Brahmer Considers First-Line Immunotherapy Options in Metastatic NSCLC

Julie R. Brahmer, MD, MSC

Director of the Thoracic Oncology Program

Professor of Oncology

Marilyn Meyerhoff Professor in Thoracic Oncology

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Codirector, Upper Aerodigestive Department

Bloomberg~Kimmel Institute for Cancer Immunotherapy

Baltimore, MD

CASE SUMMARY

• A 62-year-old woman presented to the emergency department with vague reports of voice changes and a cough. She gave a history of a recent 11-lb weight loss.

Past Medical, Family, and Social History

• Hypertension, controlled with angiotensin-converting enzyme inhibitor taken orally once daily
• Hyperlipidemia, treated with oral atorvastatin once daily
• Chronic obstructive pulmonary disease, treated with maintenance fluticasone furoate, umeclidinium, and vilanterol inhalation daily
• Mother: deceased from lung cancer at age 65
• Former smoker: 10 to 15 pack-years; quit tobacco habit 25 years ago

Physical Examination

• Current weight: 125 lb
• ECOG performance status: 1

Diagnostic Workup

• CT of thorax discovered a 4-cm nodule in the left upper lobe
• CT of abdomen reveals metastases to the liver
• MRI of brain is negative for brain metastases

Final Pathology

• Consistent with squamous cell carcinoma
• Metastatic stage IV
• PD-L1 expression by immunohistochemistry: < 1%
• Next-generation sequencing: no actionable mutations
  

Treatment

• Therapeutic options were reviewed with the patient and family.

Can you provide some background on the phase 3 CheckMate 9LA trial (NCT03215706) and what the 5-year follow-up data showed in non–small cell lung cancer (NSCLC)?

BRAHMER: CheckMate 9LA explored treatment with…chemotherapy [administered every 3 weeks for 2 cycles plus] ipilimumab [Yervoy] given every 6 weeks combined with nivolumab [Opdivo] every 3 weeks for up to 2 years or unacceptable toxicity…. This is not comparing nivolumab/ipilimumab plus chemotherapy with single-agent immunotherapy with chemotherapy; it’s just comparing it with chemotherapy alone.¹

This study enrolled approximately 30% with squamous histology and 70% with nonsquamous histology. One-third of patients had PD-L1 expression of 0, so a decent number of patients were in the study.

The overall survival [OS] curves showed that even out to 5 years, there was an improvement in survival among all randomly assigned patients [5-year OS rates: 18% with nivolumab/ipilimumab vs 11% with chemotherapy alone]…. What I like about this study is that in the PD-L1–negative group, the OS outcomes seemed as good as in the PD-L1–positive group [5-year OS rates with nivolumab/ipilimumab: 22% and 18% for the PD-L1–negative and –positive groups, respectively].

Regarding histology for the nonsquamous, there was not that much of a difference in OS at 5 years [in the nivolumab/ipilimumab arm vs the chemotherapy-alone arm], but it was still improved. The [improvement with nivolumab/ipilimumab was even greater in patients with] squamous histology…. Also, for squamous…11% of patients were still long-term responders at 5 years.

What did the 5-year safety data show for the nivolumab/ipilimumab plus chemotherapy regimen in the CheckMate 9LA trial?

Looking at adverse events [AEs] in the 5-year survivors, we do have patients who we get worried about with the long-term toxicities of immune-related treatment…. The CheckMate 9LA data showed, however, that the longer that you receive ipilimumab, it does not seem to increase your toxicity. It’s [important to remember that] these toxicities can occur at any point. Definitely in the long term, you can develop more hypothyroidism, thyroid diseases, or potential adrenal insufficiency. [However], the study data show that, across the board, most of the other immune-mediated toxicities tend to occur earlier on and don’t have a higher risk the longer you’re on it.

How do you decide when to stop administering nivolumab/ipilimumab?

I stop immunotherapy at 2 years if there is no unacceptable toxicity or disease progression before that point. However, with most of my patients in my practice, we’ve had to stop ipilimumab earlier due to colitis or other AEs, such as rash. I’ve been able to continue the nivolumab, but for a lot of my patients, I’ve ended up dropping ipilimumab before the 2 years.

What outcomes were observed in the trial for patients who had to discontinue all immunotherapy due to treatment-related AEs?

For patients who have to completely stop all immunotherapy, efficacy outcomes showed that patients can continue to benefit from these drugs…. Patients are always worried when they have to stop [taking the immunotherapy], but they can still have a benefit. I tell my patients…that developing an AE from these types of drugs—these immune checkpoint inhibitors—is just a sign that your immune system is active, so having to stop it does not mean you are going to lose the efficacy.

If I completely stop the immunotherapy, I start with scans every 3 months for about a year, and then I’ll start spreading those out at some point. Right now, I have a couple patients where I’m 5 years out and just imaging them once a year. But I usually start with every 3 months for 1 to 2 years, then start spreading that out, and then go to every 6 months.

What did the CheckMate 9LA data show for patients with brain metastasis?

