What Are Treatment Options After Progression in PDL-1–Positive Metastatic Lung Adenocarcinoma after Chemo/IO?

OncologyONCOLOGY Vol 33 No 8
Volume 33
Issue 8

What is the best treatment option after progression to chemotherapy/immunotherapy (chemo/IO) as first-line treatment for PD-L1–positive lung adenocarcinoma with no sensitizing mutations?





Yuly A. Remolina-Bonilla, MD,

Raul R. Trejo-Rosales, MD

Bruno Saldivar- Oviedo

Alejandro Gabutti, MD

Maria T. Bourlon MD, MS

A 49-year-old woman with no smoking history presented to the emergency room with a pathologic left hip fracture. On hip x-ray, a metastatic blastic lesion was found. Workup included a CT scan that detected a primary neoplastic lesion on the left lung. Percutaneous guided biopsy revealed lung adenocarcinoma. Molecular testing of the neoplasm revealed no targetable mutations (EGFR, ALK, ROS) and a programmed death ligand 1 (PD-L1) tumor proportion score of 1%. An F-18-fluorodeoxyglucose (18F-FDG) PET/CT demonstrated metastatic disease to the bone and lymph nodes (Figure 1), and brain MRI revealed multiple brain lesions.

The patient underwent total hip replacement for the hip fracture. She was started on first-line systemic treatment with combination cisplatin, pemetrexed, and pembrolizumab and received whole-brain radiotherapy 30 Gy in 10 daily fractions. Her scans revealed stable disease after the first 3 cycles. After 6 cycles, however, a new PET/CT showed progressive disease with increased size of the primary lung lesion, new bone lesions, new mediastinal lymph nodes, and a new liver lesion (Figure 1).

What is the best treatment option after progression to chemotherapy/immunotherapy (chemo/IO) as first-line treatment for PD-L1–positive lung adenocarcinoma with no sensitizing mutations?

A. Single-agent chemotherapy

B. Docetaxel with antiangiogenic agent

C. Clinical trial

D. All of the above


CORRECT ANSWER: D. All of the above

In recent years, the treatment of non–small-cell lung cancer (NSCLC) has changed dramatically and immunotherapy alone or in combination with chemotherapy has become the standard first-line treatment for metastatic lung adenocarcinoma without EGFR or ALK genetic alterations.[1] This recommendation is based on different results of phase III trials that demonstrated an overall survival benefit. Patients with PD-L1 expression of 1% or greater can receive treatment with pembrolizumab as monotherapy.[2,3] Furthermore, immunotherapy plus platinum-based chemotherapy can be used regardless of PD-L1 expression.[4,5] The rationale of this combination is based on two mechanisms: induction of immunogenic cell death and disruption of the immune-suppressive tumor microenvironment.[6]

Currently, patients with NSCLC PD-L1 of 1% or greater who progress after treatment with checkpoint inhibitors/chemotherapy do not have standard second-line systemic treatment options. National Comprehensive Cancer Network (NCCN) guidelines suggest treatment with chemotherapy alone or in combination with antiangiogenic agents as well as clinical trials and do not recommend routinely switching to another programmed death 1 (PD-1)/PD-L1 inhibitor.[1] However, there are no studies yet that evaluate the appropriate treatment for this scenario. For practical purposes and to facilitate the therapeutic approach, patients who progress after chemo/IO can be classified into two categories: 1) primary resistance (PR) and hyperprogressive disease (HPD), and 2) acquired resistance (AR).

1) Primary resistance (PR) and hyperprogressive disease (HPD)

In this category, both phenomena are indistinguishable and share molecular pathways. Clinically, patients have disease progression in their first image evaluation after treatment initiation. This may be a consequence of an aggreossive tumor biology or an immune-related event. PR is characterized by an exhausted T-lymphocyte phenotype, where there is an overexpression of alternative immune checkpoints, which include TIM-3, CTLA-4, LAG-3, and BTLA, as well as the infiltration of immunosuppressive regulatory T cells, which could facilitate the processes of immune escape and tumor progression.[7,8]

HPD is an immune-related progression pattern characterized by an acceleration of tumor growth during treatment with PD-1/PD-L1 inhibitors. There is no consensus for the definition of HPD,[9] but based on the criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, it can be defined as disease progression on the first CT during treatment with PD-1/PDL-1 inhibitors (Table).[10] The survival curves intersection through the first months of immunotherapy for second-line treatment can be explained by this phenomenon.[11] However, the frequency of HPD in patients receiving chemo/IO as first-line treatment has not been determined.

