cancer treatment updates - northeast kentucky ahec...lung cancer treatment updates val r. adams,...
TRANSCRIPT
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Lung Cancer Treatment UpdatesVal R. Adams, Pharm.D., FCCP, BCOP
Associate Professor
Univeristy of Kentucky, Markey Cancer Center
Objectives
• Differentiate the mechanism of action for recently approved lung cancer therapies.
• Recall the role in therapy of current and emerging targeted therapies for the treatment of metastatic non‐small cell lung cancer.
• Recognize the response rate and expected time to respond for the new immunotherapy.
• Identify strategies to prevent and manage adverse events related to the new therapies.
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All Lung CA Localized Regional Advanced
Lung Cancer Stage at Diagnosis and 5 Year Survival
5 Year Suvival (%) Spread at Diagnosis (%)
Spread of lung cancer disease at diagnosis and corresponding 5 year survival in the United States (SEER Database https://seer.cancer.gov/statfacts/html/lungb.html accessed 8/14/2017)
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The Increasing Complexity if Making Tx Decisions
Lung Cancer
Targetable Mutations
20%
10%
70%
HISTOLOGYSquamous Cell Large Cell Adenocarcinoma
BRAF +2%
ROS1+1%
ALK+5%
EGFR +15%
KRAS30%
Other47%
BRAF + ROS1+ ALK+ EGFR + KRAS Other
Kohno, T. et al. Translational Lung Cancer Research. 2015; 4:156‐64
CTL - tumor cell interactions
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Avoiding Immune Surveillance
IFN = interferon; IL = interleukin; TNF = tumor necrosis factor.
Schreiber et al. Science. 2011;331:1565‐1570. For educational purposes only.
Checkpoint Inhibitors for NSCLC
Advanced NSCLC
PD‐L1 +pembrolizumab
Targeted Therapy or Chemotherapy
After failing chemotherapy• Nivolumab or • Pembrolizumab or• Atezolizumab
Essentially, all lung cancer patients will get immunotherapy in the first or second line setting (except EGFR or ALK + patients).
NSCLC = non‐small cell lung cancer.
NonsquamousPembrolizumab +Chemotherapy
~30% ~40%
~ 30%
First Line Pembrolizumab
Pembrolizumab 200 mg IV every 3 weeks x 35 cycles
Investigator’s choice of cytotoxic chemotherapy x 4–6
cycles
Carboplatin + pemetrexed*
Cisplatin + pemetrexed*
Carboplatin + gemcitabine
Cisplatin + gemcitabine
Carboplatin + paclitaxel*Pemetrexed only for nonsquamous tumors; can continue pemetrexed as maintenance after combination therapy.
International, randomized, open-label, phase III trial
IV = intravenously.
Reck, M., et al. N Engl J Med 2016;375:1823‐33
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Median:Pembrolizumab10.4 months (95% CI 6.7–not reached)Chemotherapy6 months (95% CI 4.2–6.2)
PFS
Results from Keynote 24
OS
Estimated % patients alive at 6 months:Pembrolizumab80.2% (95% CI 72.9–85.7)Chemotherapy72.4% (95% CI 64.5–78.9)
Reck, M
., et al. N EnglJ Med
2016;375:1823‐33
Trial Design and Treatment
*Investigators could determine to continue pemetrexed as maintenance after combination therapy –maximum duration of pembrolizumab = 24 months.
Randomized, open-label, phase II trial in the US and Taiwan
Carboplatin/pemetrexed/ pembrolizumabQ21d x 4 cyclesMaintenance:* Pembrolizumab N = 60
Carboplatin/pemetrexed Every 21 days x 4 cyclesMaintenance:*
N = 63
Pembrolizumab [package insert]. Whitehouse Station, NJ: Merck & Co Inc; 2017.
Outcomes: ORR, PFS, OS
First‐Line Treatment:
Advanced‐stage NSCLC
stratified for PD‐L1 TPS (<1%)
Results
0
10
20
30
40
50
60
Chemotherapy + Pembrolizumab Chemotherapy
55
29
138.9
ORR PFS
Patients on chemotherapy offered pembrolizumab monotherapy upon progression
Pembrolizumab [package insert]. Whitehouse Station, NJ: Merck & Co Inc; 2017.
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Lung Cancer: Second‐line Check Point Inhibitor
Borghaei H, , et al. N Eng J Med 2015;373:1627‐1639. Brahmer J, et al. N Eng J Med ;2015;373(2):123‐135. Rittmeyer A, et al. Lancet. 2017;389:255‐265. Herbst RS, et al. Lancet. 2016;387(10027):1540‐1550..
