Chemoimmunotherapy Remains Best Choice for Some PD-L1–High Lung Cancers

Nasser Hanna, MD

While immunotherapy alone is the right therapy for most patients with lung cancers expressing PD-L1 greater than or equal to 50%, for those who are at risk for cancer-related morbidity with early progressive disease, chemoimmunotherapy may be the more appropriate choice, Nasser Hanna, MD, said in a presentation at the 15th Annual New York Lung Cancers Symposium.

Clinical evidence has shown that omitting chemotherapy in the front line results in earlier disease progression for some patients with non–small cell lung cancer (NSCLC), even those with a PD-L1 tumor proportion score (TPS) of at least 50%. “This might be patient with highly symptomatic disease, or a patient with bulky disease, or a patient whose performance status is okay, but the trajectory is not looking good,” said Hanna, the Tom and Julie Wood Family Foundation Professor of Lung Cancer Clinical Research at Indiana University School of Medicine. “So you want to ensure that they don’t have early progression, or at least reduce the likelihood. That’s the patient who I think I would add chemotherapy to their immunotherapy.”

In a review of studies, Hanna identified data from trials comparing immune checkpoint inhibitors (ICIs) including pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq) plus chemotherapy versus chemotherapy alone, that demonstrated a marked benefit for patients with PD-L1–high lung cancer. However, while efficacy data favor chemoimmunotherapy in these patients, questions still exist surrounding the use of ICIs upfront without chemotherapy in this patient populations.

Chemoimmunotherapy Demonstrates Benefit in PD-L1–High Population

In KEYNOTE-189 (NCT02578680) investigators evaluated platinum-based chemotherapy plus pemetrexed with or without pembrolizumab in 616 patients with metastatic, nonsquamous NSCLC without sensitizing EGFR or ALKmutations. Patients in the placebo group who had verified disease progression were allowed to crossover to pembrolizumab arm.¹

After a median follow-up of 10.5 months, the 12-month overall survival (OS) rate favored the pembrolizumab combination among those with a PD-L1 TPS of 50% or greater (73.0% vs 48.1%; HR, 0.42; 95% CI, 0.26-0.68).1These patients derived a greater benefit than in the intention-to-treat (ITT) population where the estimated 12-month OS rates were 69.2% in the pembrolizumab combination group versus 49.4% in the placebo combination group (HR, 0.49; 95% CI, 0.38-0.64; P < .001).

In updated results published in May 2020, the median OS was 22.0 months (95% CI, 19.5-25.2) in the pembrolizumab group versus 10.7 months (95% CI, 8.7-13.6) in the placebo arm (HR, 0.56; 95% CI, 0.45-0.70). Notably, in the population of patients with PD-L1 TPS of at least 50%, the median OS was not reached (NR) with the pembrolizumab combination (95% CI, 20.4-NR) versus 10.1 months (7.5-NR) with chemotherapy alone. Further, the estimated 24-month OS rate also favored the combination arm in patients with TPS of at least 50% (51.9% vs 39.4%) and in the ITT population 45.5% vs 29.9%).²

“When we break this down into the subset analysis…patients who had PD-L1 scores of greater than 50% had the greatest benefit when you gave pembrolizumab in combination with the chemotherapy and what you’ll see is a lack of detriment in early survival when chemotherapy was given to all patients.”

In squamous cell NSCLC, initial findings from the phase 3 IMpower130 trial (NCT02367781) presented in 2018 showed that adding atezolizumab to carboplatin and nab-paclitaxel (Abraxane) improved progression-free survival and OS among patients with high PD-L1expression.3 “Once again the magnitude of difference favoring the addition of atezolizumab was seen in those patients who had high PD-L1 scores,” Hanna said.

