The objective of maintenance therapy is to sustain response to first-line induction therapy further tumor growth rather than induce substantial tumor shrinkage.
The NSCLC maintenance therapy can be split into two basic concepts:
Continuing therapy in patients with no disease progression after firstline induction treatment by using one of the agents that formed part of that induction regimen, so-called continuation maintenance; or Switching to another agent that has known efficacy as second-line treatment immediately following initial response to or disease stabilization after induction treatment, so-called switch maintenance or early second-line treatment.
Maintenance treatment may be administered until disease progression. In practice, it’s usually administered for an average of five to six cycles, although EGFR TKI maintenance may be given for longer, especially in patients with mutant EGFR.
Generally the oncologists prefer continuation maintenance over switch maintenance therapy because it allows patients to remain on a treatment that they are familiar with and does not exhaust a patient’s treatment options. In the moment, the oncologist has different maintenance schemes. For example, if a patient receives bevacizumab in the first-line treatment, he will receive bevacizumab maintenance. If somebody receives a platinum agent plus pemetrexed, he will continue pemetrexed at least for a while as a kind of maintenance.
But for some cases the oncologist will move to a switch maintenance. That means that somebody gets carboplatin and gemcitabine and is then put on erlotinib or pemetrexed as switch maintenance, because most of the patients need a drug holiday.
Continuation Maintenance with Chemotherapy
The first Phase III trial to present the idea that maintenance was a viable and useful concept was a continuation maintenance trial of gemcitabine, carried out by the Central European Cooperative Oncology Group (CECOG) and published in 2006 (Brodowicz T, 2006). The study met its primary end point of significantly increasing TTP but failed to show significant improvement. However, the E4599 trial and, later, the AVAiL study successfully continued bevacizumab as maintenance monotherapy in patients achieving response or SD after induction treatment with bevacizumab plus chemotherapy (Sandler A, 2006; Reck M, 2009). These results sparked new interest in this area of research. Since then, several trials have investigated the role of maintenance therapy in advanced NSCLC, with varying degrees of success.
The CECOG trial randomized patients with stage IIIB with PE/stage IV NSCLC who achieved response or SD after four cycles of induction therapy with gemcitabine/cisplatin 2:1 to continuation maintenance monotherapy with gemcitabine or to BSC following gemcitabine/cisplatin induction therapy. Results showed that, for the maintenance period, patients receiving gemcitabine had a near doubling of TTP compared with those receiving BSC, as well as a significantly longer TTP for the study’s entire duration The increase in responders in the maintenance gemcitabine arm suggests that maintenance therapy can induce substantial tumor shrinkage, and the improvements in survival, though not significant in the case of OS, were encouraging. Of note, this study was limited by its size.
The PARAMOUNT trial for pemetrexed as continuation maintenance were presented at the ASCO annual meeting. Patients in the PARAMOUNT trial (non-squamous-cell NSCLC; ECOG PS = 0-1) (n = 539) initially received four cycles of firstline treatment with pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Those patients who achieved a response or had disease stabilization after completion of first-line therapy were randomized to continuation maintenance therapy with pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) and BSC or to placebo/BSC. All patients received concomitant folic acid and vitamin B12 supplementation. Both treatment arms were equally matched. More patients in the pemetrexed arm (23%)
completed more than six cycles of treatment compared with the placebo arm (14%). Median PFS (investigator-assessed; primary end point) for patients in the pemetrexed maintenance arm was longer (4.1 months) compared with mPFS for patients in the placebo arm (2.8 months) (HR = 0.62; P = 0.00006). Subgroup analysis revealed that pemetrexed maintenance appeared better for female patients, never-smokers, and treatment responders to firstline treatment. Independent review of the data show that mPFS for patients in the pemetrexed maintenance arm was longer (3.9 months) compared with the placebo arm (2.6 months) (HR = 0.64; P = 0.0002). When PFS is considered for the complete duration of treatment from first-line therapy through the maintenance period, mPFS for patients receiving continuation maintenance with pemetrexed is longer (6.9 months) compared with patients
who received placebo during the maintenance phase (5.59 months) (HR = 0.59; P < 0.00001) (investigator-assessed). Not surprisingly, more patients in the pemetrexed arm (5.3%) discontinued treatment as a result of adverse events compared with patients in the placebo arm (3.3%). More patients in the pemetrexed maintenance arm experienced serious adverse events (8.9%) compared with patients in the placebo arm (2.8%) (a statistically significant result). The most frequently occurring grade 3/4 adverse events includedfatigue (pemetrexed arm: 4.2%, placebo arm: 0.6%), anemia (pemetrexed arm: 4.5%, placebo arm: 0.6%), and neutropenia (pemetrexed arm: 3.6%, placebo arm: 0%).