Drug (study) Comparisons PFS Overall Survival
Atezolizumab
(OAK)
Atezolizumab 1200 mg IV q3week
vs.
Docetaxel 75 mg/m2 IV q3week
Median 2.8 months vs.
4 months
Median 13.8 months
vs. 9.6 months
(p = 0.0003)
Nivolumab
(CheckMate 017)
Squamous Histology
Nivolumab 3mg/kg IV q2week
vs.
Docetaxel 75 mg/m2 IV q3week
Median 3.5 months vs.
2.8 months
Median 9.2 months vs.
6.0 months
(p < 0.001)
Nivolumab
(CheckMate 057)
Non‐Squamous
Nivolumab 3mg/kg IV q2week
vs.
Docetaxel 75 mg/m2 IV q3week
Median 2.3 months vs.
4.2 months
Median 12.2months
vs. 9.4 months
(p =0.002)
Pembrolizumab
(KEYNOTE‐010)
Pembrolizumab 2 mg/kg IV q3week
vs.
Docetaxel 75 mg/m2 IV q3week
Median 3.9 months vs.
4 months
Median 10.4months
vs. 8.5 months
(p = 0.0008)
Recent Update PACIFIC Trial
Durvalumab after chemoradiotherapy Stage III
Antonia, SJ, et al. N Engl J Med. epub Sept 8, 2017
Patterns of Response to PembrolizumabObserved in Advanced Melanoma
Hodi, FS, et al. J Clin Oncol 2016;34:1510‐7.
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RECISTUnidimensional Measurement
irRECISTBidimensional Measurement
CR Disappearance of all lesions
PR≥ 30% decrease in tumor burden compared with baseline†
≥50% decrease in tumor burden compared with baseline†
SD Not PR, CR, or PD
PD
≥ 20% + 5-mm absolute increase in tumor burden comparedwith nadirAppearance of new lesions or progression of nontarget lesions
≥ 25% increase in tumor burden compared with baseline,nadir, or reset baseline†New lesions added to tumor burden†
irRECIST
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease
Hodi, FS, et al. J Clin Oncol 2016;34:1510‐7.
† Confirmation Required – next scan ≥ 4 weeks later
Immune‐Related Adverse Events by System
Pulmonary: Pneumonitis, respiratory failure
Endocrine: Thyroiditis, hypothyroidism, hyperthyroidism, hypophysitis, hypopituitarism, adrenal insufficiency
Cardiac: Pericarditis, myocarditis, vasculitis
GI: Nausea, colitis, perforation, pancreatitis
Heme: Red cell aplasia, pancytopenia, autoimmune neutropenia
Ocular: Uveitis, iritis, conjunctivitis, scleritis, blepharitis
Skin: Vitiligo, pruritus, rash, lichenoid deposits
Liver: Transaminitis, hepatitis
Kidney: Nephritis, renal insufficiency
Musculoskeletal: Arthralgias, myalgias
Neurologic: Neuropathy, meningitis, Guillain‐Barré syndrome, myasthenia gravis, temporal arteritis
Immunotherapy‐Related AEs
• Median time to onset for treatment‐related select AEs ranged from 5.0 weeks for skin AEs to 15.1 weeks for renal AEs.
• Circles represent median; bars signify ranges.
Time to Onset of Select Treatment-Related AEs
(any grade; N = 474)
AE = adverse event.Wolchok J, et al. J Clin Oncol. 2015;33:abstract LBA1.
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POPLAR: All‐Cause AEs (≥5% diff. between arms)
• AE profiles consistent with previous studies
• For atezolizumab, other immune‐mediated AEs (any grade) included:
• AST increased (4%)
• ALT increased (4%)
• Pneumonitis (2%)
• Colitis (1%)
• Hepatitis (1%)
ALT = alanine aminotransferase; AST = aspartate aminotransferase. Spira et al. J Clin Oncol. 2015;33:abstract 8010.
Dry skin, stomatitis, and nail disorder were additional AEs with ≥5% higher frequency with docetaxel. Safety population includes patients who received any amount of either study treatment. Data cut-off January 30, 2015
Immune‐Related Adverse Events
• Assume new symptoms are autoimmune and drug related if all other causes have been ruled out
• Can affect any organ system
• Early recognition, evaluation, and treatment are critical to adequate management and opportunity for re‐treatment.
