Targeted Therapy Toxicities in Lung Cancer

Transcription

1 Targeted Therapy Toxicities in Lung Cancer Kristie A.D. Morydz Nurse Practitioner Thoracic Disease Site Group

2 Presenter Disclosure Faculty: Kristie A.D. Morydz Relationships with commercial interests: none

3 Mitigating Potential Bias Not Applicable

4

5 Objectives Regarding two drugs Erlotinib, Gefitinib and Crizotinib, participants in this session will be able to: 1. List and review the management of common toxicities 2. List and review the management of serious events caused by these drugs 3. Recognize how to conduct follow up with patients 4. Identify the blood work required in the assessment of patients on these drugs. 5. Determine when to dose reduce and when to delay

6 Treatment algorithm (2013)

7 Erlotinib Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor Inhibits EGF dependent cell proliferation EGFR mutation are seen in approximately 10% of patients with Non Small Cell Lung Cancer

8 Erlotinib Stage IV NSCLC adenocarcinoma EGFR testing does not need to be done at this time prior to the patient being on Erlotinib Maintenance

9 Erlotinib- Interactions Avoid concurrent use with CYP3A4 inhibitors (azole antifungals, clarithromycin, erythromycin, etc) May result in increased toxicity and dose adjustment may be required Concomitant CYP3A4 & CYP1A2 inhibitor (eg ciprofloxacin)- avoid

10 Erlotinib- Interactions Continued CYP3A4 inducers- eg. carbamazepine, phenytoin, St John s Wort)- some trials/centers increase the Erlotinib dose in these patients Concomitant Smoking- Some trials looked at increasing dosing up to 300mg daily

11 Smoking Cessation Clinic Individualized smoking cession program Multidisciplinary team Addressed both addition and habit Cessation medications free for patients in the program (Verenicline, Wellbutrin or NRT) Referral through CCMb consults

12 Erlotinib Interactions- Continued Anticoagulation- Increased INR and bleeding events- monitor INR closely Protein Pump Inhibitors- May decrease concentration of Erlotinib eg Ranitidine separate dosing Grapefruit- may increase Erlotinib concentrations

13 Erlotinib Prescribed as a oral medication 150mg once daily To be taken 1 hour before or 2 hours after eating If dosing adjustment is necessary, adjust by 50mg increments

14 Gefitinib Tyrosine Kinase Inhibitor Dosing- 250mg by mouth daily

15 Erlotinib Toxicities Skin Rash (49-85%- grade %)- median onset 8 days Diarrhea (20-62%, grade 3 2-6%)- median onset 12 days Fatigue (9-52%) Weakness (50%) Cough (33-48%) Dyspnea (41-45%, grades ¾ 8-28%)

16 Erlotinib Toxicities- Continued Anorexia (9-52%) Nausea (23-33%) Vomiting 13-23%) Back pain (19%) Arthralgia (13%) Alopecia (15%) Puritis (7-16%)

17 Erlotinib Toxicities- Continued Conjunctivitis (12-18%) Keratoconjunctivitis sicca (12%) Increased susceptibility to infection (4-24%) Mucositis (18%) Chest Pain (18%) Anemia (11%) UTI (18%)

18 Erlotinib Toxicities- Continued Fever (11%) Peripheral Edema (5%) Headache (7%) Hyperbilirubinemia (7%) Increased ALT (4%), Hepatic failure (1%) Dizziness (4%)

19 Erlotinib Toxicities- Continued Weight loss (5%) Pneumonitis (3%) Pulmonary Embolis (4%) RTI (4%) Pneumonitis (3%) Pulmonary Fibrosis (3%) Renal failure (1%)

20

21 Erlotinib Serious Events Acute peptic ulcer with hemorrhage Bronchiolitis Corneal perforation GI hemorrhage GI perforation Hearing loss Hematemesis Hematochezia MI Stevens-Johnson Syndrome Tympanic Membrane Perforation

22 Erlotinib- Follow up Baseline CT scanning and blood work including LFTs is required Initially patients are seen q4 weeks X 2 months with physical exam and BW Initial CT scan is done 2 months after starting treatment CT scanning is then dose every 3 months Can be extending to every 6 month CT scanning for those on treatment for some time

23 Erlotinib- Blood work CBC Electrolytes Renal Function Liver Functions Tests

24 Case Mrs. Hope started on Erlotinib within the past 2 weeks She is calling because she s got some sort of rash. She feels she must be having a reaction and the medication must not be agreeing with her. What do you say?

25 Erlotinib- Treatment Adjustment Rash- Papulopustular Rash Presents most commonly to face, scalp, torso and pubic area* A positive predictor in some

26

27 Erlotinib Rash Hydration with moisturizing lotion, cool water to wash, pat dry, watch sun exposure Hydrocortisone 1% to face Betamethasone Valerate 0.1% lotion for scalp Betamethasone Valerate 0.1% cream for torso Doxycycline 100mg by mouth bid x 14 days if required Dose hold/reduction if necessary. Elidel cream 1% cream topically bid (Pimecrolimus)- Calcineurin Inhibitor

28 Rash Continued If severe rash blistering or exfoliative skin toxicity- discontinue treatment. Treat with the previous suggested. Pulse dosing of steroids (monitor GI). Re evaluate once resolved and consider restarting at a lower dose

29

30 Erlotinib- Treatment Adjustment Diarrhea- Treat with Lomperamide 4mg by mouth at onset, then 2 mg every 2-4 hours until diarrhea free for 12 hours Monitor for dehydration Dose reduction may be required

31 Erlotinib- Treatment Adjustment Liver Function If normal LFTs initially- hold if total bilirubin is >3x ULN If normal LFTs initially- hold if transaminases are >5x ULN If abnormal LFTs initially- hold if bilirubin doubles If abnormal LFTs initially- hold if transaminases triple

32 Case Mrs. Hope calls because something is wrong with her eyes. They are dry like sandpaper. You see her in clinic for assess. What do you suggest?

