In this case scenario, a 59-year-old White man presented with chest pain, cough, and dyspnea. The patient was later diagnosis with non–small cell lung cancer.
During a Targeted Oncology Case-Based Roundtable event, Wassim McHayleh, MD, MBA, a medical oncologist/hematologist at AdventHealth Medical Group in Altamonte Springs, FL, discussed a 59-year-old patients with non–small cell lung cancer.
Targeted OncologyTM: What would be the preferred regimen for this patient?
MCHAYLEH: The NCCN [National Comprehensive Cancer Network] has guidelines for patients with non–small cell lung cancer [NSCLC] who are positive for PD-L1 expression [with a TPS of 1% to 49%] and negative for actionable molecular markers with no contraindication to PD-L1 or PD-1 inhibitors.1
For adenocarcinoma, large cell, and NSCLC not otherwise specified, the preferred first-line therapy is carboplatin or cisplatin plus pemetrexed [Alimta]/ pembrolizumab [Keytruda], which is a category 1 recommendation. Another option is carboplatin plus paclitaxel plus bevacizumab [Avastin] or atezolizumab [Tecentriq], which is also a category 1 recommendation. Carboplatin plus albumin-bound nab-paclitaxel [Abraxane] plus atezolizumab, or ipilimumab [Yervoy]/nivolumab [Opdivo]/ pemetrexed plus carboplatin or cisplatin, is also recommended. In certain circumstances, nivolumab/ipilimumab or pembrolizumab as a single agent is recommended. If the patient has a positive response or stable disease, you can continue with maintenance pembrolizumab, pembrolizumab/pemetrexed, atezolizumab/bevacizumab, atezolizumab, or ipilimumab/nivolumab. If they have progression, switch treatment.1
For squamous NSCLC, the preferred option is carboplatin plus paclitaxel or nab-paclitaxel plus pembrolizumab, which is a category 1 recommendation. Another recommended regimen is ipilimumab/nivolumab/paclitaxel/carboplatin. Both ipilimumab/nivolumab and pembrolizumab as a single agent are useful in certain circumstances. If [patients] have a positive response, continue maintenance with pembrolizumab alone or ipilimumab/nivolumab, and if they progress, move to the next line of therapy.1
Which clinical trial data support the regimens recommended in the NCCN guidelines, such as pembrolizumab?
The KEYNOTE-189 study [NCT02578680] enrolled patients with untreated stage IIIb or IV nonsquamous NSCLC with no activating EGFR mutation or ALK translocation. They also had a sample for PD-L1 assessment, an ECOG performance status of 0 or 1, no untreated brain metastases, and no interstitial lung disease or pneumonitis requiring systemic steroids. They randomized 616 patients 2:1 with 2 for the pembrolizumab arm and 1 for the control arm. In the experimental arm, patients received carboplatin or cisplatin plus pemetrexed plus 200 mg pembrolizumab every 3 weeks for 4 cycles, followed by pembrolizumab plus pemetrexed maintenance until progression of disease [PD]. In the control arm, patients received carboplatin or cisplatin plus pemetrexed plus placebo followed by pemetrexed and placebo maintenance. If they progressed, they were allowed to cross over. Primary end points were overall survival [OS] and progression-free survival [PFS].2
At 12 months, 70.0% of the patients in the pembrolizumab arm were alive compared with 48.1% in the control arm, and at 24 months it was 45.5% compared with 29.9%. The median OS [mOS] was 22 months in the pembrolizumab arm compared with 10.7 months in the placebo arm [HR, 0.56; 95% CI, 0.45-0.70]. The follow-up period was 23.1 months.3
The OS rate in the PD-L1–negative group at 1 year was 63.4% for the pembrolizumab arm vs 47.6% for the placebo arm, and at 2 years it was 38.5% vs 15.5% for the pembrolizumab arm vs placebo arm, respectively. The mOS was 17.2 months in the pembrolizumab arm vs 10.2 months in the placebo arm [HR, 0.52; 95% CI, 0.36-0.74]. For those with a PD-L1 TPS ranging from 1% to 49%, the OS rate at 1 year was 71.7% for pembrolizumab compared with 50% for the placebo arm and 44.3% compared with 33% at 2 years. The mOS was 21.8 months compared with 12.1 months for the pembrolizumab and placebo arms, respectively [HR, 0.62; 95% CI, 0.42-0.92]. For the high expressors with a PD-L1 TPS greater than 50%, the OS rate was 73.3% vs 48.6% at 1 year and 51.9% vs 39.4% at 2 years for the pembrolizumab arm and placebo [arm], respectively. The mOS was not reached in this group [HR, 0.59; 95% CI, 0.39- 0.88]. The benefit across all groups was consistent.3
What were the design and efficacy of the KEYNOTE-042 trial?
