Version 1 Flashcards
What is the preferred TKI for rare EGFR mutations such as EGFR mutations L861Q, G719X, and/or S768I?
Afatinib. Definitely
Osimertinib. Phase II data
Currently, Afatinib is the only EGFR tyrosine kinase inhibitor (TKI) approved by the FDA for patients with NSCLC and the rare, nonresistant EGFR mutations L861Q, G719X, and/or S768I.[1,2]
Afatinib was approved in this setting based on a pooled analysis of 32 patients with these rare EGFR mutations who were enrolled on the late-phase LUX‑Lung 2, LUX-Lung 3, and LUX-Lung 6 trials. In this pooled population, 21 had a response to afatinib confirmed by independent radiology review, yielding an ORR of 66%. Among the 21 responders, 52% had a duration of response lasting 12 months or more, with 33% responding for at least 18 months.
Recent data suggest that osimertinib may have activity against these rare EGFR mutations. At the 2018 ASCO Annual Meeting interim analysis of an open-label phase II trial assessing the efficacy and safety of osimertinib in 36 patients with metastatic or recurrent NSCLC who harbored an activating EGFR mutation other than exon 19 deletion, L858R, T790M, or exon 20 insertion.
What would you do in the setting of Afatinib toxicity at full dose of 40mg?
Reduce dosage to 30mg then 20mg. Data suggests no loss of efficacy based on post hoc analysis of LUX-LUNG 3 and 6
Is there data for the use of immunotherapy in 2nd line setting for EGFR mutants?
Yes.RCT Phase III IMpower150 trial
THIS IS THE QUADRUPLE TRIAL - Pac/Carbo/Atezo/Bev
Only study to date that allowed for patients with EGFR mutations or ALK translocations who had disease progression or unacceptable toxicity with targeted therapy.
1202 patients with advanced nonsquamous NSCLC.
3 arms: atezolizumab/carboplatin/paclitaxel (ACP), bevacizumab/carboplatin/paclitaxel (BCP), or atezolizumab/BCP (ABCP) every 3 weeks for 4 or 6 cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both.
In the subpopulation with EGFR or ALK alterations, the median PFS was prolonged with the ABCP quadruplet vs the BCP triplet (9.7 vs 6.1 months, respectively; unstratified HR: 0.59; 95% CI: 0.37-0.94).
Regarding the population wild-type for EGFR and ALK, the IMpower150 trial showed that patients with liver metastases experienced a PFS benefit (7.4 vs 4.9 months; unstratified HR: 0.42; 95% CI: 0.26-0.66). Furthermore, an interim analysis found a significant OS benefit among those with wild-type EGFR and ALK (median OS: 19.2 vs 14.7 months; stratified HR: 0.78; P = .02). These positive results recently led the FDA to approve the ABCP quadruplet for first-line treatment of nonsquamous NSCLC in patients with no EGFR/ALK aberrations.[11]
Although the ABCP regimen showed consistent improved efficacy in the overall population and across subgroups in IMpower150, clinicians should be aware of some important toxicities associated with this quadruplet.
What is the first line and possible standard of care for Mets Sq Cell Carcinoma?
A. PD-L1 >50% : Single agent immuno
B. PD-L1<50%, PS 0/1:
Ph III KN- 407
Pac/Carbo/Pembro - Superior PFS, RR, DOR
- 559 chemotherapy-naive patients with metastatic squamous NSCLC to 4 cycles of carboplatin with the investigator’s choice of paclitaxel or nab-paclitaxel plus either pembrolizumab or placebo, followed by pembrolizumab or placebo maintenance.
Placebo-treated patients could cross over to pembrolizumab upon disease progression.
The addition of pembrolizumab to chemotherapy was shown to significantly improve median OS vs chemotherapy alone in the overall population (15.9 vs 11.3 months, respectively; HR: 0.64; P = .0008) and across most patient subgroups, including those defined by tumor PD-L1 expression.
The pembrolizumab–chemotherapy combination also proved superior to chemotherapy alone for median PFS, response rate, and duration of response. Based on these supportive data, current recommendations for squamous cell carcinoma of the lung are that patients with PD-L1 expression < 50% should receive pembrolizumab plus carboplatin with either paclitaxel or nab‑paclitaxel.
