Case Studies Showcase Recent Advances in Nonsquamous, Squamous NSCLC

Practice-changing phase III trials including KEYNOTE-189, KEYNOTE-407, REVEL, and IMpower131, among several others, are laying the groundwork for how to treat patients with non–small cell lung cancer, specifically on an individualized basis.

Roy S. Herbst, MD, PhD

Practice-changing phase III trials including KEYNOTE-189, KEYNOTE-407, REVEL, and IMpower131, among several others, are laying the groundwork for how to treat patients with non—small cell lung cancer (NSCLC), specifically on an individualized basis.

During the 2019 International Lung Cancer Congress, the plethora of data that have led to regulatory decisions were highlighted and leaders in the field identified how they best fit into the evolving lung cancer paradigm.

"We want to share how new data and approvals are changing our overall management of metastatic disease, understand factors that influence our treatment selection and plan with a focus on new data and targeted agents, and gain insight into how we are thinking about treating patients," Roy S. Herbst, MD, PhD, chief of Medical Oncology and professor of medicine at Yale Cancer Center, Smilow Cancer Hospital, said during the meeting.

In a discussion during the meeting, Herbst, along with David S. Gandara, MD, and Paul Baas, MD, PhD, covered case-based scenarios and how they would treat select patients with NSCLC based on pivotal data that have emerged over the last year.

Case 1: Nondriver Metastatic Adenocarcinoma

A 69-year-old Caucasian female patient, who is a never-smoker, presents with symptoms of visual disturbances, nausea, fatigue, and headaches. She had prior hypertension and hyperlipemia, which were managed on systemic agents; her blood pressure was 148 over 70. Beyond decreased breath sounds, her ECOG performance status was 1. The complete blood count was within normal limits.

Moreover, a brain MRI demonstrated a right parietal mass at the gray—white junction with vasogenic edema, and a CT scan of the chest, abdomen, and pelvis revealed a 3.4–cm mass in the left lower lobe and several small liver nodules. A transthoracic needle biopsy of the lung lesion showed that the patient had grade 2 adenocarcinoma and a PD-L1 test via 22C3 pharmDx showed 55% PD-L1 expression on tumor cells.

After stressing the need for next-generation sequencing (NGS), the panel mentioned that the assay results showed that an EGFR exon 19 deletion was present, which warranted use for an EGFR TKI.

“This is why you want to do something like NGS,” said Gandara, who is director of the Thoracic Oncology Program, professor of medicine, and senior adviser to the director at the University of California Davis Comprehensive Cancer Center, and 2017 Giant of Cancer Care® in Lung Cancer.

“In reality, you don't want to be testing for EGFR and the patient really has RET. When you get a bunch of genes tested, whether it's blood or tissue, you will pick up the uncommon thing—it will pick up NTRK, pick up MET, exon 14 skipping mutation, etc.”

Case 2: Nondriver Metastatic Adenocarcinoma

A 62-year-old male presents with persistent right-sided neck pain, followed by decreased appetite, lethargy, and a dry cough 2 months later. His ECOG performance status is 1, he is a former smoker, and has hypercholesterolemia that is managed on pravastatin. He also has no allergies, no family history of lung cancer, and osteoarthritis.

A chest CT scan demonstrated a 2.3-cm right upper lobe (RUL) mass with enlarged subcarinal lymph nodes, and a PET scan showed an 18FDG uptake in the RUL mass, mediastinal nodes, and multiple metastases in the thoracic vertebrae and pelvis. Findings showed TTF-1 positive adenocarcinoma with a diagnosis of metastatic lung cancer.

Molecular findings showed that the patient's tumor was negative for EGFR, ROS1, RET, BRAF, HER2, and NTRK, and immunohistochemistry showed no ALK rearrangements and 0% PD-L1 expression. Lab results showed normal creatinine levels and liver function.

When choosing treatment, various factors must be taken into consideration when choosing either single-agent immunotherapy or a combination of PD-1 inhibition and chemotherapy.

Initially based on results of cohort G of the phase II KEYNOTE-021 trial, the combination of pembrolizumab (Keytruda) and standard chemotherapy is available as an option for patients with metastatic nonsquamous NSCLC. In May 2018, the FDA granted a full approval to the regimen, based on findings from the phase III KEYNOTE-189 study.

In KEYNOTE-189, the addition of pembrolizumab to pemetrexed and either cisplatin or carboplatin in the first-line setting led to a 51% reduction in the risk of disease progression or death in patients with NSCLC without EGFR or ALK mutations.1 The median overall survival (OS) was not reached with the pembrolizumab regimen versus 11.3 months in the chemotherapy-alone arm.