The KEYNOTE-042 study [NCT02220894] included patients with untreated, locally advanced or metastatic NSCLC of any histology. They had a PD-L1 TPS of 1% [or greater], no EGFR or ALK mutations, an ECOG performance status of 0 to 1, no untreated or unstable central nervous system metastases, and no history of pneumonitis that required systemic corticosteroids.
[Investigators] randomized them 1:1, with 637 patients in each arm. One arm [received] pembrolizumab 200 mg every 3 weeks for up to 35 cycles, and the other arm [received] carboplatin plus paclitaxel or pemetrexed for up to 6 cycles. Stratification factors were the region— East Asia vs the rest of the world—performance status, histology, and PD-L1 level of expression: 1% to 49% and more than 50%. The primary end point was OS in the different PD-L1 expression groups, and secondary end points were PFS and overall response rate [ORR] in the different PD-L1 expression groups.4,5
In the group with a PD-L1 TPS of greater than 50%, the OS rate at 24 months was 44.7% in the pembrolizumab arm vs 30.1% in the chemotherapy arm [HR, 0.69; 95% CI, 0.56-0.85]. The mOS was 20 months in the pembrolizumab arm compared with 12.2 months in the chemotherapy arm. In the group with a PD-L1 TPS greater than or equal to 1%, the 2-year OS rate was 39.3% in the pembrolizumab arm compared with 28% in the chemotherapy arm [HR, 0.81; 95% CI, 0.71-0.93; P = .0018] and the mOS was 16.7 months vs 12.1 months. The PD-L1 group with a TPS greater than 20% had an OS rate at 2 years of 40.5% compared with 29.6%, and the mOS was 17.7 months compared with 13 months [HR, 0.77; 95% CI, 0.64-0.92].5
In an exploratory analysis that was done in the group with a PD-L1 TPS of 1% to 49%, the OS rate at 2 years was 34.6% in the pembrolizumab group compared with 26.5% in the chemotherapy group [HR, 0.92; 95% CI, 0.77-1.11]. The mOS was 13.4 months in the pembrolizumab group compared with 12.1 months in the chemotherapy group.5
Can you go into detail on the data regarding atezolizumab and bevacizumab?
The IMpower150 trial [NCT02366143] was a large study that enrolled 1202 patients with stage IV recurrent or metastatic nonsquamous NSCLC. [They were] chemotherapy naive, with tumor tissue available for biomarker testing and with any PD-L1 IHC [immunohistochemistry] status. They were stratified by sex, PD-L1 IHC expression, and liver metastases.6,7
The study had 3 arms [randomized 1:1:1]. Arm B was atezolizumab plus carboplatin plus paclitaxel plus bevacizumab for 4 or 6 cycles, followed by atezolizumab plus bevacizumab for maintenance therapy. Arm C was carboplatin plus paclitaxel plus bevacizumab for 4 or 6 cycles followed by maintenance with bevacizumab. Patients were treated until PD or unacceptable toxicities. [No crossover was permitted.]6,7
The mOS for arm B vs arm C was 19.2 months compared with 14.7 months [HR, 0.78; 95% CI, 0.64-0.96; P = .02]. At 12 months, the OS rate was 67.3% in arm B vs 60.6% in arm C, and 43.4% compared with 33.7% at 24 months. This was a statistically significant and meaningful OS of arm B compared with arm C.6.7
How did patients do in the trial of ipilimumab/nivolumab?