An interesting finding from the PARAMOUNT trial was that there was no statistical difference between the two treatment arms in health-related quality of life as measured by the EQ-5D index or the visual analog scale. These data may help convince some oncologists or patients who insist that a treatment holiday is needed before receiving second-line therapy because they think that maintenance therapy compromises quality of life.
Switch Maintenance with Chemotherapy
The trial of note that focused on switch maintenance therapy in advanced NSCLC compared the efficacy and safety of docetaxel given immediately after gemcitabine/cisplatin induction therapy or upon disease progression.
Results were first presented at ASCO 2007 and final results were published in 2009 (Fidias P, 2007; Fidias P, 2009). OS was the primary end point. OS for the ITT population trended in favor of immediate docetaxel therapy, but the difference was not statistically significant
There was a statistically significant more than doubling of PFS, a secondary end point, in the immediate docetaxel arm.
Several aspects of this trial are interesting. For example, it seems welldesigned in that the intention was to directly compare survival in patients receiving docetaxel before progression (maintenance) as opposed to after progression (second line), thereby allowing any improvement in survival in the immediate docetaxel arm to be attributed to the drug’s administration as maintenance per se, as opposed to its administration at all. However, what actually occurred is that more than one-third of the patients in the delayed arm—37%—never received docetaxel therapy because of symptomatic deterioration by the time they progressed. When survival was adjusted to account for the differing rates of docetaxel treatment in each arm, there was absolutely no difference. Therefore, it appears that the trend toward improved survival in the immediate docetaxel arm was simply because more people in that arm received docetaxel at all, not because they received it as maintenance. Furthermore, in their assessment of patients in each treatment arm who did receive docetaxel, the study investigators discovered no difference in quality of life (QOL) between treatment arms.
These results seem to suggest that although docetaxel monotherapy is beneficial, there is no increased benefit from giving it immediately after induction treatment, as opposed to following progression. The fact that so many patients in the delayed docetaxel arm were not fit to receive the drug following progression does support, to some degree, the concept that certain patients may benefit from immediate secondline/maintenance treatment following induction.
Switch Maintenance with an EGFR TKI
In April 2010, the EGFR TKI erlotinib was approved in both the USA and Europe as a first-line switch maintenance treatment.
Erlotinib’s approval as maintenance therapy is based on the Phase III SATURN trial, a placebo-controlled study whose primary end points were PFS in all analyzable patients regardless of EGFR protein status and PFS in patients with EGFR protein-expressing (IHC-positive) tumors. As with pemetrexed in the H3E-MC-JMEN trial, erlotinib was given immediately following four cycles of induction platinum-based doublet chemotherapy.