33 Erlotinib- Treatment Adjustment Vision Changes- Painful Eyes Conjunctivitis- Assess eyes, consider holding Use moisturizing eye drops If painful or vision changes- hold treatmenturgent referral for ophthalmology concern for developing Keratoconjunctivitis, corneal perforation or ulceration May require dose reduction/discontinuation of treatment

34 Erlotinib- Treatment Adjustment Interstitial Lung Disease Can develop within days of starting treatment to up to a year Monitor if acute onset or worsening of dyspnea, cough, fever Treatment should be held Treatment should be discontinued if diagnosis of Interstitial Lung Disease is confirmed

35

36 Crizotinib ALK inhibitor Benefits patients who have a rearrangement of the ALK gene 3-5% of patients have a rearrangement of the ALK gene Objective response rate of approx 57% Disease control rate of approx 87% Medscape

37 Crizotinib Testing has to be done prior to starting Who has the ALK rearrangement? No apparent difference in ethnicity Tend to be younger at dx (50 yrs of age) 70-75% are never smokers or light smokers No sex preference Histologic features- acinar, papillary, micropapillary, bronchioalveolar, signet ring

38 Rapid Responses Seen In Some Patients September 2012 November 2012

39 Crizotinib- Common Toxicities Overall fairly well tolerated Visual disturbances (62%)- visual brightness, photopsia, photophobia, blurred vision, visual impairment, visual field deficit- dawn and dusk GI- nausea (53%0, vomiting (40%), diarrhea (43%), constipation (27%), decreased appetite (19%), taste changes (12%), esophageal disorders (11%)

40 Crizotinib- Common toxicities Edema (28%) cont d Fatigue (20%), dizziness (16%) Neuropathy (13%, grades 3/4 <1%) ALT increase (13%, grade 3/4 5%) AST increase (8%, grades 3/4 2%) Rash (10%) Bradycardia (5%), chest pain (1%), headache (4%), insomnia (3%), abdominal pain (8%)

41 Crizotinib- Interactions CYP3A4 Substrate Can decrease absorption of Digoxin May increase serum concentrations of Dabigatran May increase serum concentration of Fentanyl Grapefruit may increase concentration QT prolonging effect agents* May increase concentration of Salmeterol St John s Wort can increase concentrations of Crizotinib May enhance the anticoagulation effect of Vitamin K antagonists

42 Crizotinib- Serious Events Bradycardia Hepatotoxicity Visual Changes Pneumonitis QT prolongation

43 Crizotinib Prescribed as an oral medication 250mg twice a day

44 Crizotinib- Follow up Physical exam, CT scan, ECG and blood work initially Physical exam and blood work in 2 weeks, then after one month Physical exam, blood work and CT scan after two months of treatment ECG if required

45 Crizotinib- Blood work CBC Electrolytes Renal Function Tests Liver Function Tests including total bilirubin

46 Crizotinib- Treatment Adjustment Bradycardia-If occurs, avoid with other drugs that cause bradycardia if possible Monitor heart rate and blood pressure regularly If symptomatic requiring medical intervention (gr 2) or sever with urgent intervention (gr3)- hold treatment until recovery then restart at 200mg BID If life threatening with urgent intervention (gr 4) permanently discontinue If grade 4 and on other meds causing bradycardiawithhold until recovered. If able to discontinue other meds causing bradycardia resume at 250mg OD with frequent monitoring

47 Crizotinib- Treatment Adjustment Hepatotoxicity- can occur within two months of starting treatment May require dose adjustment or drug discontinuation Grade 3 or 4 ALT/AST elevation (>5 x ULN) with bili <1.5 x ULN- hold until recovered (ALT/AST <2.5 or 3 x ULN)- resume at 200mg BID Recurrent grade 3 or 4 ALT/AST elevation withhold and restart at 250mg OD once recovered Recurrent grade 3 or 4 ALT/AST elevation on 250mg OD- permanently discontinue Grade 2, 3 or 4 ALT/AST elevation with T bili elevation (>1.5 x ULN) permanently discontinue

48 Crizotinib- Treatment Adjustment Pneumonitis- Monitor for pulmonary symptoms. Onset on average within two months. Can be life threatening. Discontinue treatment if confirmed

49 Crizotinib- Treatment Adjustment QT Prolongation- Consider periodic ECG monitoring, especially for those with heart failure, arrhythmias and electrolyte abnormalities. May require dose adjustment or discontinuation

50 Crizotinib- Treatment Adjustment Mild to moderate renal impairment no dose adjustment Severe impairment (crea cl <30mL/min) not requiring dialysis start at 250mg daily

51 Case Mrs. Lobe calls because she has just started her Crizotinib and now is seeing stars. What do you do?

52 Crizotinib- Visual Changes Can occur within 2 weeks of starting the medication Common side effect If photopsia or vitreous floats presentrefer to ophthamology Can develop retinal hole or impending detachment

53

54 Thank you! Questions? References available upon request