Studies on HPD have been performed mainly in patients receiving immunotherapy as a second line of treatment.[13] In the retrospective study by Ferrera et al of 406 patients treated with immunotherapy, HPD was more frequent in the group treated with immunotherapy compared to chemotherapy. However, just one case occurred in the first-line setting. It is likely that the use of chemotherapy in combination with PD-1/PD-L1 inhibitors has a favorable impact on decreasing the proportion of patients who have this immune-related phenomenon.[14] The crossing of the Kaplan-Meier curves is not observed in KEYNOTE-189 patients treated with chemo/IO compared with patients treated with pembrolizumab alone, both in first-line settings (Figure 2).[4]

Whether these scenarios represent truly defined clinical entities is controversial. Although HPD is a possibility in cases that show progression in the first months of treatment, primary resistance cannot be ruled out as part of the spectrum of a more aggressive disease.

The best treatment of patients with PR/HPD has yet to be defined. Current information suggests that the use of chemotherapy with docetaxel with or without antiangiogenic agents or pemetrexed is a reasonable option.{1]

Studies evaluating the effectiveness of chemotherapy after IO mainly include patients treated with IO as monotherapy in second and subsequent lines. These are retrospective and single-institution studies with a limited number of patients.[15-20] They have mostly explored the effectiveness of chemotherapy alone or with antiangiogenic agents after treatment with nivolumab. Park et al compared efficacy of chemotherapy before and after IO in 73 patients. They did not find differences in terms of progression-free survival and overall survival; however, they reported better objective response rates (ORRs) in the group of patients treated with platinum-based combination chemotherapy after IO compared to before IO, 66.7% vs 39.5% (P = .03), respectively. ORRs for patients receiving nonplatinum monotherapies were 46.9% vs 25%, respectively (P = .09).[20] This trend toward better effectiveness in patients treated with chemotherapy after immune checkpoint inhibitors has been reported by other authors in patients treated with docetaxel with or without ramucirumab or docetaxel as monotherapy.[18,21]

2) Acquired resistance (AR)

In this category, patients show disease progression or relapse after an initial stabilization of the disease (ie, partial response or complete response) which had been maintained over a period of several months or years. These patients can be subclassified as oligometastatic vs multimetastatic progression. Recently, Gettinger et al showed results of 26 patients treated with immunotherapy, 9 of them in the first-line setting. Oligometastatic progression limited to 1 or 2 sites occurred in 8% of cases; exclusive lymph-node involvement occurred in 40% of the entire cohort. Fifty-eight percent of patients received local treatment in the sites of progression, without initiating second-line or later systemic treatment, with a 2-year survival of 92%. After local treatment, 11 patients continued with the same immunotherapy treatment.[22]

Patients with limited progression to 1 or 2 sites may receive local treatment at the site of progression with radiotherapy or surgery, maintaining the same immunotherapy treatment. Cases with multimetastatic disease can be treated with immunotherapy re-challenge. Treatment with chemotherapy with docetaxel with or without antiangiogenic agent or pemetrexed is also a reasonable option.

The mechanisms associated with acquired resistance include the loss of neoantigens by T-cell–dependent immunoselection processes, mutations in JAK1/JAK2, and mutations in beta-2–macroglobulin.[23-25] Shah et al reported the clinical findings of 57 patients with NSCLC with acquired resistance to immunotherapy. The progression of previously existing lesions occurred in 60.6% of cases, rather than the development of de novo metastatic disease. In addition, 66.7% of patients had progression in a unique disease site and in 30% the progression was diffuse.[26]

Ongoing studies may help select appropriate treatment sequences in NSCLC. The phase III INSIGNA trial (NCT03793179) plans to enroll 846 metastatic nonsquamous NSCLC patients with PD-L1 1% or greater and will be randomized in 3 arms. In arm A, patients will receive upfront pembrolizumab and, at time of disease progression, they will receive pemetrexed and carboplatin. In arm B, patients will receive upfront pembrolizumab and, at time of disease progression, they will receive pembrolizumab beyond progression and pemetrexed and carboplatin combination chemotherapy. In arm C, participants will receive pembrolizumab, pemetrexed, and carboplatin as first-line therapy and pembrolizumab and pemetrexed as maintenance until disease progression. The study plans to end in 2021.