Results, given in terms of HR, were presented at both ASCO and the World Conference on Lung Cancer 2009 (Cappuzzo F, 2009a; Cappuzzo F, 2009b; Brugger W, 2009a; Brugger W, 2009b), and final results were published in 2010 (Cappuzzo F, 2010). PFS was significantly prolonged with erlotinib as opposed to placebo in both the ITT population and those patients with EGFR-expressing tumors (HR = 0.71 and 0.69, respectively), although it translated to an increase in median PFS of just 1.2 weeks in both populations. A significant OS benefit (secondary end point) was also seen with erlotinib in both the ITT and IHC-positive populations (HR = 0.81 and 0.77, respectively). MOS in the ITT population increased by one month in erlotinib-treated patients compared with placebo-treated patients. Of note, patients achieving SD following induction therapy experienced a more pronounced benefit in survival from erlotinib than those experiencing a response; MOS was 2.3 months longer for SD patients following treatment with erlotinib than with placebo (HR = 0.72) and just 0.5 months longer for patients with response (HR = 0.94).
Preplanned subgroup analyses of the SATURN results revealed that patients benefited from erlotinib regardless of histology, although those with adenocarcinoma benefited most in terms of PFS (HR = 0.60 compared with 0.71 in ITT population and 0.76 in squamous-cell patients) and OS (HR = 0.77 compared with 0.81 in the ITT population and 0.86 in squamous-cell patients). Erlotinib’s PFS and OS benefits occurred regardless of smoking status, although never-smokers and former smokers derived greater benefit than current smokers (PFS HR = 0.56, 0.66, and 0.80, respectively; OS HR = 0.69, 0.75, 0.88, respectively) and regardless of gender, ethnicity, and PS. Furthermore, molecular subset analyses showed a significant PFS benefit of erlotinib in both EGFR-mutated as well as EGFR wild-type tumors. However, although this benefit was statistically significant in both groups, there was a highly significant interaction between treatment and mutational status; the HR was 0.10 in the group with EGFR-mutated tumors compared with 0.78 in those with EGFR-wild-type tumors.
Switch Maintenance with Erlotinib plus Continuation Maintenance with Bevacizumab
The ATLAS trial also investigated erlotinib as switch maintenance (Miller VA, 2009; Kabbinavar FF, 2010). The Phase III study compared erlotinib plus bevacizumab maintenance with bevacizumab plus placebo maintenance following first-line treatment with bevacizumab in combination with platinum-based chemotherapy. The primary end point was PFS. The trial was stopped early, in February 2009, on the recommendation of an independent data safety monitoring board after a preplanned interim analysis showed that the combination of bevacizumab and erlotinib significantly increased PFS compared with maintenance bevacizumab plus placebo. The data showed that PFS was significantly improved—by 4.4 weeks—in patients treated with erlotinib and bevacizumab as maintenance compared with those treated with bevacizumab alone.
Interestingly, the PFS in patients treated with the dual biologic combination as maintenance was 8.2 weeks longer than that of patients treated with erlotinib as maintenance in the SATURN trial.
The ATLAS trial results suggest that a subset of patients may benefit from maintenance treatment with erlotinib plus bevacizumab in combination, but whether the benefit outweighs the extreme expense of using not one but two premium-priced agents as maintenance therapy is open to debate.
Switch Maintenance with Erlotinib vs. Continuation Maintenance with Chemotherapy
Erlotinib as switch maintenance examined both switch and continuation maintenance but, unlike ATLAS, compared the two in different treatment arms. IFCT-GFPC 05.02 randomized patients achieving response or SD following induction gemcitabine/cisplatin treatment to continuation maintenance with gemcitabine, switch maintenance with erlotinib, or observation alone (Perol M, 2010). The study target was to investigate further if patients responding to first-line therapy do benefit from continuation maintenance as the Brodowicz trial (and subsequently the Belani trial) suggested, especially given that the switch maintenance studies seem to indicate that patients with SD following induction benefit most from this “early second-line” strategy.
Although, almost 40% of the patients enrolled in each arm of this study were never-smokers, and about two-thirds in each arm had adenocarcinoma. The primary end point was PFS, and results showed significant improvements for both maintenance therapies compared with observation alone, although greater improvement in PFS occurred with gemcitabine continuation maintenance (HR = 0.55) . Compared with observation only, the chances of being progression-free at three and six months improved by 25% and 13.5%, respectively, with gemcitabine maintenance but by just 5% and 7.7%, respectively, with erlotinib maintenance.
