Frontline ICI Therapy Gains Traction Across NSCLC Settings

Oncology Live®Vol. 22/No. 4
Volume 22
Issue 04

Treatment strategies for patients with advanced-stage non–small cell lung cancer have shifted away from platinum-based doublet chemotherapy and toward combination strategies that include immune checkpoint inhibitors.

Stephen V. Liu, MD

Stephen V. Liu, MD

Treatment strategies for patients with advanced-stage non–small cell lung cancer (NSCLC) have shifted away from platinum-based doublet chemotherapy and toward combination strategies that include immune checkpoint inhibitors (ICIs). Data from the KEYNOTE-024 trial (NCT02142738) showed an overall survival (OS) benefit with pembrolizumab (Keytruda) in patients with advanced-stage NSCLC and PD-L1 expression on at least 50% of tumor cells.1 The data led to the first approval of an ICI for patients with PD-L1–positive advanced NSCLC, and since then a variety of ICIs have been show-ing increasing benefit across larger subsets of patients in the first-line setting, including those without PD-L1 expression, especially when used as part of a combination regimen.

During a recent OncLive Peer Exchange®, a panel of thoracic cancer experts convened to discuss several important immune-oncology (I/O) studies presented during key meetings in 2020, including the European Society for Medical Oncology (ESMO) Virtual Congress 2020 and the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. The panelists reviewed the data, their key take-aways from the regimens assessed, and how these regimens may impact clinical practice in the future.

ONO-4538-52: Nivolumab/Carboplatin/Paclitaxel/Bevacizumab

ONO-4538-52 (NCT03117049) is a randomized phase 3 trial assessing nivolumab (Opdivo) in combination with carbopla-tin, paclitaxel, and bevacizumab (Avastin) as a first-line treatment for patients with advanced or recurrent NSCLC who do not have EGFR or ALK alterations and could have any level of PD-L1 expression.2 “There are a lot of parallels between the regimen used here and the approved IMpower150 [NCT02366143] regimen, which builds on the backbone of carboplatin/paclitaxel/bevacizumab, showing that when you add atezolizumab [Tecentriq], outcomes were improved,” Stephen V. Liu, MD, said. “[Investigators of ONO-4538-52 used] a similar approach, except instead of the PD-L1 antibody atezolizumab, [they] used the PD-1 inhibitor nivolumab,” he explained.

All patients in the study received carboplatin/paclitaxel/bevaci-zumab and were then randomized 1:1 to receive concurrent nivolumab (n = 275) or placebo (n = 275). Following induction therapy, all patients received maintenance bevacizumab and continued either nivolumab or placebo.

At the interim analysis, which occurred after a median follow-up of 13.7 months, progression-free survival (PFS) was significantly improved in the nivolumab arm versus the placebo arm, with a PFS of 12.1 months versus 8.1 months, respectively (HR, 0.56; 96.37% CI, 0.43-0.71; P < .0001). The objective response rates (ORRs) were 61.5% and 50.5% in these treatment arms, respectively. The OS data were not mature but trended toward benefit with nivolumab (25.4 vs 24.7 months; HR, 0.85; 95% CI, 0.63-1.14). Despite the unclear survival benefit, Liu said the preliminary data suggest there is “some signal” that when you add nivolumab to the carboplatin/paclitaxel/bevacizumab back-bone, you can improve outcomes.

WJOG @BE STUDY: Atezolizumab/Bevacizumab

WJOG @Be Study is a phase 2 Japanese study evaluating the doublet of atezolizumab plus bevacizumab in 40 patients with NSCLC and high PD-L1 expression (≥ 50%).3 The study’s primary end point was ORR and secondary end points included PFS, duration of response (DOR), OS, and safety. “This trial fell under the radar,” Liu said, but he noted it had impressive end point data with an ORR of 64%. However, all responses were partial responses, with 28% of patients having stable disease and just under 8% having progressive disease. Patients had a median PFS of 15.9 months (95% CI, 5.6515.93), with a median duration of response of 10.4 months (95% CI, 4.63-NR). “We have a 1-year PFS rate of 55%, which is quite impressive,” Liu said. The 1-year OS rate was 70.6% (95% CI, 50.5%-83.4%).