The CheckMate 227 [NCT02477826] study enrolled patients with stage IV or recurrent NSCLC who had no prior systemic chemotherapy, no known sensitizing EGFR or ALK alterations, and an ECOG performance status of 0 or 1. They enrolled 1189 patients with a PD-L1 expression greater than or equal to 1% and 550 patients who had a PD-L1 expression less than 1%. Patients with positive PD-L1 expression were randomized 1:1:1 into 3 arms. In 2 arms, ipilimumab plus nivolumab or nivolumab alone were given. Ipilimumab was given at 1 mg/kg every 6 weeks and nivolumab at 3 mg/kg every 2 weeks. These arms both had 396 patients. The third arm, which used histology-based chemotherapy, had 397 patients. Patients with negative PD-L1 expression were also randomized 1:1:1. One arm with 187 patients [received] ipilimumab plus nivolumab. The histology-based chemotherapy arm had 186 patients, and the nivolumab plus histology-based chemotherapy arm had 177 patients. This was a complex trial design. Patients with positive PD-L1 expression and TMB greater than or equal to 10 mutations per megabase [received a] coprimary analysis. The OS in the PD-L1 selected populations was a coprimary end point.8
In the group with positive PD-L1 expression, the OS rate for the ipilimumab plus nivolumab arm compared with the histology-based chemotherapy arm was 63% vs 56% at 1 year, 40% vs 33% at 2 years, and 33% vs 22% at 3 years. The HR for PFS at 30 months was 0.79 [97.72% CI, 0.65-0.96].9,10
Additional exploratory subgroup analyses showed [a survival benefit of nivolumab plus ipilimumab]. The group with a PD-L1 TPS of 1% to 49% had an HR of 0.94 [95% CI, 0.75-1.18], and those with a PD-L1 TPS greater than or equal to 50% had an HR of 0.70 [95% CI, 0.55-0.90].9
Grade 3 and 4 adverse events [AEs] were very similar for the chemotherapy and the immunotherapy arms. All grade 3 or 4 AEs were 32.8% in the immunotherapy arm vs 36% in the chemotherapy arm. As expected, there were diarrhea and other immune toxicities in the immunotherapy arm and chemotherapy-specific toxicities in the chemotherapy arm.9
Please describe the CheckMate 9LA trial for patients with NSCLC.
The CheckMate 9LA [NCT03215706] study enrolled patients with stage IV or recurrent NSCLC with no prior systemic therapy, no sensitizing EGFR or ALK mutations, and an ECOG performance status of 0 or 1. They were stratified by PD-L1 TPS, histology, and sex. A total of 719 patients were randomized 1:1, with 361 in the ipilimumab/nivolumab plus chemotherapy arm and 358 in the chemotherapy only arm. The patients received a nivolumab dose of 360 mg every 3 weeks, ipilimumab 1 mg/kg every 6 weeks, and 2 cycles of chemotherapy. They continued the immunotherapy until PD or unacceptable toxicities. The second arm received chemotherapy with optional pemetrexed maintenance in the nonsquamous NSCLC group. The primary end point was OS, and secondary end points were PFS, ORR, and efficacy by tumor PD-L1 expression.11,12
At 6 months, the OS rate was 81% in the chemoimmunotherapy arm compared with 73% in the chemotherapy alone arm, and at 1 year it was 63% compared with 47%, [respectively]. The ORR was higher in the chemoimmunotherapy group at 38% compared with 25% in the chemotherapy group. The mOS was 15.6 months in the chemoimmunotherapy arm vs 10.9 months in the chemotherapy only arm [HR, 0.66; 95% CI, 0.55-0.80].11,12
In the subgroups based on PD-L1 expression, the OS rate of the PD-L1–negative group was 63% vs 45% at 1 year for the chemoimmunotherapy and chemotherapy alone arms, respectively [HR, 0.62; 95% CI, 0.45-0.85]. It was 66% vs 47% for the group with a PD-L1 TPS greater than or equal to 1% [HR, 0.64; 95% CI, 0.50-0.82]. In the group of interest with a PD-L1 TPS between 1% to 49%, the OS rate was 63% vs 43% at 12 months [HR, 0.61; 95% CI, 0.44- 0.84]. In the PD-L1 high expressors with a TPS greater than or equal to 50%, the OS rate was 70% compared with 51% at 12 months [HR, 0.66; 95% CI, 0.44-0.99].11,12
The chemoimmunotherapy arm had a toxicity profile that was very acceptable, with very few grade 3 and 4 toxicities compared with the chemotherapy alone arm.11,12
So ipilimumab plus nivolumab was approved [by the FDA] on May 15, 2020, for use in NSCLC PD-L1 tumors with a TPS greater than 1%.13 Later there was an FDA approval based on the CheckMate 9LA study for ipilimumab plus nivolumab in combination with chemotherapy for first-line treatment of metastatic NSCLC.14
What trials have looked at ramucirumab (Cyramza) in this setting?
Patients eligible for the REVEL trial [NCT01168973] had stage IV NSCLC after 1 platinum-based chemotherapy with or without maintenance. Patients with prior bevacizumab therapy, all histology types, and an ECOG performance status of 0 or 1 were included. They excluded patients with major blood vessel involvement, intratumor cavitation, thromboembolic events 6 months or less before randomization, gross hemoptysis within 2 months, and grade 3 or 4 gastrointestinal bleeding within 3 months. Stratification was based on ECOG performance status, sex, prior maintenance therapy, and region—East Asia vs the rest of the world. Patients were randomized 1:1. A total of 628 patients received docetaxel 75 mg/m2 plus ramucirumab at 10 mg/kg every 3 weeks and 625 patients received docetaxel 75 mg/m2 with placebo every 3 weeks.
