLC.5 The ORR with the combination was 19%. The median progression-free survival was 29.4 weeks and the 1-year rate with the combination was 73%.

"I think this is a very interesting finding. I think there is a signal here that we can find a subset of patients with durable responses to this combination," explained Kelly.

Ongoing studies are assessing PD-1 and PD-L1 inhibition in combination with EGFR TKIs. A phase I dose escalation study is assessing pembrolizumab plus afatinib in patients with EGFR-mutant NSCLC following a prior EGFR TKI (NCT02364609). Additionally, the phase III CAURAL study is assessing the PD-L1 inhibitor MEDI4736 in combination with AZD9291 versus AZD9291 monotherapy following a prior EGFR therapy for patients with T790M-positive NSCLC (NCT02454933).

Radiotherapy Combination Data Needed

In the ALK-positive setting, ongoing studies are assessing ceritinib plus nivolumab in pretreated patients with ALK-positive NSCLC (NCT02393625). Additionally, the CTLA-4 checkpoint inhibitor ipilimumab is being explored with either erlotinib or crizotinib in EGFR or ALK-mutant NSCLC in a phase Ib study (NCT01998126).At this time, there is very little data regarding the combination of immune checkpoint inhibitors with radiation therapy, explained Corey Langer, MD, from the University of Pennsylvania, during a talk at the meeting. Clinical trials are assessing these combinations, but results are not yet available nor were many preclinical trials conducted, Langer explained.

The clinical trial design for studies assessing PD-1/PD-L1 agents plus radiotherapy were guided by the design of the large phase III START trial, which examined the MUC1 antigen vaccine tecemotide in patients with stage IIIA/B NSCLC following definitive platinum-based chemotherapy and radiation at ≥50 Gy.

Although findings from the START study did not demonstrate a benefit with maintenance tecemotide, they provided an example of how immunotherapy could be used in conjunction with radiation therapy. In a subgroup analysis of this study, those who received sequential chemoradiotherapy seemed to fair worse with tecemotide compared with patients who received concurrent treatment, Langer explained.

Corey Langer, MD

"Across the board in the concurrent group with every demographic variable you see a benefit. What's paradoxical here is that the sequential group in the placebo arm had a better median overall survival, and this flies in the face of prior work that has shown concurrent is superior to sequential," Langer explained. "This really informs our discussion on the introduction of checkpoint inhibitors."

Following a similar study design, the phase III PACIFIC study is assessing MEDI4736 following concurrent chemoradiotherapy for patients with stage III unresectable NSCLC. In the study, maintenance MEDI4736 will be compared with placebo in a 2:1 ratio. The primary endpoints are OS and PFS, with a host of other secondary measures. The study hopes to enroll 702 participants (NCT02125461).

Another phase III study looking at multimodal therapy is currently being developed by the RTOG in collaboration with Bristol-Myers Squibb, according to Langer. This protocol will assess cisplatin, etoposide, and thoracic radiation therapy (60 Gy) followed by nivolumab or placebo for patients with NSCLC. The study is expected to begin enrolling by the end of the year, with a goal of accruing 660 participants.

Other smaller studies are looking at various strategies for improving responses with immunotherapy. A phase I/II prospective trial is attempting to determine whether stereotactic body radiation therapy can induce a response to pembrolizumab in patients with melanoma or NSCLC who have already progressed on anti—PD-1 therapy (NCT02407171).

Another phase II study is planned that will assess pembrolizumab following concurrent chemotherapy and proton beam radiation therapy. The primary endpoint of the study is PFS. The study will assess 48 patients with a local recurrence following chemoradiotherapy.


  1. Antonia SJ, Brahmer JR, Gettinger S, et al. Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer (NSCLC). Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. Abstract: 3.
  2. Papadimitrakopoulou V, Patnaik A, Borghaei H, et al. Pembrolizumab (pembro; MK-3475) plus platinum doublet chemotherapy (PDC) as front-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 Cohorts A and C. J Clin Oncol. 2015;33 (suppl; abstr 8031).
  3. Liu SV, Powderly JD, Camidge DR, at al. Safety and efficacy of MPDL3280A (anti-PDL1) in combination with platinum-based doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33 (suppl; abstr 8030).
  4. Gainor JF, Sequist LV, Shaw AT, et al. Clinical correlation and frequency of programmed death ligand-1 (PD-L1) expression in EGFR-mutant and ALK-rearranged non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33 (suppl; abstr 8012).
  5. Rizvi NA, Chow LQM, Borghaei H, et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC. J Clin Oncol. 2014;32:5s (suppl; abstr 8022)

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