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For most ovarian cancer patients, treatment begins with surgery to remove the affected area, usually including the uterus (hysterectomy), both ovaries, and both fallopian tubes (bilateral salpingo-oophorectomy) and the fatty apron of tissue called the omentum (omentectomy).
Surgery parameters and post-surgical treatment, including chemotherapy, vary depending on the specific characteristics of the cancer. A combination regimen of paclitaxel and carboplatin (Taxol, generics, BMS & Paraplatin, generics, BMS) is the gold-standard first-line treatment for patients with ovarian cancer.
From December 2011, only 2 drugs had received FDA approval for second-line therapy of ovarian cancer, Hexamethylmelamine (Hexalen, altretamine) Topotecan hydrochloride (Hycamtin). However, several other drugs may also be considered if first-line therapy fails, Ifosfamide (Ifex), Etoposide (VP-16) (VePesid), 5-flourouracil (5-FU)
Generally patients will receive the gold-standard at least one time in their treatments. Furthermore, as the medical unmeet need is important in kind of tolerability, efficacy, or convenience, the ovarian cancer market is open for new therapies.
Otherwise, the clinical breakthrough that physicians, patients, and developers are seeking most likely lies in a targeted therapy. Regarding the pharmaceutical innovation it’s look like new ovarian cancer treatment will remain in the use of current gold standart (platinums+ taxanes) and that targeted therapies will be used in combination with chemotherapy.
We estimate that targeted therapy will be used in several situations as:
1- First-line therapy in combination with gold standard in order to increase the medical response
2- Maintenance to amplify the chemotherapy reaction
3- Combination for patient in refractory treatment
4- Monotherapy for a niche of patient specially with and BRCA1 and BRCA2 mutation (tumor gene suppressor in chromosome 17)
The target therapies place in the algorithm of treatment is clearly linked to the marked access, medico-economics and pricing evaluation. Several of these molecularly targeted agents have entered Phase II and III development, including angiogenesis inhibitors and epidermal growth factor inhibitors, such as
• Anti-EGFR Antibody – Cetuximab(Erbitux)
– ABX-EGF, EMD7200, IRC-62
• EGFR TK Inhibitors – Reversible
– ZD-1839 (Iressa), OSI-774 (Tarceva)
• EGFR TK Inhibitors – Irreversible
• Pan-HER TK Inhibitors- Reversible
• Pan-HER TK Inhibitors- Irreversible
Numerous other agents, including several small lmolecule tyrosine kinase inhibitors (TKIs) targeting the VEGF pathway, the folate receptor (FR) targeting agents and the polyadenosine 5’-diphosphoribose polymerase (PARP) inhibitors are in currently developed in ovarian cancer.
Based on negative Phase III results, ViRexx Medical discontinued development of the immunotherapy oregovomab (OvaRex, B43-13).
Novartis had expected to submit for regulatory approval of the cytotoxic agent patupilone (EPO-906, epothilone B) based on a Phase III study evaluating the molecule as a single agent in platinum-resistant and refractory ovarian cancer patients.
Today as the overall survival rate for ovarian cancer patients is around 50%, and the medical unmeet need important, the real question is how to balance the medico-economic parameters with ovarian cancer the patient journey and the poor molecule in development?
Healthcare authorities across the G7markets (France, Germany, Italy, Spain, UK, USA and the Japan) have been busy implementing oncology regulatory, pricing, and reimbursement reforms from 2008.
Driven by their high budget deficits post-recession, governments through their austerity packages want a significant drug price cuts to reduce overall oncology expenditures. Pharmaceutical companies need to be mindful of the new market access and reimbursement requirements. New drugs and indications in oncology need to prove their cost effectiveness against marketed comparators in Germany and France. However, several countries are working on improving breast cancer patient access to certain innovative and expensive drugs.