Updated data from the trial, which were presented at the 2019 ASCO Annual Meeting, showed that at a median follow-up of 18.7 months, the median OS was 22.0 months in the pembrolizumab arm versus 10.7 months in the chemotherapy-alone arm (HR, 0.56; 95% CI, 0.45-0.70).2 Results also showed that the 1- and 2-year OS rates with pembrolizumab were 70.0% and 45.5% versus 48.1% and 29.9% with chemotherapy. The updated PFS data showed that there was a 52% reduction in the risk of disease progression (HR, 0.48; 95% CI, 0.40-0.58; P <.00001).

“In KEYNOTE-189, you will see that starting with the carboplatin and pemetrexed and pembrolizumab really gives a great advantage,” said Baas, thoracic oncologist, Division of Medical Oncology Netherlands Cancer Institute, and professor, Thoracic Oncology at the University of Leiden, Amsterdam, The Netherlands.

When stratified by PD-L1 expression, updated data also showed that OS outcomes did not differ significantly between those with PD-L1 tumor proportion score (TPS) ≥50 (HR, 0.59; 95% CI, 0.39-0.88), TPS 1% to 49% (HR, 0.62; 95% CI, 0.42-0.92), and <1% (HR, 0.52; 95% CI, 0.36-0.74).

However, there were more significant differences in PFS with the different PD-L1 TPS groups, at ≥50% (HR, 0.36; 95% CI, 0.26-0.51), 1% to 49% (HR, 0.51; 95% CI, 0.36-0.73), and <1% (HR, 0.64; 95% CI, 0.47-0.89).

“There is the subdivision that if you have low TPS, the curves are getting much closer,” said Baas. “But it's important to see what we have.”

For patients with high (≥50%) PD-L1 expression, the panel noted that single-agent pembrolizumab may be the optimal strategy, citing results from the phase III KEYNOTE-042 trial.

In KEYNOTE-042, 1274 patients with locally advanced or metastatic NSCLC were randomized to receive pembrolizumab or paclitaxel/carboplatin or pemetrexed/carboplatin. Patients were stratified into 3 arms according to TPS: ≥50% (n = 599), ≥20% (n = 818), and ≥1% (n = 1274). An equal number of patients in each PD-L1 expression group received pembrolizumab or chemotherapy. Patients were randomized 1:1 to receive either 200 mg of pembrolizumab every 3 weeks for ≤35 cycles or investigator’s choice of chemotherapy regimens for ≤6 cycles.

Findings showed that frontline pembrolizumab led to a median overall survival (OS) of 16.7 months compared with 12.1 months with standard chemotherapy in patients with advanced or metastatic NSCLC and TPS ≥1% (HR, 0.81; 95% CI, 0.71-0.93; P = .0036).3 In an exploratory analysis that examined all patients with PD-L1 TPS of 1% to 49%, the median OS was 13.4 months and 12.1 months with pembrolizumab and chemotherapy, respectively (HR, 0.92; 95% CI, 0.77-1.11).

These data led to the April 2019 FDA expanded approval of pembrolizumab monotherapy for the frontline treatment of patients with stage III NSCLC, who are ineligible for surgery or definitive chemoradiation, or metastatic NSCLC, with a PD-L1 expression TPS level of ≥1% and have no EGFR or ALK aberrations.

In referring back to the case being discussed, the panel noted that the patient was started on pembrolizumab combined with carboplatin/pemetrexed, along with vitamin B12 and folic acid supplements. After 2 cycles of chemotherapy, imaging showed progression in the right lung mass at 5.2 cm and several bone lesions, and there was also a decrease in hemoglobin.

At this point, the panel debated whether this could be a case of hyperprogression or pseudoprogression.

“The first thing to say is that pseudoprogression, although it's well established in melanoma, yet almost never happens in NSCLC. In the trials that really looked at this, 800-patient trials, there was almost no pseudoprogression,” said Gandara. “If the patient has what ‘might’ be pseudoprogression, let's say in a measurable way, and the patient is sicker, they're losing weight and have increased symptoms, [they have actual disease] progression.”

As a second-line option, the patient was given docetaxel and the monoclonal antibody ramucirumab (Cyramza).

The decision to give this doublet regimen was based on findings from the phase III REVEL trial, an exploratory post-hoc analysis of which demonstrated an OS benefit versus placebo/docetaxel in patients with advanced NSCLC who had rapid disease progression on frontline therapy.

