The Growing Role of Immunotherapy in Targeting NSCLC

Sujith R. Kalmadi, MD

Chief Medical Officer

Ironwood Cancer and Research Centers

Chandler, AZ

CASE SUMMARY

• A 62-year-old woman presented to the emergency department with vague complaints of voice changes and cough. She had a history of a recent weight loss of 11 lb.
• A CT scan of her thorax showed a 4-cm nodule in the left upper lobe.
• A CT of her abdomen also revealed metastases in the liver.
• A brain MRI was negative for brain metastases.
• Past medical history: hypertension, hyperlipidemia, chronic obstructive pulmonary disease managed with inhalers
• Smoking: 10-15 pack-years, stopped 25 years ago
• Family history: Her mother died from lung cancer aged 65 years.
• Physical exam: weight, 125 lb; ECOG performance score, 1
• Final pathology is consistent with squamous cell carcinoma.
• Staging: metastatic stage IV
• PD-L1 expression by immunohistochemistry: 0%
• Next-generation sequencing: no actionable mutations
• Treatment options were reviewed with the patient and family.
• Patient was initiated on nivolumab (Opdivo) 360 mg/mL intravenously every 3 weeks and ipilimumab (Yervoy) 1 mg/kg intravenously every 6 weeks plus 2 cycles of chemotherapy every 3 weeks.

TARGETED ONCOLOGY: What data support the combination of nivolumab and ipilimumab plus 2 cycles of chemotherapy for this patient?

KALMADI: The CheckMate 9LA trial [NCT03215706] supports this treatment combination.1 In this study design, the key eligibility criteria were stage IV or recurrent NSCLC [non–small cell lung cancer] with no previous treatment and no sensitizing EGFR or known ALK mutations. Their ECOG performance status was 0 or 1, and we randomly assigned 719 patients [to either] ipilimumab plus nivolumab plus chemotherapy or to chemotherapy alone, with optional pemetrexed maintenance. [Patients with] squamous and nonsquamous disease were allowed in this trial. The primary end point was overall survival [OS], and the secondary end points were progression-free survival [PFS] and objective response rate [ORR].

At 1 year, the OS [rate] was 63% with ipilimumab/nivolumab plus chemotherapy vs 47% with chemotherapy alone.¹ The median OS with combination therapy was 15.6 months as compared to 10.9 months with chemotherapy alone, which was about a 4.8-month improvement in OS, and an HR of 0.66—so a 26% improvement in OS.¹ That is meaningful.

With immunotherapy drugs, the median PFS does not change much because of a simple reason. The reason PFS improves with immunotherapy is not because of the response rate, although that does contribute. When you look at the Kaplan-Meier analysis, it is because of the duration of response. The benefit that you get with these immunotherapies— always on the right side of the curve and not on the left side of the curve. With chemotherapy and targeted therapy, it is almost invariably on the left side of the curve in a Kaplan-Meier analysis because the area under the curve gets affected so much more on the left side.

How have these data impacted patients and subgroups of patients on the trial?

The median PFS in CheckMate 9LA was about 1 month different with an HR of 0.70 (95% CI, 0.59-0.83).¹ ORR did increase from 25% to 38%,² with the duration of response more than doubling. So if a patient has a response, it increased from 5.6 months with chemotherapy alone to 12.4 months with ipilimumab/nivolumab plus chemotherapy, [with] a long durable response, ongoing at 14 months with chemotherapy vs 23 months with combination therapy.²

At 3 years, investigators looked at OS in subgroups of PD-L1 of 1% or greater and less than 1%.² Essentially there was not a whole lot of difference. Initially when we first got these drugs, we thought they would work better in the PD-L1–positive patients. But in the PD-L1-less-than-1% subgroup, the HR was 0.67 and improvement in OS was about 8 months. In the PD-L1–positive patients, the HR was 0.74, making it a similar improvement in OS. Lastly, the 3-year data showed that patients with a PD-L1 of 50% or greater had similar data, as the HR still stayed at 0.75 and the OS was significantly improved.²

There [were] also data at 3 years looking at brain metastases because the theory has been immunotherapy may not cross into the brain—so is there really a benefit in using it? It was not a very fair comparison, I should say. In patients with brain metastases, the survival does improve—there was an HR of 0.43, [whereas in] patients without brain metastases, the HR was 0.79. So, it seems to have activity in patients with brain metastases.²

What safety data are important to know about treatment with nivolumab/ipilimumab plus chemotherapy?