The most widely used drugs for breast cancer are hormonal therapies and chemotherapies – two types of therapies with long-established histories in breast cancer treatments. Hoffmann Krueger reports the countries oncology reimbursement particularities.
Drugs treatments for breast cancer are generally covered by private insurance and/or Medicare in US. Under private insurance, reimbursement varies according to the index plan as well as formulary tier placement within the index plan. In some cases, expensive treatment may not be reimbursed, such as trastuzumab and bevacizumab.
Office-based oncologists still receive a fee-for-service for administering intravenous therapies. In contrast, prescription of oral chemotherapy garners no specific fee-for-service. Medicare reimbursement policies are shaped by the United States Pharmacopeia’s (USP) Guidelines. These guidelines indicate that health plans must cover “all or substantially all” drugs in six classes, including antineoplastics.
Cancer patients in France do not have to worry about payments for essential drugs. In general, oncology drugs are fully reimbursed because they treat life-threatening diseases. Initiatives taken by the French government including the creation of the Institut National du Cancer (INCa; National Cancer Institute) and the Plan Hôpital (Hospital Plan) have improved care to cancer patients.
To control spending on drugs that qualify for supplementary reimbursement, ceiling prices are determined either through negotiations between the manufacturers and the Comité Economique des Produits de Santé (CEPS; Economic Committee for Health Care Products)
Manufacturers are also subject to price/volume constraints, they have to reduce their prices if sales volume is judged to have grown excessively. High-priced new drugs can be added to this list as soon as they receive marketing authorization in France.
After 12 months on the market, a drug is either approved to remain on this list, in which case it becomes subject to a ceiling price, or it is removed from the supplementary reimbursement list and covered by the relevant disease-associated tariff payable to the hospital.
To encourage hospital pharmacies to negotiate manufacturer discounts on these medicines, hospitals are permitted to keep a proportion of any price difference they secure between the ceiling price and their actual purchase price. When evaluating agents for reimbursement, France’s Transparency Commission considers the Service Medical Rendu (SMR; therapeutic benefit) and melioration du Service Medical Rendu (ASMR; improvement in therapeutic benefit) of the agents and target population characteristics. Because the SMR and ASMR ratings are considered important for drugs as bevacizumab, docetaxel, paclitaxel, and capecitabine and because breast cancer is a serious disorder, the treatments are fully reimbursed.
Unlike in many other European markets, cancer patients in Germany are frequently treated by office based physicians. Office-based physicians are currently subject to Richtgrößen—indicative prescribing amounts those determine the maximum expenditure on medicines per patient per quarter. Clinicians who exceed these amounts by more than 25% face the prospect of heavy fines. Some expensive therapies are excluded from indicative prescribing amounts.
In Germany, cancer patients frequently have out-of-pocket costs that are high by European standards. In line with the German Social Security Code’s goal of maintaining cost-effectiveness in medical treatments, German law dissuades off-label prescribing of any medications, levying a fine on the prescribing physician
In UK all citizens are eligible for prescription drug reimbursement from the National Health Service (NHS) for licensed therapies. Patients pay a low, flat prescribing fee per prescription; seniors and cancer patients are exempt from copayments.
The NICE (National Institute for Health and Clinical Excellence – NICE) have an important role in evaluation of the cost-benefit balance for new drugs and indications treatments. If NICE issues a negative opinion, most Primary Care Trusts (PCTs) exclude the drug from their formularies, obligating patients to either pay out-of-pocket treatment
Many NICE decisions regarding expensive treatments have been reimbursement controversies (e.g., trastuzumab in early-stage HER2-positive; trastuzumab beyond progression; lapatinib in combination with capecitabine as a second-line treatment).