Management of Immune‐Related AEs Algorithm
Management dose represents steroid doseGrade 2 is prednisoneGrade 3/4 toxicity is IV methylprednisoloneHRT = Hormone Replacement Therapy
Eigentler, TK, et al. Ca Treat Rev 2016;45:7‐18
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Precision Medicine/Targeted Therapy
Lung Cancer
Patient CaseSJ is a 61 yo WF who presents with NSCLC
HPI: After failing antibiotics a CXR revealed a left lower lobe mass– FNA confirmed adenocarcinoma of the lung
PMH: N/A
FH/SH: Married w/ two sons 28 and 34 (none smoker)
Drug History: NKDA
PE: Findings consistent with lung cancer – otherwise WNL (PS 0‐1)
Labs: Hepatic, renal, and chemistry levels WNL
Radiology: Multiple lesions in the liver– stage IV
Genetics: KRas – WT, EGFR exon 19 deletion, no ALKrearrangement, no ROS1 rearrangement, PD‐L1 unknown
What Treatment would you recommend?
1. None
2. Pembrolizumab
3. Carboplatin – paclitaxel – Bev
4. Erlotinib
5. Crizotinib
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OPTIMAL = Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive NSCLC; G/C = Gemcitabine/Carboplatin.Zhou C, et al. Lancet Oncol. 2011;12(8):735-742.
OPTIMAL: First‐line Erlotinib is Associated with Longer PFS vs G/C in EGFR Mutant NSCLC
Time (months)
Pro
gre
ssio
n-f
ree
surv
ival
(%
)
100
60
40
20
0
80
0 5 10 15 20
Erlotinib (N=82)Gemcitabine plus carboplatin (N=72)
HR 0.16 (95% CI 0.10 – 0.26)Log-rank p<0.0001
Number at riskErlotinib 82 70 51 20 2
72 26 4 0 0Gemcitabine pluscarboplatin
First Line EGFR TKIAgents N Outcome1 Outcome2 Comment
Gefitinib vs Carbo‐Tax
1217 1 yr PFS 25% vs 7%
Median OS19 mo vs 17 mo
IPASS trial
Erlotinib vs platinum doublet
228 Median PFS10 mo vs 5 mo
Median OS19 mo vs 19 mo
EURTAC trial
Afatinib vs Cisplatin‐Pem
1269 Median PFS11 mo vs 7 mo
Median OS28 mo vs 28 mo
Lung‐LUX3
CHI, A, et al Biomarker Research 2013;1:1‐10, Yang, JC, et al. Lancet Oncol2015;16:141‐51
• Better than Chemo first line based on PFS, OS roughly equivalent likely due to cross‐over.
• Survival curves do not plateau – Resistance develops during treatment.
Resistance to EGFR TKIs
Nguyen, K.H., Kobayashi, S., Costa,k D.B., Clin Lung Cancer 2009;10:281‐9
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Comparison to Chemotherapy: AURA3
• Stratification variables• Asian vs non‐Asian
Mok, TS, et al. N Engl J Med 2017;376:629-40
Osimertinib 80 mgPO DailyN=279
Cisplatin or carboplatin +Pemetrexed
repeat every 3 weeks up to 6 cycles – maintenance pemetrexed allowed
N=140
Eligibility:Progression on 1st line EGFR TKIT790M mutationStable CNS metastases w/o steroids
Primary Endpoint – PFSSecondary Endpoints include – ORR, DoR, OS, Safety
Osimertinib vs Chemotherapy: AURA3
Mok, TS, et al. N Engl J Med 2017;376:629-40
First line Osimertinib: FLAURA
ESMO 2017 Congress: Abstract LBA2. Presented September 8, 2017
Osimertinib 80 mgPO DailyN=279
Gefitinib 250 mg PO daily orErlotinib 150 mg PO daily
N=277
Eligibility:Advanced Stage NSCLCEGFR activating mutation (Exon 19d or L858R mutation)
Primary Endpoint – PFSSecondary Endpoints include – ORR, DoR, OS, Safety
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FLUARA Results
18.9
15.2
19.1
17.2
10.2 9.6 10.18.5
0
5
10
15
20
25
PFS (mo) PFS w‐CNS (mo) PFS wo‐CNS (mo) Duration of Response(mo)
Progression Free Survival
Osimertinib EGFR SOC
ESMO 2017 Congress: Abstract LBA2. Presented September 8, 2017
Months
FLUARA Results
80
34
76
45