Second-line treatment after progression on chemo/IO in PD-L1–positive lung adenocarcinoma with no sensitizing mutations has not yet been established. Treatment decisions depend on the time to treatment failure and affected sites and may include chemotherapy with or without antiangiogenic agent, local therapy, enrollment in a clinical trial, or reintroduction of immunotherapy.



1. National Comprehensive Cancer Network. Non-small cell lung cancer. (Version 5.2019) June 7, 2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf Accessed July 30, 2019.

2. Mok TSK, Wu YL, Kudaba I, et al. 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;393:1819-30.

3. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823-33.

4. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078-92.

5. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288-301.

6. Wang C, Kulkarni P, Salgia R. Combined checkpoint inhibition and chemotherapy: new era of 1st-line treatment for non-small-cell lung cancer. Mol Ther Oncolytics. 2019;13:1-6.

7. Thommen DS, Schreiner J, Muller P, et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res. 2015;3:1344-55.

8. Wei T, Zhang J, Qin Y, et al. Increased expression of immunosuppressive molecules on intratumoral and circulating regulatory T cells in non-small-cell lung cancer patients. Am J Cancer Res. 2015;5:2190-201.

9. Champiat S, Ferrara R, Massard C, et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol. 2018;15:748-62.

10. Ferrara R, Mezquita L, Texier M, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy. JAMA Oncol. 2018;4:1543-52.

11. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627-39.

12. Kato S, Goodman A, Walavalkar V, et al. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23:4242-50.

13. Proto C, Ferrara R, Signorelli D, et al. Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out. Cancer Treat Rev. 2019;75:39-51.

14. Onesti CE, Freres P, Jerusalem G. Atypical patterns of response to immune checkpoint inhibitors: interpreting pseudoprogression and hyperprogression in decision making for patients’ treatment. J Thorac Dis. 2019;11:35-8.

15. Corral J, Majem M, Rodriguez-Abreu D, et al. Efficacy of nintedanib and docetaxel in patients with advanced lung adenocarcinoma treated with first-line chemotherapy and second-line immunotherapy in the nintedanib NPU program. Clin Transl Oncol. 2019;21:1270-79.

16. Costantini A, Corny J, Fallet V, et al. Efficacy of next treatment received after nivolumab progression in patients with advanced nonsmall cell lung cancer. ERJ Open Res. 2018;4.

17. Shiono A, Kaira K, Mouri A, et al. Improved efficacy of ramucirumab plus docetaxel after nivolumab failure in previously treated non-small cell lung cancer patients. Thorac Cancer. 2019;10:775-81.

18. Tamura N, Horinouchi H, Sekine K, et al. Efficacy of subsequent docetaxel +/- ramucirumab and S-1 after nivolumab for patients with advanced non-small cell lung cancer. Thorac Cancer. 2019;10:1141-8.

19. Yano Y, Kurebe H, Edahiro R, et al. Post-progression survival after cessation of treatment with nivolumab for advanced non-small cell lung cancer: a retrospective study. PLoS One. 2018;13:e0203070.

20. Park SE, Lee SH, Ahn JS, et al. Increased response rates to salvage chemotherapy administered after PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer. J Thorac Oncol. 2018;13:106-11.

21. Schvartsman G, Peng SA, Bis G, et al. Response rates to single-agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non-small cell lung cancer. Lung Cancer. 2017;112:90-5.

22. Gettinger SN, Wurtz A, Goldberg SB, et al. Clinical features and management of acquired resistance to PD-1 axis inhibitors in 26 patients with advanced non-small cell lung cancer. J Thorac Oncol. 2018;13:831-9.

23. Anagnostou V, Smith KN, Forde PM, et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 2017;7:264-76.

24. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819-29.

25. Restifo NP, Marincola FM, Kawakami Y, et al. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst. 1996;88:100-8.

26. Shah S, Wood K, Labadie B, et al. Clinical and molecular features of innate and acquired resistance to anti-PD-1/PD-L1 therapy in lung cancer. Oncotarget. 2018;9:4375-84.

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