Treatment was continued until PD or unacceptable toxicity, and the primary end point was OS.15
The mOS was 10.5 months in the ramucirumab arm compared with 9.1 months in the placebo arm [HR, 0.86; 95% CI, 0.75-0.98; P = .02]. The median PFS was 4.5 months in the ramucirumab arm vs 3 months in the placebo arm [HR, 0.76; 95% CI, 0.68-0.86; P < .0001]. The ORR was 23% in the ramucirumab arm compared with 14% in the placebo arm [odds ratio, 1.89; 95% CI, 1.41-2.54; P < .0001].15
They also did an exploratory analysis for the outcomes of patients with aggressive or refractory disease. In patients with refractory disease, they looked at the best response of progressive disease to first-line treatment. They also did a sensitivity analysis on other subgroups of patients with aggressive or rapidly progressive disease from the intent-to-treat population. This included patients with all histology types or only adenocarcinoma who remained on first-line therapy for less than 4 weeks, less than 8 weeks, and less than 12 weeks from initiation of frontline therapy. The trial did not include patients with prior immunotherapy at the time of the trial, immunotherapy was not used as a first-line therapy.16
The benefit including OS was consistent across all groups. In the patients who progressed in less than 4 weeks, the mOS was 8.8 months vs 3.2 months in the placebo arm [HR, 0.40; 95% CI, 0.22-0.73]. In those who progressed in less than 8 weeks, mOS was 8.6 months vs 6.9 months [HR, 0.83; 95% CI, 0.61-1.15], and in those who progressed in less than 12 weeks, mOS was 9.2 months vs 7.2 months in the placebo arm [HR, 0.85; 95% CI, 0.68-1.05]. The PFS was 2.9 months vs 1.4 months in the rapid progressors [HR, 0.44; 95% CI, 0.25-0.78]. In the ramucirumab arm, the ORR was 24.2% in the rapid progressors, 23.2% in those who progressed in 8 weeks or less, and 26.2% in those who progressed in 12 weeks or less. This was consistent and significantly better than [the ORR in] the placebo arm.16
For the toxicity profile, total AEs were 98% vs 95% in the ramucirumab and placebo arms, respectively. Grade 3 or more AEs were 79% in the ramucirumab and 71% in the placebo arm. Discontinuation rates were 15% in the ramucirumab and 9% in the placebo arm, and dose adjustment was 33%…and 23%, [respectively]. AEs leading to death were similar between the 2 arms.15,16
1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 5.2021. March 3, 2021. Accessed August 17, 2021. https://bit.ly/3sGbmfC
2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005
3. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non–small-cell lung cancer. J Clin Oncol. 2020;38(14):1505-1517. doi:10.1200/JCO.19.03136
4. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) vs 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. J Clin Oncol. 2018;36(suppl 18):LBA4. doi:10.1200/JCO.2018.36.18_suppl.LBA4
5. Mok TSK, Wu YL, Kudaba I, et al; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi:10.1016/ S0140-6736(18)32409-7
6. Socinski MA, Jotte RM, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36(suppl 15):9002. doi:10.1200/JCO.2018.36.15_suppl.9002
7. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi:10.1056/NEJMoa17169488
8. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093- 2104. doi:10.1056/NEJMoa1801946
9. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231
10. Ramalingam SS, Ciuleanu TE, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: three-year update from CheckMate 227 part 1. J Clin Oncol. 2020;38(suppl 15):9500. doi:10.1200/JCO.2020.38.15_suppl.9500
11. Reck M, Ciuleanu TE, Cobo Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38(suppl 15):9501. doi:10.1200/ JCO.2020.38.15_suppl.9501
12. 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
13. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA. May 15, 2020. Accessed August 17, 2021. https://bit.ly/2W2spMI'
14. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. FDA. Updated May 27, 2020. Accessed August 17, 2021. https://bit.ly/35tnarl
15. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. doi:10.1016/S0140-6736(14)60845-X
16. Reck M, Paz-Ares L, Bidoli P, et al. Outcomes in patients with aggressive or refractory disease from REVEL: a randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer. Lung Cancer. 2017;112:181-187. doi:10.1016/j.lungcan.2017.07.038