Final overall survival data from IMpower 131 (NCT02367794) further supported the observed benefit with the the chemoimmunotherapy combination. Among patients with high PD-L1 expression (≥ 50% staining on tumor cells or ≥10% tumor infiltrating immune cells), the median OS was 23.4 months (95% CI, 17.8­–not evaluable) with the atezolizumab triplet compared with 10.2 months (95% CI, 7.1-17.5) in patients receiving carboplatin plus nab-paclitaxel alone (HR, 0.48; 95% CI, 0.29-0.81).⁴

Finally, interim OS analysis from IMpower 150 showed that the combination of atezolizumab, bevacizumab (Avastin), carboplatin and paclitaxel (ABCP) extended survival compared with bevacizumab plus carboplatin and paclitaxel (ACP) in patients with untreated nonsquamous metastatic NSCLC. In the ITT–wild-type population, the median OS was 19.2 months for the ABCP arm compared with 14.7 months in the ACP arm (HR, 0.78; 95% CI, 0.64-0.96; P =.02). Median OS also favored the quadruplet in the PD–L1-high subset (25.2 vs 15.0 months; HR, 0.70; 95% CI, 0.43-1.13).^5,6

“Giving chemotherapy with immunotherapy for at least the beginning of treatment was the rationale behind CheckMate 9LA,” Hanna said. “It was thought that there may be a detriment in early outcomes if you don’t give chemotherapy and you simply gave immunotherapy.”

CheckMate 9LA (NCT03215706) randomized patients to either chemotherapy alone or chemotherapy for 2 cycles in combination with nivolumab plus ipilimumab (Yervoy). Overall survival rate in the ITT population was 63% at 12 months compared with 70% (HR, 0.66; 95% CI, 0.44-0.99) in those patients with PD-L1 expression of at least 50%.⁷

Finding Clearer Answers in ECOG/ACRIN 5163

Hanna said that while OS at 1 and 2 years was similar regardless of treatment strategy in 4 key trials (Table2,^7-9), there are still unanswered questions for patients with high PD-L1 expression in terms of optimal sequencing strategies. The data that exist suggest that there is a role for ICIs plus chemotherapy for some patients. There is, however, relatively little research comparing ICIs alone versus ICIs plus chemotherapy, Hanna said, noting that it is the early part of the survival curve that is cause for concern.

“Should we start patients with chemotherapy/IO [immunotherapy] or can we give them IO alone? And if we do give them IO alone, do we abandon the IO when they progress, or can we continue the IO and simply add chemotherapy? This is a really important sequencing question, [the answer to which] I think will greatly help us,” Hanna said.

Investigators are looking to data from the phase 3 ECOG/ACRIN 5163 study (NCT03793179) help clarify how best to administered chemoimmunotherapy in this patient population.

Patients with stage IV nonsquamous NSCLC will be randomized to 1 of 3 treatment arms: first-line treatment with pembrolizumab monotherapy followed by pemetrexed and carboplatin after disease progression; the same regimen plus pembrolizumab in second line; or pembrolizumab plus pemetrexed and carboplatin followed by maintenance therapy with pembrolizumab and pemetrexed.

“This is a really important sequencing question which will, I think, greatly help us,” Hanna said. “When we look at this study, we’ll pay close attention to the PD-L1 [greater than] 50% subset, which would be anticipated to be half of the patients in this PD-L1–positive study population.”

Table. Overall Survival Results for Patients with PD–L1-High Lung Cancer^2,7-9

References

1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005
2. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020;38(14):1505-1517. doi:10.1200/JCO.19.03136
3. Cappuzzo F, McCleod M, Hussein M, et al. IMpower130: progression-free survival (PFS) and safety analysis from a randomised phase III study of carboplatin 1 nab-paclitaxel (CnP) with or without atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. Ann Oncol. 2018;29(suppl 8):VIII742-VIII743. doi:10.1093/annonc/mdy424.065
4. 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
5. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948
6. Socinski MA, Jotte RM, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36(suppl 15):9002. doi:10.1200/JCO.2018.36.15_suppl.9002
7. Hellmann MD, Paz-Ares L, Caro RB, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019; 381(21):2020-2031. doi:10.1056/NEJMoa1910231
8. Reck M, Ciuleanu TE, Dols MC, et al. Nivolumab plus ipilimumab plus 2 cycles of platinum doublet chemotherapy vs 4 cycles of chemo as first-line treatment for stage IV/recurrent non-small cell lung cancer: CheckMate 9LA. J Clin Oncol. 2020;38(suppl 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501
9. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019;37(7):537-546. doi:10.1200/JCO.18.00149