Cancer Treatment Today

The U.S. Food and Drug Administration initially granted accelerated approval for Keytruda (pembrolizumab) to treat patients with advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments and with tumors that express a protein called PD-L1. Keytruda is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test.

After initially only approving Keytruda as a single agent in previously treated patients, Keytruda, in combination with pemetrexed and carboplatin, is now indicated since May 2017 for the first-line treatment of patients with metastatic nonsquamous NSCLC  This indication is approved under accelerated approval based on tumor response rate and progression-free survival.It was approved based on the open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan.  PD-1 testing was not required by this new indication. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory,

Subsequently, FDA approved as follows:
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with stage III NSCLC, who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations

Currently, ALIMTA is indicated as a single agent for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Some of the studies sued the combination of AlLimta and Keytruda for maintenance and it is generally accepted.

Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators.. 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 Nov;17(11):1497-1508.

Edward B. Garon, M.D., Naiyer A. Rizvi, M.D., Rina Hui, M.B., B.S., Natasha Leighl, M.D., Ani S. Balmanoukian, M.D., Joseph Paul Eder, M.D., Amita Patnaik, M.D., Charu Aggarwal, M.D., Matthew Gubens, M.D., Leora Horn, M.D., Enric Carcereny, M.D., Myung-Ju Ahn, M.D., Enriqueta Felip, M.D., Jong-Seok Lee, M.D., Matthew D. Hellmann, M.D., Omid Hamid, M.D., Jonathan W. Goldman, M.D., Jean-Charles Soria, M.D., Marisa Dolled-Filhart, Ph.D., Ruth Z. Rutledge, M.B.A., Jin Zhang, Ph.D., Jared K. Lunceford, Ph.D., Reshma Rangwala, M.D., Gregory M. Lubiniecki, M.D., Charlotte Roach, B.S., Kenneth Emancipator, M.D., and Leena Gandhi, M.D., for the KEYNOTE-001 Investigators, Pembrolizumab for the Treatment of NonSmall-Cell Lung CancerN Engl J Med 2015; 372:2018-2028May 21, 2015.

Claud Grigg et al, PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction? J Immunother Cancer. 2016; 4: 48.

NCCN, NSCL Cancer 2018

KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. 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 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains verified protocol supplementary appendixPubMed
KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092.

For TMB+

The FDA has approved pembrolizumab (Keytruda) to treat adult and pediatric patients with unresectable or metastatic solid tumors that are tissue tumor mutational burden (TMB)–high (≥10 mutations/megabase) and have progressed following prior therapy and who have no satisfactory alternative treatment options.1

The FDA has also approved the FoundationOneCDx assay, deveoped by Foundation Medicine, as a companion diagnostic for pembrolizumab.

The approval is based in part on data from a prospectively planned, retrospective analysis of 10 cohorts of patients with several previously treated, unresectable or metastatic, TMB-high solid tumors who were enrolled on the phase 2 KEYNOTE-158 trial. In this trial, a link was established between TMB-high status and improved overall response rate (ORR) with the PD-1 inhibitor in patients with various solid tumors.

The multicenter, multicohort, nonrandomized, open-label trial accrued patients with anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma, mesothelioma, a neuroendocrine tumor, or small cell lung cancer. Patients had to have an ECOG performance status of 0 or 1 and have progressed on or be intolerant to at least 1 prior line of standard treatment. The investigators used the FoundationOne CDx assay to assess TMB in FFPE tumor samples, with 10 Mut/Mb used as the threshold for TMB-high status.

Pembrolizumab was administered intravenously at 200 mg every 3 weeks for 35 cycles or until progressive disease, unacceptable toxicity, or physician/patient choice. The main efficacy outcome measures included ORR and duration of response (DOR) in patients who had received at least 1 dose of pembrolizumab as evaluated by blinded independent central review in accordance with RECIST v1.1 criteria, which were modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The key secondary outcome measures progression-free survival (PFS), overall survival (OS), and safety.

Overall, there were 755 patients with evaluable TMB, 102 (13%) of whom had tumors that were classified as TMB-high. Results showed that the ORR with pembrolizumab in these patients was 29% (95% CI, 21-39), which was comprised of a 4% complete response rate and a 25% partial response rate. The median DOR had not been reached; more than half, or 57%, of patients experienced response durations of ≥12 months and half (50%) of patients had response durations of ≥24 months.

Previously reported data showed that the median PFS for the TMB-high group with pembrolizumab was 2.1 months (95% CI, 2.1-3.7), and was also 2.1 months (95% CI, 2.1-2.3) in the TMB-low cohort.2 The 12-month PFS rates were 24.3% versus 14.0%, respectively. The median OS was 11.1 months (95% CI, 8.1-16.1) in the TMB-high group, compared with 13.3 months (95% CI, 11.5-14.8) in the TMB-low group. The 12-months OS rates were 48.0% versus 52.9%, respectively.

With regard to safety, adverse events (AEs) between those with TMB-high tumors who were enrolled on the trial were found to be comparable to those occurring in patients with other solid tumors who had received the PD-1 inhibitor. The most commonly reported AEs included fatigue, musculoskeletal pain, decreased appetite, pruritis, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. The agent is also associated with immune-related AEs, such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and adverse skin reactions.

Additionally, prescribing information for the agent includes a “Limitation of Use” in that the safety and effectiveness of the drug in pediatric patients with TMB-high central nervous system cancers have not yet been established.

FDA approves pembrolizumab for adults and children with TMB-H solid tumors. News release. FDA. June 16, 2020. Accessed June 16, 2020. bit.ly/3el8pck.
Marabelle A, Fakih MG, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Ann Oncol. 2019;30(suppl 5):11920. doi:10.1093/annonc/mdz253.018
FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. News release. FDA. May 23, 2017. Accessed June 16, 2020. bit.ly/2UV9yzC.