Immunotherapy Combos Expand Across Lung Cancer Subtypes

Lawrence E. Feldman, MD

Combinations with checkpoint inhibitors and chemotherapy have become a standard therapeutic choice for some patients with non—small cell lung cancer (NSCLC), and such regimens continue to be explored in other subtypes—showing benefit in those with high tumor mutational burden (TMB) and squamous cell disease.

“It has reached a standard of care to receive chemoimmunotherapy as a combination,” Lawrence E. Feldman, MD, said. “I think that the data with ipilimumab and nivolumab in high TMB patients is very intriguing and is something that will probably become one of the standards of care in the near future.”

Findings from the pivotal phase III CheckMate-227 trial demonstrated superior progression-free survival (PFS) with the first-line combination of nivolumab (Opdivo) and ipilimumab (Yervoy) compared with chemotherapy for patients with advanced NSCLC who have high TMB.

For years, there has been an unmet need for effective treatments for patients with squamous cell NSCLC or small cell lung cancer (SCLC), Feldman explained. However, data from the KEYNOTE-407 trial suggest that chemoimmunotherapy regimens may benefit the squamous cell lung cancer population. In October 2018, the FDA approved first-line pembrolizumab (Keytruda) combined with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) for the treatment of patients with metastatic squamous NSCLC, based on the KEYNOTE-407 findings.

Results of the study showed that combining pembrolizumab with chemotherapy reduced the risk of death by 36% versus chemotherapy alone. The median overall survival (OS) was 15.9 months (95% CI, 13.2-not evaluable) with pembrolizumab versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0017).

OncLive^®: Please provide an overview of your presentation on immunotherapy combinations in lung cancer.

What are the combinations being evaluated in this space and what new data are being reported?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on NSCLC, Feldman, professor of Clinical Medicine at the University of Illinois, Chicago, discussed exciting new data surrounding immunotherapy combinations in the lung cancer.Feldman: I discussed the immunotherapy combinations, nivolumab and ipilimumab, and durvalumab (Imfinzi) and tremelimumab. I also discussed data pertaining to combinations consisting of chemotherapy and immunotherapy, particularly the KEYNOTE-189 study that was recently presented at the 2018 ASCO Annual Meeting, which showed an overall survival advantage with pembrolizumab added to carboplatin/pemetrexed compared with chemotherapy alone.The CheckMate-026 trial retrospectively showed that when we looked at patients with high TMB versus those with low to medium TMB, the patients with high TMB had a longer PFS when they received frontline nivolumab versus chemotherapy.

The CheckMate-227 trial and the CheckMate-568 trial confirmed the finding that patients with high TMB seemed to have a longer PFS than those with low to medium TMB; those are patients who received a combination of nivolumab and ipilimumab. We don’t have overall survival (OS) comparative data, but it was announced that the combination may move forward to receive a fast-track approval by the FDA; we’re still waiting to hear about that.

Could you discuss data pertaining to the combination of durvalumab and tremelimumab?

There is also the combination of carboplatin/pemetrexed and pembrolizumab, and that has shown a benefit in terms of getting the combination versus chemotherapy no matter what the PD-L1 status was; any patients who had less than 1%, 1% to 49%, or greater than 50%, had benefit with the combination of chemotherapy and pembrolizumab.The dosing for the combination treatment—durvalumab at 20 mg/kg every 4 weeks plus tremelimumab at 1 mg/kg—was established in a phase Ib study. Results from the trial were published in 2016, by Dr Scott Antonia, et al in the Lancet Oncology and showed many responses to that combination that appeared to be durable.

Could you discuss updates in squamous cell and SCLC?

There are a number of ongoing trials evaluating that particular combination at that particular dose, and we’re waiting on findings from those trials to be reported. We do know that the MYSTIC trial—which evaluated durvalumab as monotherapy and in combination with tremelimumab compared with chemotherapy as first-line therapy in patients with metastatic NSCLC—did not meet the PFS endpoint, but we are still anxiously awaiting the results of the trial in terms of OS. I believe that the MYSTIC trial is important, especially if it shows a survival advantage, but we don’t know yet.Both of those cancers have been an unmet need for many years. In the space of squamous cell carcinoma, we have the KEYNOTE-407 study, which looked at carboplatin and paclitaxel plus pembrolizumab compared with chemotherapy alone. The study showed an improvement in OS with the combination of carboplatin, either paclitaxel or nab-paclitaxel, plus the addition of pembrolizumab. These data were presented at the 2018 ASCO Annual Meeting.

We also have the IMpower131 study, which is in the squamous cell space, and looked at carboplatin/paclitaxel or nab-paclitaxel with the addition of atezolizumab. (Tecentriq) Investigators showed an improvement in PFS with the addition of atezolizumab, but we don’t have OS data for that trial yet.

The KEYNOTE-407 trial could potentially change the standard of care in terms of squamous cell lung cancer, to add a checkpoint inhibitor to first-line chemotherapy.

In terms of SCLC, there were data from the IMpower133 study, which were presented at the 19th World Conference on Lung Cancer; this evaluated the use of carboplatin/etoposide plus atezolizumab. That study showed an OS advantage with the addition of atezolizumab; it was a median survival difference of about a little over 12 months versus more than 10 months—and that was highly statistically significant.

What challenges do we face in the treatment of patients with squamous cell and SCLC?

What is your outlook on the treatment landscape for these diseases?

That would also lead to a change in the upfront management of SCLC where there is, again, an unmet need. We haven’t had new regimens in the upfront setting for many years in this space.The main challenge is, unlike with adenocarcinoma, we don’t have any targetable mutations to go after right now. There are some mutations that are under investigation, but we don’t have any specific medications to treat patients with targetable mutations in those diseases.Squamous cell lung cancer and SCLC are now entering the arena of first-line chemoimmunotherapy in a similar setting that we’ve seen in [nonsquamous] non—small cell cancers. We do know that the treatment for [patients with] adenocarcinoma with chemoimmunotherapy is dramatically improving, and the same scenario will come along with squamous and SCLC.

Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36 (suppl; abstr 105). doi: 10.1200/JCO.2018.36.15_suppl.105.