0
10
20
30
40
50
60
70
80
90
ORR Grade 3/4 Toxicity
Osimertinib EGFR SOC
ESMO 2017 Congress: Abstract LBA2. Presented September 8, 2017
Percentage
EGFR + Advanced Disease Summary
Osimertinib monotherapy or 2 sequential oral EGFR TKIs provide a median of 19 ‐ 20 months of disease free survival. Overall survival yet to be determined – With chemotherapy and immunotherapy Median OS could be 3‐4 years
PFS = 10 MonthsPFS = 10 months
PFS = 19 months
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ALEX: New Standard is Coming for ALK+
• Primary endpoint – PFS
• Secondary endpoints– ORR– OS– Time to CNS progression– Safety
Treatment Naïve ALK+
Advanced DzStratified for PS 0 or 1 vs 2
Asian vs Non‐AsianCNS mets
1:1
Alectinib600mg PO twice dailyn = 152
Crizotinib 250 mg PO twice daily
n = 151
Peters, S. et al. N Engl J Med 2017;377:829‐38
Alex Results
Peters, S. et al. N Engl J Med 2017;377:829‐38
Median PFSAlectinib = 25.7 monthsCrizotinib = 10.4 months
ORRAlectinib = 82.9%Crizotinib = 75.5%
CNS complete responseAlectinib = 38%Crizotinib = 5%
ALEX Results
Peters, S. et al. N Engl J Med 2017;377:829‐38
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Alectinib Toxicity
Grade ¾ differences of 5% or moreTransaminases Crizotinib > Alectinib
Peters, S. et al. N Engl J Med 2017;377:829‐38
ALK+ Summary of PFS
Chemo PFS = 7 months
Crizotinib PFS = 10 months
Ceritinib PFS = 17 months
Alectinib PFS = 25.7 months
Toxicity – Chemotherapy similar to crizotinib‐ Chemotherapy slightly less than ceritinib‐ Crizotinib more toxic that alectinib
Crizotinib Remains the Standarde for ROS1+
• ORR = 72%• 6% CR
• 66% PR
• Duration of Response = 17.6 months
• 7 ROS1 fusion partners
• Toxicity consistent with prior experience
PFS = 19 months
Shaw, A., et al. N Engl J Med 2014;371:1963‐71
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Dabrafenib/Trametinib for BRAF+• Single Arm Phase II trial (n=57)
• 1 prior tx 66%
• 2 or 3 prior txs 33%
• Adenocarcinoma 98%
• Smoking History• Never Smoker (28%), Former smoker (61%)
• Endpoints• PFS
• ORR
• DoR
Planchard, D., et al Lancet Oncol 2016;17:984‐93
PFS
Planchard, D., et al Lancet Oncol 2016;17:984‐93
Median 9.7 months
Response
Planchard, D., et al Lancet Oncol 2016;17:984‐93
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All Cause Toxicity Grade 3/4Toxicity % Toxicity %
Asthenia 4% Respiratory Dist 4%
Anemia 6% Neutropenia 9%
Hypertension 4% Hemorrhage 4%
Dehydration 4% Hypercalcemia 4%
Hyponatremia 7% AST/GGT 4%
Leukopenia 4% Sq. Skin Cancer 4%
Planchard, D., et al Lancet Oncol 2016;17:984‐93
Efficacy Changes Summary
• Platinum Doublet PFS = 3.7 mo OS = 8 mo
• PD‐L1+ disease in ~ 30% of advanced stage patients• PFS with Pembrolizumab 10 months (first line monotherapy)
• Targetable Driver Mutation in ~ 20%
• PFS w/ targetable mutational drivers• EGFR 19‐20 months (first line)
• ALK 25‐26 months (first line)
• ROS1 19 months (first line)
• BRAF 10 months (2nd line)
Schiller, JH, et.al. N Engl J Med 2002;346:92‐8 Peters, S. et al. N Engl J Med 2017;377:829‐38Shaw, A., et al. N Engl J Med 2014;371:1963‐71 Planchard, D., et al Lancet Oncol 2016;17:984‐93Reck, M., et al. N Engl J Med 2016;375:1823‐33 ESMO 2017 Congress: Abstract LBA2. Presented September 8, 2017
The Best Science Requires Implementation
Make Sure Patients Get Tested!!!
Percent of Patients w/Lung Cancer Not Tested in 2016
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