Forde Recaps Chemoimmunotherapy Activity in PD-L1–Negative NSCLC


Immunotherapy plus chemotherapy is a standard of care for patients with advanced PD-L1–negative non–small cell lung cancer who do not harbor actionable driver mutations.

Patrick Forde, MD

Patrick Forde, MD

Immunotherapy plus chemotherapy is a standard of care for patients with advanced PD-L1–negative non–small cell lung cancer (NSCLC) who do not harbor actionable driver mutations, said Patrick Forde, MD, during a virtual presentation at the 18th Annual Winter Lung Cancer Conference®, a program hosted by Physicians Education Resource®, LLC.

Moreover, dual immunotherapy plus chemotherapy has also shown notable activity, suggesting that the addition of another agent, such as the CTLA-4 inhibitor ipilimumab (Yervoy), could further improve the responses observed with single-agent immunotherapy plus chemotherapy in this patient population.

“When we see a newly diagnosed patient with metastatic lung cancer, it’s become much more complex in terms of how we manage [the disease],” explained Forde, director of the Thoracic Oncology Clinical Research Program and an associate professor of oncology at Johns Hopkins University.

“Perhaps it is the effect of chemotherapy and early tumor destruction or neoantigen release, or the addition of an anti–CTLA-4 agent, as seen in newer studies, that gives us the additional boost needed in PD-L1–negative patients,” added Forde.

Chemoimmunotherapy Demonstrates Responses, Irrespective of PD-L1 Status

Patients with metastatic NSCLC that lacks targetable mutations represent a population of significant need, Forde said. In practice, firstline treatment decisions should be based on patients’ disease burden, performance status, comorbidities, disease histology, and PD-L1 expression level.

Findings from the phase 3 KEYNOTE-189 trial (NCT02578680) showed significant improvements in overall survival (OS) and progression-free survival (PFS) with pembrolizumab (Keytruda) plus chemotherapy vs placebo plus chemotherapy as first-line therapy for patients with EGFR/ALK-negative metastatic nonsquamous NSCLC.1

During the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, the results of the protocol-specified final analysis of the KEYNOTE-189 trial were presented, showing that the addition of pembrolizumab continued to improve efficacy outcomes compared with placebo.2 Moreover, OS, PFS, PFS after the next line of therapy, and overall response rate favored the pembrolizumab arm vs placebo, irrespective of PD-L1 expression by tumor proportion score (TPS).

Notably, in patients with PD-L1 expression of less than 1%, the median OS was 17.2 months with pembrolizumab vs 10.2 months with placebo (HR, 0.51; 95% CI, 0.36-0.71).

“We all have our own characteristics we use when we see new patients; however, PD-L1 expression is the 1 test that will be most beneficial. Genotyping is important, particularly for nonsquamous tumors. Assuming there is no targetable alteration, it is hard to beat chemotherapy with pembrolizumab in PD-L1negative NSCLC,” explained Forde.

However, other chemoimmunotherapy options are available. For example, findings from the phase 3 IMpower130 trial (NCT02367781) demonstrated improved OS and PFS with frontline atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane)/carboplatin vs nab-paclitaxel/ carboplatin alone in patients with stage IV, EGFR/ ALK-negative NSCLC.3 Moreover, OS and PFS were improved in all patients regardless of PD-L1 status, which was evaluated by immunohistochemistry with the VENTANA PD-L1 SP142 assay. However, the difference in OS was not statistically significant for patients with PD-L1–negative disease (HR, 0.81; 95% CI, 0.61-1.08).

“One limitation [of atezolizumab plus chemotherapy] is [that the IMpower130 trial] partnered platinum with nab-paclitaxel,” said Forde. “[Nab-paclitaxel] does have some different toxicities, such as neuropathy and hair loss. However, it may be an option for those patients who cannot receive pemetrexed [Alimta] because of renal function.”

Atezolizumab was also evaluated in the phase 3 IMpower150 trial (NCT02366143) in combination with bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) vs bevacizumab plus carboplatin and paclitaxel (BCP) in patients with chemotherapy-naïve nonsquamous NSCLC.

The results from the study showed that ABCP continued to show improved PFS and OS at 20 months of follow-up compared with BCP in this patient population.4 Moreover, PD-L1 expression level by immunohistochemistry did not appear to diminish the efficacy of ABCP vs BCP, with all subgroups (PD-L1 high, low, and negative) favoring the quadruplet regimen.

Similar activity has been observed with chemoimmunotherapy in patients with squamous cell histology. Findings from the phase 3 KEYNOTE-407 trial (NCT02775435) demonstrated an improvement in OS and PFS with the combination of pembrolizumab and chemotherapy vs placebo and chemotherapy among patients with treatment-naïve, squamous NSCLC.5

By TPS, patients derived OS and PFS benefit irrespective of PD-L1 status, and the HR for OS in patients whose PD-L1 expression was less than 1% was 0.61.

Dual Immunotherapy With Chemotherapy Offers New Options in Metastatic NSCLC

Findings from the phase 3 CheckMate 227 trial (NCT02477826) showed that first-line nivolumab (Opdivo) plus ipilimumab prolonged OS vs chemotherapy in patients with NSCLC, independent of PD-L1 expression level.6 The regimen was granted FDA approval in May 2020 for the frontline treatment of patients with metastatic EGFR/ALK-negative NSCLC whose tumors have at least 1% PD-L1 expression.7

Additionally, at a minimum follow-up of 37.7 months, the median OS in patients with PD-L1 expression of less than 1% was 17.2 months with nivolumab/ipilimumab vs 12.2 months with chemotherapy.8 The National Comprehensive Cancer Network guidelines have since been updated to include nivolumab/ ipilimumab as a recommendation for patients with PD-L1–negative disease, explained Forde.

Also in May 2020, nivolumab/ ipilimumab in combination with short-course chemotherapy received FDA approval for the treatment of patients with metastatic or recurrent EGFR/ ALK-negative NSCLC based on findings from the phase 3 CheckMate 9LA trial (NCT03215706).9

The results of the study, which were presented virtually during the 2020 ASCO Virtual Scientific Program, showed similar HRs across PD-L1 expression subgroups.10 Notably, the 12-month OS rate was 63% with chemoimmunotherapy vs 45% with chemotherapy alone in patients with PD-L1–negative disease (HR, 0.62; 95% CI, 0.45-0.85).

“Limiting chemotherapy is a potential benefit of [the CheckMate 9LA] regimen; however, we do have the added immune-related toxicities,” explained Forde.

“All these studies give us strong evidence that the addition of PD-L1 pathway blockade to chemotherapy improves survival. Outside a clinical trial, I think this is the best option for these patients,” Forde concluded.


1. 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

2. Rodríguez-Abreu D, Powell SF, Hochmair M, et al. Final analysis of KEYNOTE-189: pemetrexed-platinum chemotherapy (chemo) with or without pembrolizumab (pembro) in patients (pts) with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9582. doi:10.1200/JCO.2020.38.15_suppl.9582

3. West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):924-937. doi:10.1016/S1470-2045(19)30167-6

4. 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

5. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. N Eng J Med. 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865

6. Hellmann MD, Paz-Ares L, Caro RB, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Eng J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231

7. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA. Published May 15, 2020. Accessed February 8, 2021.

8. 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

9. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. FDA. Published May 26, 2020. Accessed February 8, 2021.

10. 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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