Immunotherapy Combos Crowd Frontline NSCLC Landscape

Alex A. Adjei, MD, PhD

Immunotherapy, alone and in combination with chemotherapy, has transformed the frontline treatment of patients with advanced non–small cell lung cancer (NSCLC) who do not harbor actionable alterations, said Alex A. Adjei, MD, PhD.

The frontline treatment of patients with stage IV NSCLC, Adjei explained, “has become very complex in terms of treating patients without druggable genomic alterations. We have to look at histology in terms of the chemotherapy backbone, and then we have to look at PD-L1 expression.”

During a 2020 OncLive^® Institutional Perspectives in Cancer webinar on lung cancer, Adjei, professor of oncology and pharmacology and a consultant in the Division of Medical Oncology and Department of Oncology at Mayo Clinic, discussed the data supporting frontline treatment options for patients with advanced NSCLC, as well as some of the nuances of selecting the optimal therapy.

Single-Agent Immunotherapy

In the phase 3 KEYNOTE-024 (NCT02142738) and KEYNOTE-042 (NCT02220894) trials, pembrolizumab (Keytruda) demonstrated a statistically significant improvement in overall survival (OS) compared with chemotherapy as first-line treatment for patients with stage IV NSCLC.^1,2

Specifically, in KEYNOTE-042, the OS benefit was observed in patients with any level of PD-L1 expression (≥ 1%). However, upon further analysis, the OS improvement appeared to be largely driven by patients with a tumor proportion score (TPS) of 50% or greater. In this population, the median OS was 20.0 months with pembrolizumab versus 12.2 months with chemotherapy (HR, 0.69; 95% CI, 0.56-0.85; P = .0003). In the group of patients with a TPS of 1% to 49%, the median OS was 13.4 months versus 12.1 months, respectively (HR, 0.92; 95% CI, 0.77-1.11).

“Although we could theoretically use single-agent pembrolizumab in patients whose tumors have less than 50% PD-L1 expression, it is not ideal,” explained Adjei. “Sometimes patients have a poor performance status, and we want to give them single-agent [immunotherapy], but it is not a great treatment in terms of efficacy.”

Based on the results of the phase 3 IMpower110 trial (NCT02409342), atezolizumab (Tecentriq) also emerged as a potential single-agent option for patients with high PD-L1 expression (TPS ≥ 50%).3 The median OS with atezolizumab versus chemotherapy was 20.2 months and 13.1 months, respectively (HR, 0.59; 95% CI, 0.40-0.89; P = .0106). The median progression-free survival (PFS) was 8.1 months and 5.0 months, respectively (HR, 0.63; 95% CI, 0.45-0.88).

Additionally, the chemotherapy-free regimen of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated encouraging efficacy in the phase 3 CheckMate 227 trial (NCT02477826) for patients with stage IV or recurrent NSCLC.⁴

In part 1a of the study, patients with at least 1% PD-L1 expression were randomized to nivolumab plus ipilimumab, chemotherapy alone, or nivolumab alone. The 24-month OS rates were 40%, 33%, and 36%, respectively. The 24-month PFS rates were 22%, 7%, and 14%, respectively.

Part 1b of CheckMate 227 randomized patients with less than 1% PD-L1 expression to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. The 24-month OS rates were 40%, 35%, and 23%, respectively.

“PD-L1 expression did not seem to significantly affect the responses,” said Adjei. “It appears that the ipilimumab and nivolumab combination is very effective [irrespective] of PD-L1 expression, so it is something to think about if you want to decide which agent to pick in the crowded field.”

Notably, findings from the phase 2 CCTG BR.34 study (NCT03057106) did not demonstrate an OS improvement with the addition of durvalumab (Imfinzi) to tremelimumab plus chemotherapy compared with durvalumab/ tremelimumab alone in patients with stage IV squamous or nonsquamous NSCLC.⁵ The median OS was 16.6 months versus 14.1 months, respectively (stratified HR, 0.88; 95% CI, 0.67-1.16; log-rank P = .46).

“Immunotherapy is more complex than we think. Just a PD-1/PD-L1 [plus] CTLA-4 combination may not always be a one-size-fits-all [option],” explained Adjei.

In a prepresentation survey, when Adjei queried the audience viewing the program about which regimen would be an appropriate frontline treatment for a 70-year-old patient with stage IV adenocarcinoma and 75% PD-L1 expression on tumor cells, the audience was largely split between singleagent atezolizumab and nivolumab (Graph 1).

Graph 1

Chemotherapy Plus Immunotherapy

For eligible patients, the combination of a checkpoint inhibitor and chemotherapy has also shown utility in the frontline setting, Adjei explained.