“I would have loved to have seen a second arm with atezolizumab monotherapy to really see how this stands up. But those high response rates suggest that there may be synergy between these 2 pathways,” Liu said.

Antiangiogenic/Anti-VEGF/ICI Combinations: Poised to Change Clinical Practice?

“The whole concept of combining antiangiogenic or anti-VEGF targeted therapies with immune checkpoint inhibition is something that’s widely pursued not just in lung cancer, but many other cancers,” Suresh Ramalingam, MD, said.

“I still have difficulties finding the role for bevacizumab in the first-line setting, and I personally haven’t used it much,” Martin F. Dietrich, MD, PhD, said, noting concerns over the cumulative toxicity, especially when used as part of a quadruplet therapy. In the ONO-4538-52 study (NCT03117049), serious treatment-related adverse effects (AEs) were significantly more common in the nivolumab arm than in the placebo arm, occurring in 41.8% of patients and 26.9% of patients, respectively.2 “I would like to understand in the first-line setting what’s the contribution to efficacy,” Dietrich said.

The participants agreed that although the WJOG @Be study data are promising, they require verification in larger studies. “I would like to see that confirmed with randomization against atezolizumab, which the [study investigators] pointed out, is something that’s planned,” Christine Bestvina, MD, said. “When we talk about triplet therapy, chemotherapy plus immunotherapy in the patients with high PD-L1 expression, one of the arguments that providers will make for using the triplet over monotherapy is if a high response rate is needed, you may choose the triplet. But with seeing this high response rate with the addition of bevacizumab to atezolizumab, I wonder if we’ll be able to use angiogenesis inhibitors in a similar fashion, while still sparing more traditional chemotherapy agents,” she said.

EMPOWER-LUNG 1 Study: Cemiplimab

EMPOWER-Lung 1 (NCT03088540) is a phase 3 trial comparing the newer PD-1 inhibitor cemiplimab-rwlc (Libtayo) with investigator’s choice of platinum-doublet chemotherapy in 710 treatment-naïve patients with advanced NSCLC who have high PD-L1 expression (≥ 50%) and no EGFR, ALK, or ROS1 mutations.4 The primary end points were OS and PFS and the secondary endpoints included ORR, DOR, health-related quality of life, and safety. “Randomization to a PD-1 inhibitor versus chemotherapy may sound familiar,” Liu said, adding that this is a similar design to the KEYNOTE studies, including the landmark KEYNOTE-024 trial.

EMPOWER-Lung 1 met its primary and secondary end points. In the intention-to-treat population with PD-L1 of at least 50%, the median OS was not reached in the cemiplimab arm (n = 283) and was 14.2 months in the chemotherapy arm (n = 280; HR, 0.57; 95% CI, 0.42-0.77; P = .0002). The median PFS was 8.2 months versus 5.7 months in these arms, respectively (HR, 0.54; 95% CI, 0.43-0.68; P < .0001). The ORR corresponded with patients’ PD-L1 expression levels in the cemiplimab arm (Table4).

Table. ORR by PD-L1 Expression Level in the EMPOWER-Lung 1 Study4

“Cemiplimab had a better response rate, a better PFS, better overall survival, and a better toxicity profile—a winner across the board. This was despite having a high crossover rate, in fact, higher than what we saw in KEYNOTE-024. The crossover rate in this study was 74%,” Liu said. Patients in the cemiplimab arm had significantly fewer treatment- related AEs, including grade 3 to 5 AEs (37.2% vs 48.5%).

The panelists noted that an interesting feature of EMPOWER-Lung 1 was that 45% of patients had squamous cell carcinomas. When examining OS events in these patients compared with those who had nonsquamous tumors, the panelists were not surprised to see that those with squamous histology showed greater benefit.