Three-year follow-up data showed that patients with brain metastasis can have long-term progression-free survival [PFS]; it’s very similar to PFS outcomes in patients without brain metastasis.²

What did the 5-year update of the KEYNOTE-407 trial (NCT02775435) show for the use of pembrolizumab (Keytruda) plus chemotherapy in patients with squamous NSCLC?

The 5-year update in this population of [only patients with squamous NSCLC] showed an improvement in survival out to 5 years [18.4% with pembrolizumab/chemotherapy vs 9.7% with chemotherapy alone], as well as in PFS [5-year PFS: 10.8% with pembrolizumab/chemotherapy vs 3.5% with chemotherapy alone].³

When you start looking at the subsets, you see that in patients with PD-L1–negative [tumor proportion score (TPS) < 1%] squamous cell carcinoma, there’s less of an OS benefit at 5 years with the pembrolizumab regimen vs chemotherapy alone compared with the 5-year OS benefit with the pembrolizumab combination in patients who have PD-L1–intermediate [TPS, 1%-49%] or PD-L1–high [TPS, ≥ 50%] tumors…. The 5-year OS in this patient population just does not seem quite as good in PD-L1–negative patients compared with if you have PD-L1– intermediate or –positive disease.

The 5-year PFS update for KEYNOTE-407 showed similar results for the PD-L1 subgroups as were seen with the OS data. The PD-L1–negative group just did not show a separation of the curves out at 5 years as was seen with the 5-year PFS results for the PD-L1–positive subgroups, [in which the curves continued to separate and show a benefit at 5 years].

What was the randomization in the phase 3 POSEIDON trial (NCT03164616)?

The POSEIDON trial is the newest on the block. I’ve only used this in a very small subset of patients…. This was a 3-arm trial, and patients in the first arm received dual immunotherapy plus chemotherapy.⁴ The nice thing about this trial is you continued on the chemotherapy for up to 4 cycles with the durvalumab [Imfinzi] and tremelimumab [Imjudo] every 3 weeks, but then the CTLA-4 inhibitor tremelimumab was not continued; you only received 1 more dose after the 4 cycles. If there’s a concern about giving continued CTLA-4 inhibition, at least in this study, it was very finite. In the second study arm, patients received only durvalumab plus chemotherapy, and these 2 arms were compared with the third study arm, in which patients received only platinum-based chemotherapy.

What were the efficacy outcomes for the durvalumab regimens vs chemotherapy alone in the POSEIDON trial?

For the 4-drug regimen [durvalumab/tremelimumab plus doublet chemotherapy] compared with chemotherapy alone, there was an improvement in PFS and OS out to 4 years.⁴ Then updated 5-year OS data for the 4-drug regimen compared with chemotherapy showed a 5-year survival of almost 16% [compared with approximately 7%] for chemotherapy alone.⁵ There was also a 5-year OS benefit with durvalumab plus chemotherapy vs chemotherapy alone [13% vs approximately 7%], but it did not have the same statistical improvement [regarding the HR and CI] as with the 4-drug regimen vs chemotherapy. There are no head-to-head data for the 4-drug regimen vs the durvalumab/chemotherapy regimen.

What else did the 5-year update from POSEIDON show?

In patients with nonsquamous histology, the 4-drug regimen compared with chemotherapy maintained OS improvement at 5 years. [However], for patients with squamous cell histology, we are not seeing quite the same 5-year survival compared with the CheckMate 9LA study.

Everyone is worried about the safety of a 4-drug regimen compared with single-agent chemotherapy, but there was not that much of a difference looking across the different arms for serious AEs or AEs leading to death. Looking at the 4-drug regimen vs durvalumab plus chemotherapy, [safety outcomes] were very similar.

_REFERENCES

_{1. Reck M, Ciuleanu TE, Schenker M, et al. Five-year outcomes with first-line (1L) nivolumab + ipilimumab + chemotherapy (N + I + C) vs C in patients (pts) with metastatic NSCLC (mNSCLC) in CheckMate 9LA. J Clin Oncol. 2024;42(suppl 16):8560. doi:10.1200/JCO.2024.42.16_suppl.8560}

_{2. Paz-Ares LG, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone for metastatic NSCLC in CheckMate 9LA: 3-year clinical update and outcomes in patients with brain metastases or select somatic mutations. J Thorac Oncol. 2023;18(2):204-222. doi:10.1016/j.jtho.2022.10.014}

_{3. Novello S, Kowalski DM, Luft A, et al. Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study. J Clin Oncol. 2023;41(11):1999-2006. doi:10.1200/JCO.22.01990}

_{4. Johnson ML, Cho BC, Luft A, et al. Durvalumab (D) ± tremelimumab (T) + chemotherapy (CT) in 1L metastatic (m) NSCLC: overall survival (OS) update from POSEIDON after median follow-up (mFU) of approximately 4 years (y). Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089}

_{5. Peters S, Chul Cho B, Luft A et al. Durvalumab ± tremelimumab + chemotherapy in first-line metastatic NSCLC: 5-year overall survival update from the POSEIDON study. Ann Oncol. 2023;20(suppl 1):100535. doi:10.1016/iotech/iotech100535}