Chemoimmunotherapy Combos Solidified as Frontline Standard in Nonsquamous NSCLC

The rationale for frontline chemoimmunotherapy in stage IV nonsquamous non–small cell lung cancer, now made evident by several phase III trials, stems from its synergistic activity, stimulatory effects on neoantigens, and tolerable safety profile.

Claude Denham, MD

The rationale for frontline chemoimmunotherapy in stage IV nonsquamous non—small cell lung cancer (NSCLC), now made evident by several phase III trials, stems from its synergistic activity, stimulatory effects on neoantigens, and tolerable safety profile.

Although chemotherapy was initially considered to be immunosuppressive, its addition to immunotherapy has been shown to increase tumor mutational burden, triggering greater expression and release of neoantigens, therein inciting an immune response, explained Claude Denham, MD, in a presentation during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer.

In addition, Denham, a medical oncologist at Baylor Charles A. Sammons Cancer Center, Texas Oncology, noted that chemoimmunotherapy combinations can augment major histocompatibility complex antigen expression, increase sensitivity of tumor cells to T-cell effector cytokines, increase PD-L1 expression, and decrease immune suppressor cells.

A phase III trial designed to replicate the benefit of such combinations in smaller randomized studies was KEYNOTE-189.1 In the trial, patients with stage IV nonsquamous NSCLC were randomized 2:1 to receive pembrolizumab (Keytruda) plus pemetrexed, and investigator’s choice of cisplatin or carboplatin, followed by pemetrexed maintenance with pembrolizumab or placebo.

The addition of pembrolizumab demonstrated a clear benefit in overall survival (OS) compared with chemotherapy alone (HR, 0.49; 95% CI, 0.38-0.64; P <.001), with a notable separation in survival curves at around 3 months. Progression-free survival (PFS) was also superior at 8.8 months with the chemoimmunotherapy regimen versus 4.9 months with the placebo arm (HR, 0.52; 95% CI, 0.43-0.64; P <.001). At 1 year, 34.1% of patients in the immunotherapy arm were alive, which was approximately double that of those in the placebo arm.

“This trial established combination chemoimmunotherapy as [a standard of care] for patients with stage IV nonsquamous, largely adenocarcinomas of the lung,” said Denham. Based on those data, the FDA granted a full approval to frontline pembrolizumab in August 2018 for use in combination with standard chemotherapy for patients with metastatic nonsquamous NSCLC, which followed an accelerated approval in May 2017.

Also in KEYNOTE-189, an extension in PFS was observed in all cohorts when stratified by PD-L1 expression and a combined tumor proportion score (TPS) <1% (n = 190), 1% to 49% (n = 186), and ≥50% (n = 202); however, the only statistically significant differences in PFS were noted in those with a TPS 1% to 49% (HR, 0.55; 95% CI, 0.37-0.81) and a TPS ≥50% (HR, 0.36; 95% CI, 0.25-0.52).

Undoubtedly, pembrolizumab has become one of the preferred immunotherapy agents in the space, but atezolizumab (Tecentriq) appears to be equally valuable to the paradigm based on data from the IMpower trials, said Denham.

Despite these data, it is unknown which chemoimmunotherapy regimen confers the greatest benefit. As no head-to-head trials are planned, this question will likely remain unanswered, said Denham.

Both pembrolizumab and atezolizumab operate on the same axis, PD-1 and PD-L1, respectively, but atezolizumab may theoretically produce fewer autoimmune adverse events (AEs), he added.

In the phase III IMpower150 trial,2 patients were randomized to 1 of 3 arms: carboplatin/paclitaxel/atezolizumab (arm 1; ACP), carboplatin/paclitaxel/bevacizumab (Avastin; arm 2; BCP), or carboplatin/paclitaxel/bevacizumab/atezolizumab followed by maintenance atezolizumab and/or bevacizumab (arm 3; ABCP).

The survival curves between arms 2 and 3 appeared to be superimposable until patients reached the 8-month mark, said Denham. At that time, a statistically significant benefit in OS with ACBP versus BCP (stratified HR, 0.78; 95% CI, 0.64-0.96; P = .02) was noted. The median OS was 14.7 months in the BCP arm compared with 19.2 months in the ABCP arm.

Patients with a high immunogenic phenotype derived a significantly longer OS benefit compared with those with a moderate or low immunogenic phenotype, added Denham.

At a median follow-up of about 20 months, the median OS was 19.4 months in the ACP arm versus 14.7 months in the BCP arm. The OS benefit, although not statistically significant at the time, will be assessed again in the final analysis.

“There are a lot of moving parts to this trial,” said Denham. “Adding bevacizumab to an already expensive regimen raises the question of how much better it is than [ACP] and whether we want to add another $10,000 worth of drug every month to that regimen.”

The IMpower130 trial,3 presented but not yet published, showed similar findings to those of the KEYNOTE-189 trial. In the trial, patients were randomized 2:1 to receive carboplatin/nab-paclitaxel (Abraxane) and atezolizumab as induction therapy followed by maintenance atezolizumab, or chemotherapy alone followed by maintenance pemetrexed or best supportive care in stage IV nonsquamous NSCLC.

“Median PFS was moderately better [with the atezolizumab combination], but not hugely better at 7.0 months versus 5.5 months,” said Denham. At 1-year, 29.1% of patients in the atezolizumab arm and 14.1% of patients in the control arm were progression free. At 2 years, investigators noted a bigger differential in OS, at 18.6 months versus 13.9 months, with 2-year survival rates of 39.6% and 30.0% in the immunotherapy and control arms, respectively. These results serve as the basis for the regimen’s supplemental biologics license application, which was accepted by the FDA in January 2019.

Also, in line with the results of KEYNOTE-189 were the findings from the IMpower132 trial,4 said Denham, in which patients were randomized to receive carboplatin or cisplatin/pemetrexed alone or in combination with atezolizumab, followed by pemetrexed or atezolizumab plus pemetrexed maintenance.

Early separation of the survival curves signaled, and ultimately translated to a PFS benefit with atezolizumab (HR, 0.60; 95% CI, 0.49-0.72; P <.0001), although the follow-up was too short to claim an OS advantage (HR, 0.81; 95% CI, 0.64-1.03; P = .0797).

Taken individually, and in a meta-analysis of chemoimmunotherapy combination trials,5 the benefit in the nonsquamous cell histology populations is clear, said Denham.

All patient subsets derived benefit with combination chemoimmunotherapy, but Denham noted that patients with an ECOG performance status of 0, PD-L1 expression ≥50%, females, those <65 years of age, and those who received a PD-1 inhibitor, experienced the most dramatic benefit in PFS and OS.

“PFS, OS, and response rates are all consistently better when you combine chemotherapy with immunotherapy,” concluded Denham. “Other than expense or concern about autoimmune complications in select patients, there is little reason to give cytotoxic chemotherapy alone.”


  1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. 2018;378(22):2078-2092. N Engl J Med. doi: 10.1056/NEJMoa1801005.
  2. 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.
  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 + nab-paclitaxel (CnP) with or without atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. Ann Oncol. 2018;29(supp 8; abstr LBA53). doi: 10.1093/annonc/mdy424.065.
  4. Papadimitrakopoulou V, Cobo M, Bordoni R, et al. IMpower132: PFS and safety results with 1L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. J Thorac Oncol. 2018;13(10):S332-S333. doi: 10.1016/j.jtho.2018.08.262.
  5. Zhou, Y, Chen C, Zhang X, et al. Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis. J Immunother Cancer. 2018;6(1): 155. doi: 10.1186/s40425-018-0477-9.