Cancer Treatment Updates - Northeast Kentucky AHEC...Lung Cancer Treatment Updates Val R. Adams,...

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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

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60

Chemotherapy + Pembrolizumab Chemotherapy

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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)

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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

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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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