For example, pembrolizumab plus pemetrexed and carboplatin or cisplatin followed by pembrolizumab plus pemetrexed demonstrated superior median OS (not reached) compared with placebo plus pemetrexed plus carboplatin or cisplatin followed by placebo and pemetrexed (11.3 months; HR, 0.49; 95% CI, 0.38- 0.64; P < .001) in patients with treatment-naïve stage IV nonsquamous NSCLC, according to findings from the phase 3 KEYNOTE-189 trial (NCT02578680).⁶ Moreover, the benefit was observed irrespective of PD-L1 status.

Similar results were observed in the phase 3 KEYNOTE-407 trial (NCT02775435) in patients with squamous histology. The median OS with pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel (Abraxane) was 15.9 months versus 11.3 months with placebo plus chemotherapy. The benefit was observed across PD-L1 expression cohorts.⁷

However, findings from the phase 3 IMpower131 trial (NCT02367794) evaluating atezolizumab plus chemotherapy did not yield positive OS results for patients with advanced squamous NSCLC.⁸

In a prepresentation survey, when Adjei queried the audience viewing the program about which regimen would be an appropriate frontline treatment for a 60-year-old man with stage IV squamous cell carcinoma with unknown PD-L1 expression on tumor cells, 40% said atezolizumab/ chemotherapy (Graph 2).

Graph 2

Chemotherapy Plus Immunotherapy and VEGF Inhibitors

The phase 3 IMpower150 trial (NCT02366143) randomized patients with stage IV or recurrent metastatic nonsquamous NSCLC to atezolizumab plus carboplatin and paclitaxel (arm A); atezolizumab plus carboplatin, paclitaxel, and bevacizumab (Avastin; arm B); or carboplatin, paclitaxel and bevacizumab alone (arm C).⁹

Looking at arms B and C, the median PFS was 8.3 months with the addition of atezolizumab versus 6.8 months with chemotherapy alone (HR, 0.59; 95% CI, 0.50-0.70; P < .0001). The median OS was 19.2 months versus 14.7 months, respectively (HR, 0.78; 95% CI, 0.64-0.96; P = .0164).

Notably, benefit was observed across all subgroups analyzed, including those defined by PD-L1 expression, presence of liver metastases, and EGFR/ALK positivity. Moreover, patients with an EGFR mutation had a median OS that was not estimable with atezolizumab versus 17.5 months with the control regimen (HR, 0.54).

“This is a hotly debated area,” said Adjei. “Based on these data, we tend to use this combination when we have a patient with an EGFR [mutation] who has gone through all options.”

Chemotherapy Plus Dual Immunotherapy

Adjei closed out his presentation by highlighting the role of chemotherapy plus dual immunotherapy, as was explored in the CheckMate 9LA trial (NCT03215706).¹⁰

In the study, patients with stage IV or recurrent NSCLC were randomized to nivolumab plus ipilimumab and chemotherapy or chemotherapy alone.

The median OS was 15.6 months with the chemoimmunotherapy combination compared with 10.9 months with chemotherapy alone (HR, 0.66; 95% CI, 0.55-0.80). Notably, this benefit was observed across histologies (nonsquamous vs squamous) and PD-L1 expression level (< 1%, ≥ 1%, 1%-49%, and ≥ 50%).

Secondary end points were also intriguing, said Adjei. The overall response rates were 38% with chemoimmunotherapy and 25% with chemotherapy alone. Respectively, 9% and 13% of patients experienced progressive disease. Finally, the median duration of response was 11.3 months with nivolumab/ipilimumab/ chemotherapy versus 5.6 months with chemotherapy alone.

Toxicity is a potential caveat of the CheckMate 9LA regimen, said Adjei. Treatment-related select adverse effects, including skin, endocrine, gastrointestinal, hepatic, renal, pulmonary, and hypersensitivity/infusion reaction events, were observed with chemoimmunotherapy. Grade 3/4 events occurred in 4%, 3%, 6%, 4%, 2%, 2%, and 1% of patients, respectively

References

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2. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1–expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7
3. Spigel D, de Marinis F, Giaccone G, et al. IMpower110: interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC. Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394
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5. Leighl NB, Laurie SA, Goss GD, et al. CCTG BR.34: a randomized trial of durvalumab and tremelimumab +/- platinum-based chemotherapy in patients with metastatic (stage IV) squamous or nonsquamous non-small cell lung cancer. J Clin Oncol. 2020;38(suppl 15):9502. doi:10.1200/JCO.2020.38.15_suppl.9502
6. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small–cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005
7. Paz-Ares L, Luft A, Vincente D, et al. Pembrolizumab plus chemotherapy for squamous non–small–cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865
8. Jotte R, Cappuzzo F, Vynnychenko I, et al. Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial. J Thorac Oncol. 2020;15(8):1351-1360. doi:10.1016/j.jtho.2020.03.028
9. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948
10. Reck M, Ciuleanu TE, Cobo Dols M, 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