Results showed that the median OS in those treated with ramucirumab/docetaxel was 10.5 months versus 9.1 months for docetaxel alone (HR, 0.86; 95% CI, 0.75-0.98; P = .02).4 The median PFS was 4.5 months and 3.0 months in the ramucirumab and docetaxel-alone arms, respectively (HR, 0.76; 95% CI, 0.68-0.86; P <.0001). Additionally, the ORR was 23% with ramucirumab/docetaxel and 14% with docetaxel alone (odds ratio [OR], 1.89; 95% CI, 1.41-2.54; P <.0001).

Based on earlier REVEL data, the FDA approved ramucirumab in December 2014 for use in combination with docetaxel for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy.

Additional follow-up showed that the median OS was comparable across those who had differing durations of first-line therapy, including those on frontline treatment for ≤4 weeks (median OS, 8.8 months with ramucirumab/docetaxel and 3.2 months with docetaxel; HR, 0.40; 95% CI, 0.22-0.73) ≤8 weeks (8.6 months vs 6.9 months, respectively; HR, 0.83; 95% CI, 0.61-1.15), and ≤12 months (9.2 months vs 7.2 months, respectively; HR, 0.85; 95% CI, 0.68-1.05).

Case 3: Metastatic Squamous NSCLC

A 74-year-old male presents with cough, dyspnea, and fatigue; past medical history includes hypertension, mild psoriasis and psoriatic arthritis, and is a former smoker with a 40-pack year history. His ECOG performance status is 1.

A PET/CT scan shows a right lower lobe mass, hilar and bilateral mediastinal lymph nodes, and bone metastasis in right femur. Following a biopsy, he is diagnosed with stage IV squamous cell NSCLC and has PD-L1 TPS expression on 65% of cells.

Due to prior data, the panel explained that patients with squamous cell NSCLC can be ideal candidates for immunotherapy, as squamous histology has a higher mutation rate and neoantigen transversion mutations are more common.

In updated findings from the KEYNOTE-024 trial, for example, a subgroup analysis showed that patients with squamous histology who were treated with pembrolizumab also had an improvement in OS (HR, 0.78; 95% CI, 0.63-0.95).5

However, it was data from the phase III KEYNOTE-407 trial that led to a practice-changing decision for this patient population. Data from the study showed that combining pembrolizumab with chemotherapy reduced the risk of death by 36% versus chemotherapy alone in patients with metastatic squamous NSCLC.6 The median 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). The survival improvement was observed across patient subgroups.

In October 2018, the FDA approved first-line pembrolizumab for use in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) for the treatment of patients with metastatic squamous NSCLC.

Another therapeutic option under investigation in these patients is the IMpower131 regimen, which comprises atezolizumab (Tecentriq) in combination with carboplatin and either paclitaxel or nab-paclitaxel in patients with advanced squamous NSCLC. In results presented at the 2018 ASCO Annual Meeting, the atezolizumab regimen delayed the risk of progression or death by 29% compared with chemotherapy alone for patients with advanced squamous NSCLC.7

At a median follow-up of 17.1 months, the median PFS was 6.3 months (95% CI, 5.7-7.1) with the addition of atezolizumab versus 5.6 months (95% CI, 5.6-5.7) with chemotherapy alone (HR, 0.71; 95% CI, 0.60-0.85; P = .0001). The 12-month PFS rates were 24.7% versus 12.0%, respectively.

“It is very important that we consider every patient separately to see whether pembrolizumab alone or combination is the best choice. If you have any doubt, hit them with a 3- or maybe 4-drug regimen,” Baas concluded.

Herbst added, “Immunotherapy is pretty much the frontline standard when we can use it, and we talk about ways to expand its use, with caution. But again, we are realizing that we're treating a very vast and aggressive disease.”


  1. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508.
  2. Gadgeel SM, Garassino MC, Esteban E, et al. KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. J Clin Oncol. 2019;37(suppl; abstr 9013). doi: DOI: 10.1200/JCO.2019.37.15_suppl.9013.
  3. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. Presented at: 2018 ASCO Annual Meeting; June 1-5; Chicago. Abstract LBA4.
  4. Rapidly Progressing Advanced Non-Small Cell Lung Cancer Patients Shown to Benefit in New CYRAMZA® (ramucirumab) Phase 3 Subgroup Analysis. Eli Lilly and Company. Accessed October 17, 2017.
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  6. 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).
  7. Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol. 2018;36 (suppl; abstr LBA9000).