“Squamous cell carcinoma is a more immunotherapy-sensitive disease. The correlation with smoking, higher tumor mutational burden, and inflammatory markers is probably more stringent than for adenocarcinomas,” Dietrich said. There was some question whether all checkpoint inhibitors would demonstrate similar outcomes, but the panelists agreed that the overall medical literature indicates that squamous cell carcinomas tend to respond better to these agents regardless of which one is being used, and that PD-1 or PD-L1 expression status and histology play a lesser role in the setting of combination regimens.

“The crossover rate was high, and despite that, the survival advantage was still seen. One might argue that if you delayed initiation of immunotherapy, then patients may not do as well. You can add a checkpoint inhibitor down the road after they’re done with chemotherapy, but we’re seeing more evidence that the earlier you adopt immunotherapy, the better the outcomes are,” Firas B. Badin, MD, said.

Liu agreed and added that while he is in favor of an approval, he is unsure of how or if he would use the agent for patients in his practice. “I don’t know if I see data that are compelling enough to make me change my practice, but I’d absolutely support combinations building on this or using this as a control in a randomized trial,” he said.

CHECKMATE 227: Nivolumab/Ipilimumab

Ramalingam presented the updated 3-year efficacy and safety data from the CheckMate 227 trial (NCT02477826), in which patients with PD-L1 expression of at least 1% (part 1a) were randomized 1:1:1 to nivolumab/ipilimumab (Yervoy), chemotherapy, or nivolumab monotherapy, and those with PD-L1 expression less than 1% (part 1b) were randomized 1:1:1 to nivolumab/ ipilimumab, chemotherapy, or nivolumab/ chemotherapy.5 None of the study participants had sensitizing EGFR mutations or known ALK alterations. The primary end points were PFS in patients with high tumor mutational burden (≥ 10 mut/Mb) and OS in patients with PD-L1 of at least 1%.

“The number that comes to my mind is the 3-year survival rate for patients treated with ipilimumab and nivolumab, which was 33%, both in the PD-L1 high and low group. This is remarkable considering that not too long ago, we were not talking about 3-year survival rates for patients with lung cancer,” Ramalingam said. He noted that the durability of response was also 3- to 4-fold higher compared with chemotherapy. “If patients had a response with chemotherapy, the duration of response was 6.5 months. With ipilimumab and nivolumab, the response duration was almost 23 months. This suggests that patients who derive response with this combined immunotherapy approach can maintain that benefit for a lot longer,” he said.

Based on the CheckMate 227 data, nivolumab/ipilimumab was approved by the FDA in May 2020 as a first-line treatment for patients with metastatic NSCLC whose tumors express PD-L1 (≥ 1%), as determined by an FDA-approved test, and who have no EGFR or ALK genomic tumor aberrations.6 Ramalingam said the National Comprehensive Cancer Network guidelines also recommend nivolumab/ipilimumab for patients with PD-L1–negative tumors.7

CHECKMATE 9LA: Nivolumab/Ipilimumab/Chemotherapy

CheckMate 9LA (NCT03215706) is a phase 3 randomized, open-label study comparing nivolumab/ipilimumab plus 2 cycles of chemotherapy (n = 361) with 4 cycles of chemotherapy (n = 358) in the first-line setting for patients with advanced NSCLC.8 “This is a novel approach,” Badin said. “We’ve never done just 2 rounds of chemotherapy. We tend to do 4 to 6 cycles. That's the standard in our clinic. But it’s a novel approach with only 2 doses of chemotherapy, trying to get some of the synergy from chemotherapy, plus nivolumab and ipilimumab, and then patients will go into nivolumab/ipilimumab maintenance.”

CheckMate 9LA met its primary end point at the preplanned interim analysis (minimum follow-up, 8.1 months), with a median OS of 14.1 months for nivolumab/ipilimumab/chemotherapy versus 10.7 months with chemotherapy (HR, 0.69; 96.7% CI, 0.55-0.87; P = .0006). When the follow-up interval was extended to a minimum follow-up of 12.7 months, the median OS was 15.6 months with nivolumab/ipilimumab/chemotherapy versus 10.9 months with chemotherapy (HR, 0.66; 95% CI, 0.55-0.80). The magnitude of benefit with the nivolumab combination was consistent across tumor histology and PD-L1 expression levels.

