Comparison of key outcomes in KEYNOTE-024 and KEYNOTE-189 study

Pembrolizumab has also been studied in combination with chemotherapy for the treatment of PDL1 unselected advanced nonsquamous NSCLC in Phase 3 KEYNOTE-189 study.[5] It also demonstrated superior OS and PFS of pembrolizumab plus chemotherapy versus chemotherapy alone in the entire population.[6] The median PFS, OS, and ORR were significantly higher in population subset with PDL1 >-50%-as shown in [Table 1].[6]

There is no trial till date which has evaluated chemotherapy plus pembrolizumab versus pembrolizumab alone in high PDL1 population. The conundrum to use pembrolizumab as a monotherapy versus combination remains a controversial area for such patients. Cross-trial comparisons between KEYNOTE-024 and the PDL1-high subgroup of KEYNOTE-189 suggest comparable outcomes between pembrolizumab and chemotherapy and pembrolizumab alone [Table 1].[3],[6] This is despite the fact that there was superior response rates in PDL1 high subset of patients in KEYNOTE-189 (61%) as compared to monotherapy in KEYNOTE-024 (44%).[4],[6] However, this comparison is only hypothesis generating and formal conclusions can only be drawn after a head-to-head trial comparisons between the two. It is also notable that the corresponding chemotherapy control arms experienced somewhat different 12-month OS rates (55%-and 48%-in KEYNOTE-024 and KEYNOTE-189 [PD-L1-high subgroup], respectively).[3],[5]

There was however a notable difference in rates of grade 3-4 toxicity between immunotherapy arms of the two studies, and as shown in [Table 1], there was 40%- more Grade ¾ toxicity observed with chemotherapy combination.[3],[5]

To answer this question, a meta-analysis of five randomized clinical trials was done in patients with high PDL1 [removed]>-50%-PDL1 score) comparing pembrolizumab monotherapy, pembrolizumab combined with chemotherapy, versus chemotherapy alone.[7] Both the immunotherapy arms were superior to chemotherapy-alone arm in terms of PFS and OS. Indirect comparison showed that pembrolizumab plus chemotherapy was superior to pembrolizumab alone, in terms of ORR (relative risk 1.62, 1.18–2.23) and PFS (hazard ratio [HR] 0.55, 0.32–0.97). A trend toward improved OS was also observed (HR 0.76, 0.51–1.14); however, it was not statistically significant.[7] The result of this meta-analysis can be very tempting for a physician to choose the combination over single-agent pembrolizumab alone, but indirect comparisons and potential for severe toxicities with a similar survival rates cast a doubt on the results.

In the absence of direct comparative data and keeping in mind the patient's desire for maximal survival with minimal toxicity, I have chosen pembrolizumab monotherapy for the patient, thus allowing for the option of using a platinum-based doublet in the second-line setting.

Atezolizumab in combination with nab-paclitaxel and carboplatin is also approved as a first-line therapy for patients with nonsquamous NSCLC in PDL1 unselected population. The approval for this is based on the pivotal Phase 3 Study IMPower 130.[8] The combination of atezolizumab with nab-paclitaxel and carboplatin significantly improved PFS and OS versus chemotherapy alone as shown in [Table 2].[8] Nab-paclitaxel was chosen as it does not require a steroid premedication, which may affect the response to immunotherapy. Grade 3–4 adverse events noted in this study were 71.3%, making it a toxic therapy. Liver metastases were present in approximately 15%-of each arm of the study. The subgroup of patients with baseline liver metastases failed to show the PFS and OS benefit.[8] The high incidence of Grade 3–4 toxicity and poorer outcomes of patients with baseline liver metastases makes the use of atezolizumab in combination with nab-paclitaxel and carboplatin, a less preferred option for our patient who has multiple liver metastases.

Key outcomes in IMPower 130 and IMPower 150 studies

The presence of hemoptysis which is a contraindication to the use of bevacizumab makes atezolizumab, bevacizumab, paclitaxel, and platinum (ABCP) an unacceptable option for our patient. ABCP had otherwise shown superiority over combination of bevacizumab, paclitaxel, and platinum (BCP) in IMPower 150 study of advanced, PDL1 unselected nonsquamous NSCLC patients.[9] An updated subgroup analysis of IMPower 150 demonstrated improved PFS and OS in patients with baseline liver metastases [Table 2], a finding which was not observed in the subset analysis of immunotherapy arm of IMPower 130.[8],[10] IMPower 150 had a third arm of atezolizumab, paclitaxel, and platinum (ACP). The ACP arm failed to show superiority over BCP in patients with baseline liver metastases.[10]

The combination of atezolizumab with pemetrexed and carboplatin has been compared to pemetrexed and carboplatin in advanced nonsquamous NSCLC in IMPower 132 study which demonstrated improved PFS (7.6 months vs. 5.2 months; HR 0.60), but there was only trend toward difference in OS at the time of first analysis (18.1 vs. 13.5 months; HR 0.46).[11] In view of nonavailability of robust data for OS for this regimen at this time, it cannot be recommended as a first-line therapy for our patient.

We have seen how there are a plethora of choices while choosing therapy for metastatic NSCLC in the first-line setting. The right choice of therapy can be decided by the presence of molecular driver alterations, PDL1 expression, comorbidities, performance status, burden of disease, and most importantly financial abilities of the patient. The various trials discussed above can guide us in choosing therapy, but the final decision must always be individualized after an informed decision-making with patient and physician. For example, in a young patient with high burden of disease, a significant response will be an ideal primary goal and a combination of chemotherapy and immunotherapy will be the best option. On the other hand, for an elderly gentleman with comorbidities and borderline performance status, single-agent immunotherapy will be a preferred choice where minimal toxicity and good quality of life with maximal survival advantage are desired. Unfortunately, not much data are available regarding the efficacy of immunotherapy drugs in Indian patients, but we can always extrapolate the data available from studies from the west. Another major concern for patients in a third world country is financial status of the family. A good fraction of patients presenting in Indian hospitals cannot afford traditional chemotherapy; immunotherapy will be out of reach of most patients which is 40–80 times costlier. It will still be long before chemotherapy can be completely done away in the management of lung cancer, particularly in an Indian healthcare system.