In other cancers where you use this regimen in higher doses, we worry about the grade 3 and 4 adverse events [AEs] crossing into double digits. That’s what we worry about with the hypophysitis, adrenal insufficiency, pneumonitis, colitis, and [other AEs of note].¹ With a lower dosing, most of the AEs are grade 1 and 2, [but some are grade 3 and 4, such as] skin-related AEs [4%], endocrine-related AEs [3%], and 6% had a GI [gastrointestinal] grade 3 to 4 AE including hepatic disfunction [4%] and renal dysfunction [2%], and there was also pulmonary AEs [2%] and hypersensitivity and infusion reactions [Figure¹].

The key here [to manage some of these AEs] is the dose of steroids. Anybody with grade 3 to 4 AEs should be pulsed with 1 to 2 mg/kg of steroids, and if they don’t respond within the first 7 to 10 days, you should be looking at second-line treatment, whether it is infliximab [Remicade] or [mycophenolate mofetil (CellCept)]. You cannot use infliximab in patients with hepatic dysfunction because it has a black box warning because it can cause hepatic failure.³ I would say [many] of the patients who are taken off this regimen due to treatment-related AEs are still in remission. That is just such a long-standing remission that they get despite discontinuing after a bad [AE]. And it’s not just for ipilimumab/ nivolumab; it’s for any immunotherapy. In the case of ipilimumab/nivolumab plus chemotherapy, the median OS was staggeringly high, 27 months, which is great in lung cancer, and the 2-year OS [rate] was 54%.⁴

What did the KEYNOTE-407 (NCT02775435) trial show for treating these patients, and how did their PD-L1 status impact the outcomes?

KEYNOTE-407 compared pembrolizumab [Keytruda] with placebo in patients with untreated metastatic squamous NSCLC.⁵ All the patients also received carboplatin plus paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel [Abraxane] for the first 4 cycles. Key eligibility criteria were [patients having] stage IV lung cancer, a PD-L1 assessment, [and no history of pneumonitis. Patients with] no symptomatic brain metastases were allowed.

Patients were stratified by their PD-L1 expression and tumor proportion score [TPS]; the groups were PD-L1 TPS of 50% or greater, PD-L1 TPS of 1% to 49%, and PD-L1 TPS less than 1%.⁵ They also had their choice of taxane. The way the trial was done, the dosing was pembrolizumab 200 mg plus carboplatin AUC [area under the curve] 6 mg/mL and 200 mg of paclitaxel. I should say the community looked at this as well; nobody uses this carboplatin AUC 6 mg/mL and paclitaxel 200 mg. There was a big study by ASCO [American Society of Clinical Oncology], and the standard dose in the community is carboplatin AUC of 5 mg/mL and paclitaxel 175 mg because the AUC 6 mg/mL and paclitaxel 200 mg is toxic overall. So they got 4 cycles of that as compared to placebo with the same combination, and then they were allowed to continue maintenance pembrolizumab for up to 31 cycles compared with placebo.

In the 5-year update from KEYNOTE-407, an OS of [18.4% for pembrolizumab compared with 9.7% for chemotherapy was seen], which was clearly an improvement there. The 5-year PFS improvement was 10.8% with pembrolizumab and 3.5% with chemotherapy.⁶ The 5-year OS was 23 months in the PD-L1 TPS of 50% or greater group vs 8% with chemotherapy [HR, 0.68; 95% CI, 0.47-0.97]. Then in the 1% to 49% group, OS was 20 months with pembrolizumab vs 7 months with chemotherapy [HR, 0.60; 95% CI, 0.45-0.81]. And this is the first trial where we got the impression that immunotherapy may not work in PD-L1-negative patients. Lastly, the OS rate in the PD-L1 TPS less than 1% group was 10.7% with pembrolizumab as compared with 13% with chemotherapy.⁶

What immune-mediated AE concerns you with pembrolizumab plus chemotherapy?

[Hypophysitis is one because], typically, patients receiving pembrolizumab plus chemotherapy present with low-grade headaches and fatigue, and unless you tell your radiologist that you are looking for hypophysitis, they will not be looking for it in their standard MRIs.⁵

That is one thing to mention on your MRI when you are ordering it is to rule out hypophysitis because they will never look at that area to make the diagnosis, and that is probably the easiest way. We can check their ACTH [corticotropin] and TSH [thyrotropin] and make the diagnosis, but I’ve found that oncologists don’t like to look at other specialties, and this is a tough one to diagnose for oncologists.

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What data are important to know from the phase 3 EMPOWER-Lung 3 trial (NCT03409614)?

The EMPOWER-Lung 3 trial studied cemiplimab-rwlc [Libtayo] plus platinum doublet chemotherapy in [patients with] NSCLC.⁶ The key eligibility criteria [were] similar to earlier studies looking at metastatic disease. Pretreated patients with clinically stable brain metastases were allowed, squamous and nonsquamous was allowed, and controlled hepatitis B and C were allowed. Exclusion criteria included EGFR, ALK, or ROS1 genomic tumor aberrations.