Dietrich said this trial was originally criticized for being too complex but added that it provided some valuable lessons. “Ipilimumab/nivolumab can be competitive in the PD-L1 positive space as a combination, and it can be competitive against chemoimmunotherapy in the PD-L1–negative space. This is going to be hard to argue that this wouldn’t be a strong consideration for every patient in the PD-L1 continuum,” he said.

I/O-I/O in the Front Line: Where Does It Fit in?

Liu said an I/O-I/O approach is an appealing one, especially for patients who are interested in chemotherapy-free regimens. However, he said he is quick to explain to patients that these regimens are not free of AEs and that the grade 3 event rate is comparable to that of chemotherapy. “You won’t necessarily see the myelosuppression, the alopecia, the nausea that we may see with cytotoxic chemotherapy, but there are still a lot of other toxicities we need to be aware of. I need to find the right patients to use that [approach],” he said.

Nevertheless, he said there are several reasons he would opt to use a dual checkpoint blockade regimen up front. “The hazard ratio in the PD-L1 negative space is compelling,” he said. He also noted that it gives him an additional treatment line. “If all things are equal and you start with dual checkpoint blockade, and if it doesn’t work, if you’re not in that group where you get that long-term survival, now my second-line option is platinum doublet chemotherapy, which I would consider an upgrade over standard secondline docetaxel-based therapies,” he said.

Bestvina agreed with this assessment. “I’ve seen the benefit [in patients] with a 0% expression of PD-L1, seeing the benefit that they can obtain with this dual checkpoint blockade is quite impressive…[and] you get to save an amazing second-line option of carboplatin/pemetrexed, which has been the backbone of management for these patients for the prior 10 to 20 years,” she said.

Badin reminded the panel that the CheckMate 9LA regimen can strike a balance and be a good option for some patients as well. “If you don’t want to miss the opportunity of using chemotherapy in the first-line setting, but at the same time you don’t want to give the full force of 4 to 6 cycles, then here is another option for our patients,” he said.


  1. Chiang AC, Herbst RS. Frontline immunotherapy for NSCLC – the tale of the tail. Nat Rev Clin Oncol. 2020;17(2):73-74. doi:10.1038/s41571-019-0317-y
  2. Lee JS, Sugawara S, Kang JH, et al. Randomized phase 3 trial of nivolumab in combination with carboplatin, paclitaxel, and bevacizumab as first-line treatment for patients with advanced or recurrent nonsquamous NSCLC. Ann Oncol. 2020;31(suppl 4):S1184-S1185. doi:10.1016/j.annonc.2020.08.2287
  3. Seto T, Nosaki K, Shimokawa M, et al. LBA55 WJOG @Be study: a phase 2 study of atezolizumab with bevacizumab for nonsquamous non–small cell lung cancer with high PD-L1 expression. Ann Oncol. 2020;31(suppl 4):S1185-S1186 doi:10.1016/j.annonc.2020.08.2288
  4. Sezer A, Kilickap S, Gümüş M, et al. LBA52 EMPOWER lung 1: phase 3 first-line (1L) cemiplimab monotherapy vs platinum doublet chemotherapy (chemo) in advanced non–small cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD L1) ≥50%. Ann Oncol. 2020;31(suppl 4):S1182-S1183. doi:10.1016/j.annonc.2020.08.2285
  5. Ramalingam SS, Ciuleanu TE, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non—small cell lung cancer: three-year update from CheckMate 227 part 1. J Clin Oncol. 2020;38(suppl 15):9500. doi:10.1200/JCO.2020.38.15_suppl.9500
  6. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA. May 15, 2020. Accessed January 25, 2021.
  7. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 2.2021. Accessed January 25, 2021.
  8. Reck M, Ciuleanu TE, Dols MC, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38(suppl 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501
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