Option of Abraxane/Carbo/Atezolizumab [IMPower 131]
If immunotherapy is a contraindication, what are possible first line options for Mets Squamous Cell Carcinoma
- Platinum doublet or
2. Gemcitabine/cisplatin plus the anti-EGFR monoclonal antibody necitumumab
Can you use TMB to determine Immunotherapy?
Open-label, randomized, phase III CHECKMATE‑227 trial in patients with squamous or nonsquamous NSCLC.
Their analysis showed a significantly longer median PFS with the combination of nivolumab/ipilimumab vs chemotherapy in the subgroup with high TMB (7.2 vs 5.5 months, respectively; HR: 0.58; P < .001).
In those with high TMB, there was a PFS benefit regardless of PD-L1 expression level. Among those with low TMB, there was no PFS benefit. OS data are not available at this time.
In CHECKMATE-227, TMB was assessed using the FoundationOne CDx assay and defined as ≥ 10 mutations/megabase. There is currently a great deal of controversy over what cutoff and which assays should be used for defining TMB. The FDA has not approved a diagnostic for TMB, and nivolumab/ipilimumab is still an investigational treatment. In my practice, I assess TMB both for research purposes and because data show it has some predictive value regarding patients who are more likely to respond well to immunotherapy.[22] At this time, TMB does not replace PD-L1 IHC in terms of our treatment algorithms.
First line immunotherapy trial in Mets NSCLC
In oncogene negative or no proven oncogene directed therapy,
- Chemo + Immuno if PDL-1<50% and asymptomatic or PDL-1>50%, symptomatic and response is rquired
(KN 189) - Immuno monotherapy if PDL-1 >50% (KN - 024)
Tell me about KN 189
KN 189:
The trial met its coprimary endpoints of OS and PFS, demonstrating significantly improved outcomes with the addition of pembrolizumab. After a median follow-up of 10.5 months, the median OS was not reached in the pembrolizumab–chemotherapy arm vs 11.3 months in the placebo–chemotherapy arm (HR: 0.49; P < .001). The median PFS was 8.8 vs 4.9 months, respectively (HR: 0.52; P < .001). Furthermore, the ORR was 47.6% in the pembrolizumab–chemotherapy arm vs 18.9% in the placebo–chemotherapy arm. These benefits were generally consistent across patient subgroups, including those defined by PD-L1 expression. Notably, the subgroup with a PD-L1 tumor proportion score ≥ 50% showed an ORR of 61.4%.
Tell me about KN 024
Pembrolizumab alone would be appropriate, however, if this patient had a contraindication to chemotherapy. The use of pembrolizumab monotherapy is supported by positive results from the phase III KEYNOTE-024 trial, which led to FDA approval in patients with previously untreated metastatic NSCLC with PD-L1 expression ≥ 50% and no actionable EGFR/ALK alterations. KEYNOTE-024 demonstrated in this population that first-line treatment with single-agent pembrolizumab significantly improved both PFS and OS vs platinum-based chemotherapy.[25] After a median follow-up of 11.2 months, the median PFS was 10.3 months with pembrolizumab vs 6.0 months with chemotherapy (HR: 0.50; P < .0001), and the median OS was also significantly prolonged, although it was not reached in either arm at the time of analysis (HR: 0.60; P = .005). The ORR was 44.8% with pembrolizumab vs 27.8% with chemotherapy.
What is the evidence for Carbo use instead of CDDP?>
The rationale for selecting cisplatin in the curative setting comes from a large meta-analysis in advanced NSCLC patients from the preimmunotherapy era by Ardizzoni and colleagues.[35]
The meta-analysis compared the efficacy of first-line cisplatin- vs carboplatin-based chemotherapy using individual patient data from 9 trials (N = 2968). The ORR was significantly higher for patients treated with cisplatin (30%) vs carboplatin (24%; odds ratio: 1.37; P < .001). There was also a trend toward higher risk of death with carboplatin vs cisplatin (HR: 1.07; 95% CI: 0.99-1.15; P = .100). Cisplatin-based chemotherapy was, however, associated with more severe nausea, vomiting, and nephrotoxicity, but carboplatin was associated with more severe thrombocytopenia.
Thus, if the goal is to cure the patient’s malignancy, I always use cisplatin.