A common question I get is asking about other mutations. This is the only place where we have level 1 evidence looking at immunotherapy to be superior to targeted therapies within the KRAS population. So if you have a KRAS-mutation population, those patients should get chemoimmunotherapy up front before they ever go on to targeted therapy.

Now you may make an argument that they should get second-line chemotherapy before they go on a KRAS G12C inhibitor. The only ones in the front line that you should exclude are [patients whose disease harbors an] EGFR, ALK or ROS1 mutation. Exclusion criteria also included a medical condition that required systemic immunosuppression.⁷

Again, we get this question of, how do you define a systemic immunosuppression? A lot of immunotherapy drugs have used different doses. Some of them have used a prednisone dose equivalent to 20 mg/day. Some of them have used 10 mg/day as a cutoff, so you can use whichever cutoff you like. Ongoing or recent autoimmune diseases that require systemic therapy were also excluded.

The trial compared standard chemotherapy given every 3 weeks for 4 cycles with the same standard chemotherapy with [cemiplimab] given every 2 weeks, randomization of 2:1 treatment until disease progression according to RECIST, unacceptable toxicity, or 108 weeks [of treatment].

Most of these companies are using the 108 weeks as a point where you can stop immunotherapy. So you have evidence that you can stop at 2 years if you want to. The OS data for cemiplimab with and without chemotherapy at 12 months had a similar benefit, 65% vs 56%, [respectively].⁷ Again, as we saw with immunotherapy, the median PFS is not relevant. The median PFS improved from 5 months to 8.2 months. And then when you look at the overall improvement at 12 months, it was 38% with cemiplimab vs 16% with the platinum doublet.⁷

How have these data impacted the field overall?

It is quite heartening to see all these trials showing a median OS of beyond 12 months. When I first graduated from Cleveland Clinic and started [treating patients with] lung cancer, the common theory was [that patients with lung cancer] don’t make it for a year, so why bother treating them?

That was the [most common] nihilism we used to get. And back when I started 15 years ago, only about 65% of patients with lung cancer saw a medical oncologist. This is huge progress we’ve made in the last 15 years that practically every [patient with lung cancer] is now seeing a medical oncologist, if not for anything else, at least to get targeted mutation testing to see [whether the] disease harbors EGFR or ALK mutations.

What other studies have been conducted with these patients in mind?

The POSEIDON trial [NCT03164616] looked at durvalumab [Imfinzi] with or without tremelimumab-actl [Imjudo] plus chemotherapy vs platinum doublet chemotherapy.⁸ So for those of you who think 3 different immunotherapy combinations are not enough, this is your fourth one. There are 4 different immunotherapy combinations with chemotherapy now available for you.

This trial looked at stage IV NSCLC, and it had very similar inclusion criteria to the previous studies.⁸ I am not going to dwell on it, but we have an interesting element, which is to add the CTLA-4 inhibitor tremelimumab to the mix. The first arm was tremelimumab/durvalumab, so combination immunotherapy plus chemotherapy. The second arm was just the durvalumab plus chemotherapy. And the last arm was platinum-based chemotherapy alone. Durvalumab plus chemotherapy had a median PFS of 5.4 months compared with chemotherapy at 4.8 months. And at 12 months, the PFS improved from 13 to 24 months. The durvalumab plus chemotherapy vs chemotherapy arm had a very similar improvement.⁸

_REFERENCES

_{1. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):198-211. doi:10.1016/S1470-2045(20)30641-0}

_{2. Paz-Ares L, 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. 2022;8(2):204-222. doi:10.1016/j.jtho.2022.10.014}

_{3. Remicade. Prescribing information. Janssen Biotech Inc; 2021. Accessed June 30, 2023. https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/REMICADE-pi.pdf}

_{4. Reck M, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021;6(5):100273. doi:10.1016/j.esmoop.2021.100273}

_{5. Paz-Ares L, Luft A, Vicente D, et al; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865}

_{6. Novello S, Kowalski D, Luft A, et al. Pembrolizumab plus chemotherapy in Squamous non­–small cell lung cancer: 5 year update of the phase 3 KEYNOTE-407 study. J Clin Oncol. 2023;41(11);1999-2006. doi:10.1200/JCO.22.01990}

_{7. Gogishvili M, Melkadze T, Makharadze T, et al. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022;28(11):2374-2380. doi:10.1038/s41591-022-01977-y}

_{8. Johnson ML, Cho BC, Luft A, et al; POSEIDON investigators. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: the phase III POSEIDON study. J Clin Oncol. 2023;41(6):1213-1227. doi:10.1200/JCO.22.00975}