British oncology experts notice that NICE recommendations do not result in automatic reimbursement of expensive treatments. For this reason, variation among PCTs in formulary coverage, yields an inequitable environment in which certain patients, depending on geographic location, can afford vital medications while others cannot. Thought leaders interviewed also indicate that because cost is such a concern, oncologists often choose the least-expensive drug within a desired class (e.g., generic paclitaxel over branded docetaxel (Taxotere)).
Oncologists in Italy indicate that any drug may be prescribed forbreast cancer if it is approved by the Agenzia Italiana del Farmaco (AIFA; Italian Medicines Agency); however, cost-containment measures have created some regional differences in prescribing. Some oncologists believe strongly that cost is a big problem, some others say they do not feel particularly constrained by the guidelines within which they are required to prescribe.
The Prontuario Farmaceutico Nazionale (PFN: National Pharmaceutical Formulary) classifies the reimbursement status of available therapies. Current metastatic breast cancer therapies are awarded class status H, indicating that full reimbursement is provided only in the hospital setting. The administration of class H requires specialist supervision.
In Spain the Sistema Nacional de Salud (SNS; National Health System) covers the full cost of medications or requires a nonrefundable patient copayment for part of the cost. oncologist note that no significant reimbursement obstacles hinder the prescribing of most breast cancer therapies. However, labeling and treatment location may affect whether a particular drug will be used because it may not be completely reimbursed.
The exception in breast cancer is trastuzumab, which was being prescribed for early-stage prior to the European Medicines Agency’s approval for that indication. Additionally, it is unlikely that expensive agents such as bevacizumab will be prescribed by hospital-based physicians because hospitals closely watch their annual pharmacy budgets.
Although lack of access to international gold-standard cancer therapies has long been one of the main deficiencies of the Japanese oncology system for many tumor types, several of the key chemotherapeutics used to treat breast cancer have been available in Japan within one to three years of their launch in other major countries. Biologics (such as trastuzumab) generally reach the market in Japan two to three years after their launch in other major pharmaceutical markets.
In an effort to accelerate the launch of important new drugs in Japan, in January 2005, the Ministry of Health, Labor, and Welfare (MHLW) established an expert panel called the Mishoninyaku Shiyo Mondai Kentokaigi (Study Council on the Use of Unapproved Drugs). Once a drug is considered to have significant potential and is recommended by the study council to the MHLW, the drug manufacturer is asked by the MHLW either to begin clinical trials or to conduct supplementary trials that would allow wider access to the agent before it is formally approved. Off-label prescribing is reportedly uncommon because it presents reimbursement problems, and the patient is forced to pay the whole cost of treatment.
The Japanese KOL reports that regulatory approval is the most critical variable in prescribing drugs in Japan, followed by efficacy; cost is generally not considered a defining variable. Once approved, drugs in Japan must undergo a rigorous pricing process and then possibly face the prospect of biennial price cuts. Although it is not the case with all chemotherapeutics, the Japanese prices of some breast cancer therapies (e.g., docetaxel) are the lowest of any of the major markets we cover— the result of several mandatory government price cuts. However, the prices of generic therapies are much higher in Japan than they are in the other major markets.
The emergence of novel targeted agents such as lapatinib and bevacizumab has resulted in growing disparity in access to expensive treatments in the G7 markets. As previously mentioned, MAbs are usually subject to intense scrutiny by payers. Even when they receive regulatory approval, not all MAbs are placed on drug formularies and reimbursement lists.
Reimbursement can be a particular problem for patients with late-stage breast cancer because premium-priced agents must show clinically relevant and cost-effective benefit in these patients.
Compared with physicians in the UK and the rest of Europe, physicians in the United States experience significantly fewer reimbursement restrictions. As we discussed, bevacizumab was conditionally approved in 2008 under the FDA’s fast-track development program to treat metastatic HER2-negative breast cancer. Most oncologists in the United States disagree with ODAC’s recommendation and tell us that they will continue to prescribe bevacizumab to their patients for as long as it continues to be reimbursed.